Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits?

Rick C. Helmich; Mark Hallett; Günther Deuschl; Ivan Toni; Bastiaan R. Bloem

doi:10.1093/brain/aws023

Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits?

Helmich, Rick C.; Hallett, Mark; Deuschl, Günther; Toni, Ivan; Bloem, Bastiaan R. 2012-03-01 00:00:00 doi:10.1093/brain/aws023 Brain 2012: 135; 3206–3226 | 3206 BRAIN A JOURNAL OF NEUROLOGY REVIEW ARTICLE Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? 1,2 3 4 1 2 Rick C. Helmich, Mark Hallett, Gu ¨ nther Deuschl, Ivan Toni and Bastiaan R. Bloem 1 Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands 2 Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology and Parkinson Centre Nijmegen (ParC), 6500 HB Nijmegen 3 Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA 4 Department of Neurology, Christian-Albrechts-University, 24118 Kiel, Germany Correspondence to: Dr. Rick C. Helmich, Radboud University Nijmegen Medical Centre, Neurology Department (HP 935), PO BOX 9101, 6500 HB Nijmegen, The Netherlands E-mail: [email protected] Tremor in Parkinson’s disease has several mysterious features. Clinically, tremor is seen in only three out of four patients with Parkinson’s disease, and tremor-dominant patients generally follow a more benign disease course than non-tremor patients. Pathophysiologically, tremor is linked to altered activity in not one, but two distinct circuits: the basal ganglia, which are primarily affected by dopamine depletion in Parkinson’s disease, and the cerebello-thalamo-cortical circuit, which is also involved in many other tremors. The purpose of this review is to integrate these clinical and pathophysiological features of tremor in Parkinson’s disease. We ﬁrst describe clinical and pathological differences between tremor-dominant and non-tremor Parkinson’s disease subtypes, and then summarize recent studies on the pathophysiology of tremor. We also discuss a newly proposed ‘dimmer-switch model’ that explains tremor as resulting from the combined actions of two circuits: the basal ganglia that trigger tremor episodes and the cerebello-thalamo-cortical circuit that produces the tremor. Finally, we address several important open questions: why resting tremor stops during voluntary movements, why it has a variable response to dopaminergic treatment, why it indicates a benign Parkinson’s disease subtype and why its expression decreases with disease progression. Keywords: Parkinson’s disease; tremor; basal ganglia; cerebellum, thalamus Abbreviations: DBS = deep brain stimulation; PIGD = postural instability and gait disability; STN = subthalamic nucleus; UPDRS = Uniﬁed Parkinson’s Disease Rating Scale; VL = ventral lateral thalamus between patients. This review focuses on the occurrence of Introduction tremor, a striking example of this phenotypic heterogeneity. Parkinson’s disease is a surprisingly heterogeneous neurodegenera- While some patients with Parkinson’s disease have a prominent tive disorder. The classical triad of motor symptoms includes rest- and disabling tremor, others never develop this symptom (Hoehn and Yahr, 1967). This observation formed the basis for classifying ing tremor, akinesia and rigidity (Lees et al., 2009). However, the patients with Parkinson’s disease into tremor-dominant and expression of these cardinal motor symptoms varies markedly Received October 10, 2011. Revised November 28, 2011. Accepted December 14, 2011. Advance Access publication March 1, 2012 The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3207 non-tremor subtypes (Zetusky et al., 1985; Jankovic et al., 1990; re-emerge during postural holding, making it difﬁcult to clinically Rajput et al., 1993; Lewis et al., 2005; Burn et al., 2006). distinguish it from essential tremor. This distinction can be made by focusing on the delay between adopting a posture and the Moreover, patients with Parkinson’s disease can manifest different emergence of tremor: in essential tremor there is no delay, while types of tremor: at rest, with action or postural, including ortho- Parkinson’s disease resting tremor re-emerges after a few seconds static. The reason for this marked phenotypic heterogeneity re- (on average 10 s) (Jankovic et al., 1999). Since the frequency of mains unclear. A better understanding of the mechanisms re-emergent and resting tremor can be similar, it has been underlying the expression of tremor could help clarify tremor hypothesized that both tremors share a similar pathophysiological pathophysiology, and as such offer potential new avenues for mechanism. One interesting patient with Parkinson’s disease had symptomatic treatment. Here, we will review some salient clinical no resting tremor, but a marked 3–6 Hz postural tremor that features of tremor in Parkinson’s disease, discuss recent studies on occurred after a delay of 2–4 s following postural holding (Louis the pathophysiology of tremor and review a newly proposed et al., 2008), thus resembling re-emergent tremor. Such observa- model (Helmich et al., 2011b) to explain the cerebral mechanisms tions point to heterogeneity in the circumstances under which the involved in generating resting tremor in Parkinson’s disease. classical Parkinson’s disease ‘resting’ tremor occurs. In the following sections, we will mainly focus on the classic resting tremor in Parkinson’s disease. We will ﬁrst describe the The tremors of Parkinson’s clinical and cerebral differences between patients with tremor- dominant and non-tremor Parkinson’s disease. Then we will disease detail how these differences may inform us about the causes Tremor is characterized clinically by involuntary, rhythmic and alter- and consequences of Parkinson’s disease resting tremor. nating movements of one or more body parts (Abdo et al., 2010). Parkinson’s disease harbours many different tremors. These tremors can vary according to the circumstances under which they occur, the The clinical phenotype of body part that is involved and the frequency at which the tremor occurs. For example, tremor may occur at rest, during postural tremor-dominant Parkinson’s holding or during voluntary movements; it can be seen in the disease hands, feet or other body parts; and tremor frequency can vary from low (4–5 Hz) to high (8–10 Hz). A consensus statement of The classiﬁcation of patients with Parkinson’s disease into tremor- the Movement Disorder Society includes a parallel classiﬁcation dominant and non-tremor subtypes is well established. Different scheme that categorizes three tremor syndromes associated with taxonomies have been used to deﬁne these two subtypes. First, Parkinson’s disease (Deuschl et al., 1998). This classiﬁcation is still tremor-dominant Parkinson’s disease has been contrasted with used widely today (Fahn, 2011). First, the most common or classical a form of Parkinson’s disease dominated by axial symptoms, i.e. Parkinson’s disease tremor is deﬁned as a resting tremor, or rest and postural instability and gait disability (the PIGD subtype) (Zetusky postural/kinetic tremor with the same frequency. This tremor is in- et al., 1985; Jankovic et al., 1990). This distinction is based on the hibited during movement and may reoccur with the same frequency relative expression of tremor and PIGD, using subscores of the when adopting a posture or even when moving. When recurring Uniﬁed Parkinson’s Disease Rating Scale (UPDRS). Second, with posture, it has been called re-emergent tremor. Second, some tremor-dominant Parkinson’s disease has been contrasted with a patients with Parkinson’s disease develop rest and postural/kinetic Parkinson’s disease subtype dominated by bradykinesia and rigid- tremors of different frequencies, with the postural/kinetic tremor ity (Rajput et al., 1993; Schiess et al., 2000), again using UPDRS displaying a higher (41.5 Hz) and non-harmonically related fre- subscores. A third, data-driven approach has identiﬁed Parkinson’s quency to the resting tremor. This form occurs in 510% of patients disease subtypes by applying clustering algorithms to several clin- with Parkinson’s disease. Some consider it to be an incidental com- ical parameters such as symptom severity, disease onset and clin- bination of an essential tremor with Parkinson’s disease (Louis and ical progression (Lewis et al., 2005). The latter approach again Frucht, 2007), but it appears more plausible that postural tremor is a produced tremor-dominant and non-tremor clusters of patients, manifestation of Parkinson’s disease. Third, isolated postural and together with a young-onset form and a rapid progression group. kinetic tremors do occur in Parkinson’s disease. The frequency of these tremors may vary between 4 and 9 Hz. A speciﬁc form of Tremor is an independent symptom (position-dependent) postural tremor is orthostatic tremor, which may occur in Parkinson’s disease at different frequencies (4–6, 8–9 Tremor may have a pathophysiology different from most other or 13–18 Hz), with or without co-existent resting tremor (Leu- Parkinson’s disease symptoms. First, tremor does not progress at Semenescu et al., 2007). Since this tremor type occurs at a higher the same rate as bradykinesia, rigidity, gait and balance (Louis age of onset than primary orthostatic tremor, and since it may et al., 1999). Second, tremor severity does not correlate with respond to dopaminergic treatment, it has been argued that it is a other motor symptoms (Louis et al., 2001). Third, tremor can manifestation of Parkinson’s disease rather than a chance association occur on the body side contralaterally to the otherwise most af- of two tremor syndromes (Leu-Semenescu et al., 2007). fected side, i.e. where bradykinesia and rigidity are most promin- The distinction between these different tremors is not always ent. This so-called wrong-sided tremor is seen in 4% of patients visible to the naked eye. For example, resting tremor can with Parkinson’s disease (Koh et al., 2010). Finally, tremor 3208 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. responds less well to dopaminergic treatment than bradykinesia particularly the lateral ventral tier (Fearnley and Lees, 1991). and rigidity (Koller et al., 1994; Fishman, 2008). This leads to dopamine depletion in the striatum, particularly in the dorsolateral putamen (Kish et al., 1988). These changes are strongly linked to bradykinesia (Albin et al., 1989), but their rele- Tremor is a marker of benign vance to resting tremor remains unclear (Rodriguez-Oroz et al., Parkinson’s disease 2009). Here, we will discuss data from post-mortem and nuclear imaging studies that examined whether resting tremor has a dopa- Clinical and behavioural differences between patients with minergic basis. tremor-dominant and non-tremor Parkinson’s disease suggest that tremor is a marker of benign Parkinson’s disease. For in- stance, there are indications that patients with tremor-dominant Post-mortem studies Parkinson’s disease have a relatively slow disease progression. This Patients with tremor-dominant Parkinson’s disease have milder idea was ﬁrst proposed by Hoehn and Yahr (1967), who found a cell loss in the substantia nigra pars compacta (particularly in the greater proportion of death and disability in patients with lateral portion) and in the locus coeruleus than patients with Parkinson’s disease with a non-tremor onset mode, at least non-tremor Parkinson’s disease (Paulus and Jellinger, 1991; during the ﬁrst 10 years of the disease. Other studies conﬁrmed Jellinger, 1999). This suggests that patients with tremor-dominant this: compared to patients with Parkinson’s disease with a Parkinson’s disease have less dopaminergic (and possibly also less tremor-dominant subtype, patients with Parkinson’s disease with nor-adrenergic) dysfunction than non-tremor patients. This could a PIGD subtype had a larger annual increase in symptom severity explain some of the clinical advantages that are associated with (Jankovic and Kapadia, 2001) and a shorter survival (Lo et al., tremor. On the other hand, patients with tremor-dominant 2009; Forsaa et al., 2010). Furthermore, a post-mortem study Parkinson’s disease have considerably more cell loss in the retro- showed that patients with tremor-dominant Parkinson’s disease rubral area of the midbrain, as assessed in a post-mortem study progressed more slowly to Hoehn and Yahr grade 4 than comparing six patients with tremulous Parkinson’s disease to ﬁve patients with akinetic-rigid dominant Parkinson’s disease (Rajput patients with non-tremor Parkinson’s disease (Hirsch et al., 1992). et al., 2009), using the subtyping scheme by Rajput et al. (1993). The small sample size in this study warrants caution although con- Another post-mortem study found that patients with ﬁrmatory evidence came from animal work. In non-human pri- tremor-dominant Parkinson’s disease had a lower degree of dis- mates, the retrorubral area contains 10% of the mesencephalic ability (Hoehn and Yahr grade) than tremor-dominant patients at dopaminergic neurons, compared with 76% in the substantia 5 and 8 years (Selikhova et al., 2009), using the subtyping scheme nigra pars compacta and 14% in the ventral tegmental area discussed earlier (Lewis et al., 2005). However, tremor-dominant (Francois et al., 1999). Injection of 1-methyl-4-phenyl-1,2,3,6- and non-tremor patients with Parkinson’s disease had similar dis- tetrahydropyridine (MPTP) destroys these dopaminergic neurons ease duration at the time of death. This led to their conclusion that (Burns et al., 1983), but with marked differences between species. tremor alone does not predict a signiﬁcantly longer survival: pa- Clinically, rhesus (Macaca mulatta) monkeys develop infrequent tients with tremor-dominant Parkinson’s disease progress more and brief episodes of high-frequency tremor, whereas vervet slowly during the initial course of the disease, but lose this relative (African green) monkeys frequently have prolonged episodes of advantage later on (Selikhova et al., 2009). Finally, patients with low-frequency resting tremor (Bergman et al., 1998b). Both spe- tremor-dominant Parkinson’s disease have better cognitive per- cies develop akinesia, rigidity and severe postural instability. Thus, formance than non-tremor patients with Parkinson’s disease vervet monkeys resemble the tremulous Parkinson’s disease sub- (Vakil and Herishanu-Naaman, 1998; Lewis et al., 2005; Burn type, while rhesus monkeys resemble the non-tremor Parkinson’s et al., 2006) and are less likely to develop dementia (Aarsland disease subtype (Rivlin-Etzion et al., 2010). There are no studies et al., 2003; Williams-Gray et al., 2007). To distinguish between directly comparing the spatial topography of MPTP-induced neural tremor-dominant and non-tremor Parkinson’s disease subtypes, all damage between these species, but in vervet monkeys, the retro- of the studies reviewed above used a combined resting and pos- rubral area (A8) is preferentially damaged (Deutch et al., 1986), tural/action tremor score on the UPDRS. Therefore, it remains while in rhesus monkeys, the substantia nigra pars compacta (A9) unclear which of these tremors best predicts the clinical advan- is more affected (German et al., 1988; Oiwa et al., 2003). tages associated with the tremor-dominant subtype. Since postural Although circumstantial, these observations lend further support and action tremors frequently occur in the akinetic-rigid subtype to the idea that tremor is related to—and possibly caused by— (Deuschl et al., 2000; Helmich et al., 2011b), it could be argued dopaminergic cell loss in the retrorubral area (Jellinger, 1999). The that the presence of resting tremor is the best predictor of clinical retrorubral area could produce tremor via its dopaminergic projec- progression. This remains to be tested. tions to, among other regions, the subthalamic region (Francois et al., 2000) and the pallidum (Jan et al., 2000). Accordingly, a study in parkinsonian vervet monkeys found that tremor The neurochemical basis of severity correlated exclusively with dopaminergic ﬁbres in the external globus pallidus (Mounayar et al., 2007). Similarly, a parkinsonian resting tremor post-mortem study in patients with Parkinson’s disease The core pathological process in Parkinson’s disease involves showed that clinical tremor severity was correlated exclusively dopaminergic cell loss in the substantia nigra pars compacta, with concentrations of the dopamine metabolite homovanillic Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3209 acid in the pallidum (Bernheimer et al., 1973). Taken together, patients with tremor-dominant Parkinson’s disease had lower levels of thalamic serotonin transporters than non-tremor patients these data suggest that tremor might result from pallidal dysfunc- (Caretti et al., 2008). This opens the possibility that abnormalities tion, triggered by a speciﬁc loss of dopaminergic projections from in the serotonergic system are involved in generating resting the retrorubral area. Note that not all ﬁndings consistently point in tremor in Parkinson’s disease although this hypothesis remains to this direction: a recent post-mortem study showed higher dopa- be tested in post-mortem studies. mine levels in the ventral internal globus pallidus of patients with These ﬁndings suggest that tremor severity does not depend on tremor-dominant than non-tremor Parkinson’s disease (Rajput the amount of nigrostriatal dopamine depletion. On the other et al., 2008). However, only few data points were measured hand, it has been argued that the expression of resting tremor is (a single hemisphere of two tremor-dominant patients), which conditional upon dopaminergic denervation in the midbrain limit the interpretation of these results. New imaging techniques (Deuschl et al., 2000). Indeed, many disorders with resting may conﬁrm the role of the retrorubral area in tremor in vivo, for tremor show a form of nigrostriatal dopamine depletion, e.g. example by measuring N-acetyl-aspartate (a marker of neuronal mono-symptomatic resting tremor (Ghaemi et al., 2002), dystonic viability) in the retrorubral area with magnetic resonance spectros- resting tremor after mesencephalic lesions (Vidailhet et al., 1999) copy or by measuring connectivity between the retrorubral area and Holmes’ tremor (formerly called rubral or midbrain tremor) and the basal ganglia using diffusion tensor imaging and func- (Remy et al., 1995; Seidel et al., 2009; Sung et al., 2009). tional MRI. Thus, we are left with the paradox that nigrostriatal dopamine depletion may be a prerequisite for developing resting tremor, In vivo dopaminergic and serotonergic but the level of tremor expression is independent of nigrostriatal degeneration. How these ﬁndings can be reconciled will be dis- imaging cussed later in this paper. Five [123I]FP-CIT SPECT studies have described neurochemical differences between patients with tremor-dominant and non-tremor Parkinson’s disease (Fig. 1). Three of these found Thalamic nomenclature that patients with tremor-dominant Parkinson’s disease had less The thalamus is one of the key regions involved in tremor. The striatal dopamine depletion than those with non-tremor nomenclature of the thalamic subregions is diverse and often con- Parkinson’s disease (Spiegel et al., 2007; Rossi et al., 2010; fusing. Here we will follow the nomenclature proposed by Jones Helmich et al., 2011b). These differences were spatially localized (Hirai and Jones, 1989). Using acetylcholinesterase and Nissl stain- to the putamen in one report (Rossi et al., 2010) and extended to ing on post-mortem thalamic sections in humans, Jones divided the caudate in the other studies (Spiegel et al., 2007; Helmich the ventral lateral (VL) thalamus into anterior and posterior nuclei. et al., 2011b). These ﬁndings ﬁt with the milder nigral pathology These two nuclei have clearly corresponding areas in the primate of tremor-dominant patients noted earlier (Paulus and Jellinger, thalamus, where information about the connectivity of these areas 1991; Jellinger, 1999). The fourth SPECT study found the opposite is available. Thus, according to Jones, the anterior VL receives pattern (Isaias et al., 2007), perhaps because of a different deﬁn- input from the pallidum, and the posterior VL receives input ition of Parkinson’s disease subgroups, or because only 10 from the cerebellum. Many clinicians, on the other hand, use tremor-dominant patients with Parkinson’s disease were included, the thalamic nomenclature by Hassler, because of its widespread whereas the other studies included 16–24 tremor-dominant pa- use in the deep brain stimulation (DBS) literature. The most tients (Spiegel et al., 2007; Rossi et al., 2010; Helmich et al., common thalamic target for tremor relief is Hassler’s ventral inter- 2011b). The ﬁfth study found different spatial distributions of mediate nucleus, which is localized during surgery based on the dopamine depletion in tremor-dominant and non-tremor presence of tremor-synchronous bursts and kinaesthetic cells, an- Parkinson’s disease subtypes. Speciﬁcally, non-tremor patients terior to cutaneous receptive cells (Krack et al., 2002). It is gen- showed pronounced dopamine depletion in the posterior striatum, erally agreed that interference with this region relieves tremor by while tremor-dominant patients had severe dopamine depletion in deafferenting the thalamus from cerebellar projections (Percheron the lateral putamen (Eggers et al., 2011). Finally, several SPECT et al., 1996; Krack et al., 2002). Therefore, the neurosurgeon’s studies have correlated the amount of striatal dopamine depletion ventral intermediate nucleus is thought to correspond to (part of) with the severity of individual symptoms. These studies consist- Jones’ posterior VL (Krack et al., 2002). To maintain a uniform ently show that, unlike other Parkinson’s disease symptoms, rest- nomenclature throughout this paper, we will refer to the ventral ing tremor does not correlate with nigrostriatal dopamine intermediate nucleus as posterior VL although it must be borne in depletion (Benamer et al., 2000, 2003; Pirker, 2003; Isaias mind that this analogy is not a strict one. et al., 2007; Spiegel et al., 2007). The weight of the evidence therefore suggests milder nigral pathology in tremor-dominant pa- tients, possibly with a different spatial distribution as well. This Neural mechanisms underlying raises the question whether other neurotransmitters could be involved in generating tremor. Two imaging studies indicate a parkinsonian resting tremor role for serotonin: one study found an association between reduced midbrain raphe 5-HT1A binding and increased tremor Parkinsonian tremor is caused mainly by central, rather than per- severity (Doder et al., 2003), and another study found that ipheral mechanisms (Elble, 1996; Deuschl et al., 2000; McAuley 3210 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Figure 1 Neurochemical correlates of Parkinson’s disease tremor. (A) Correlation between age-normalized striatal [123] I beta-CIT binding and UPDRS motor subscores for speech, facial expression, tremor (rest and action tremor), rigidity, bradykinesia, and posture and gait (n = 59). Reprinted from Pirker (2003), with permission from John Wiley and Sons. (B) Correlation between C-WAY 100635 PET in the raphe and total UPDRS tremor score (r = 0529; P5 0.01; n = 23). Reprinted from Doder et al. (2003), with permission from Wolters Kluwer. (C) Correlation between pallidal [I-123] FP-CIT binding and resting tremor severity [tremor rating scale (TRS); r = 0.57; P = 0.023], using within-patient difference scores (between most-affected and least-affected sides). This procedure controls for non-speciﬁc differences between patients. Reprinted from Helmich et al. (2011b), with permission from John Wiley and Sons. These data show that tremor severity is correlated with dopamine depletion in the pallidum (C), but not the striatum (A), and also with serotonin depletion in the raphe (B). and Marsden, 2000). Evidence for this view comes from work tremor although peripheral reﬂexes (muscle stretch) may interact showing that peripheral deafferentation (Pollock and Davis, with central oscillations (Rack and Ross, 1986). 1930), peripheral anaesthesia of tremulous muscles (Walshe, Several electrophysiological and metabolic investigations have 1924) and mechanical perturbations (Lee and Stein, 1981; studied the cerebral basis of tremor production. Methodological Homberg et al., 1987) have little effect on Parkinson’s disease differences between these studies must be considered for Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3211 Figure 2 Neuronal correlates of Parkinson’s disease tremor. (A) Simultaneous recording of thalamic posterior VL (VLp) single-unit activity and peripheral EMG during tremor in a parkinsonian patient. These data show continuous synchronization between internal globus pallidus activity and peripheral EMG. Reprinted from Lenz et al. (1988), with permission from the Society for Neuroscience. (B) Simultaneous recording of internal globus pallidus (GPi) multi-unit activity and peripheral EMG during tremor in a patient with Parkinson’s disease (PD). The two plots illustrate the raw signals of two epochs of data sampled 5 min apart. Note that in the left trace the peaks in the spike density function coincide with the EMG bursts, whereas in the right trace the oscillations in the spike density function occur at a lower frequency than the EMG. These data show that synchronization between neuronal activity in internal globus pallidus and peripheral EMG is transient in nature. Reprinted from Hurtado et al. (1999). Copyright (2011) National Academy of Sciences, USA. interpreting their results. First, different experimental designs have ganglia-cortical circuit, tremor activity is organized in parallel and been used: (i) an ‘event-related’ design, where tremor character- partly segregated subloops: intra-operative recording of local ﬁeld istics (such as ﬂuctuations in tremor amplitude) were directly potentials in the STN of patients with tremor-dominant Parkinson’s related to cerebral activity and (ii) a ‘trait’ design, where baseline disease revealed clusters of tremor-associated coupling between characteristics (such as cerebral perfusion or grey matter density) STN and tremor EMG that were spatially distinct for different were compared between tremor-dominant and non-tremor muscles (Reck et al., 2009). Another study using intra-operative Parkinson’s disease subgroups. With this latter approach, differ- STN recordings in patients with tremor-dominant Parkinson’s ences between subgroups might be related to tremor, but also disease found that neurons (episodically) oscillating at tremor fre- to other factors. Second, different recording techniques have quency were locally surrounded by non-oscillating or out-of- phase neurons, while larger populations of neurons continuously been used: (i) electrophysiological studies tried to relate cycle-to- cycle oscillations in tremor (typically 4 Hz) to neural oscillations oscillated at 8–20 Hz (Moran et al., 2008). Given the known with the same frequency as the tremor. The spatial resolution of somatotopic organization of the posterior VL (Ohye et al., such studies was limited to a group of neurons (e.g. studies in 1989), a similar organization of tremor in subloops may apply to patients with deep electrodes) or to a shallow portion of the cor- the cerebello-thalamo-cortical circuit. These ﬁndings explain why tical mantle (e.g. studies using magnetoencephalography) and (ii) tremor in different limbs is generally not coherent with each other (Hurtado et al., 2000; Raethjen et al., 2000). Importantly, the metabolic imaging methods such as PET and functional MRI are blind to the rapid cycle-to-cycle changes in neural activity, but are synchronicity of basal ganglia and thalamic activity to tremor sensitive to episodic changes in tremor output, and offer a view of varies between regions. Pallidal neurons are only transiently and the whole brain. In the following section, we brieﬂy review these inconsistently coherent with tremor (Hurtado et al., 1999; Raz studies, taking these methodological considerations into account. et al., 2000), while posterior VL neurons are highly synchronous Electrophysiological studies have identiﬁed cells ﬁring at tremor with tremor (Lenz et al., 1994) (Fig. 2). These ﬁndings suggest frequency both in the basal ganglia [subthalamic nucleus (STN) that the basal ganglia cannot be the driving force behind resting and pallidum (Levy et al., 2000; Raz et al., 2000)] and the pos- tremor (Zaidel et al., 2009). Magnetoencephalography work sup- terior VL (Lenz et al., 1994; Magnin et al., 2000). Within the basal ports this view, showing that a cerebello-thalamo-cortical circuit, 3212 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Figure 3 Oscillatory correlates of Parkinson’s disease tremor. This ﬁgure shows statistical parametric (SPM) maps of spatially normalized cerebro-muscular and cerebro-cerebral coherence of four patients with right-sided rest tremor. Cerebral activity was measured with magnetoencephalography and muscular activity with EMG. (A) Cerebro-muscular coherence at double tremor frequency is located in the contralateral primary motor cortex (M1). (B) This plot shows the coherence between M1 activity and the tremor EMG for one patient with Parkinson’s disease. The dashed line indicates the 99% conﬁdence level. (C) Cerebro-cerebral coherence was computed with the reference region in M1 and averaged for all four patients. Areas of consistent coupling with M1 were found in the secondary somatosensory cortex (S2), posterior parietal cortex (PPC), cingulate motor area (CMA)/supplementary motor area (SMA), contralateral diencephalon and ipsilateral cerebellum. Due to the poor coverage by and the large distance to the magnetoencephalography sensors, localization in the latter two areas is not as precise as at the cortical level. These data show a cerebello-thalamo-cortical circuit coupled with tremor on a cycle-by-cycle basis. Reprinted from Timmermann et al. (2003), by permission of Oxford University Press. rather than the basal ganglia, ﬁres in synchrony with ongoing 2001). Other PET studies compared baseline cerebral perfusion resting tremor in Parkinson’s disease (Timmermann et al., 2003) (a ‘trait’) between tremor-dominant and non-tremor patients (Fig. 3). with Parkinson’s disease. They found that tremor-dominant pa- Several metabolic imaging studies (PET) investigated how ‘event- tients had relatively increased perfusion of the thalamus, pons related’ cerebral activity changed after posterior VL-DBS, which and premotor cortex, compared to non-tremor patients (Antonini reduces tremor amplitude. These studies found that posterior VL et al., 1998). Compared to healthy controls, both Parkinson’s dis- stimulation was associated with reduced activity in the cerebellum ease groups had increased pallido–thalamic and pontine activity, (Deiber et al., 1993; Fukuda et al., 2004), motor cortex (Fukuda and reduced activity in premotor cortex, supplementary motor et al., 2004) and medial frontal cortex (Fukuda et al., 2004). area and parietal cortex (Antonini et al., 1998). Accordingly, bra- Another approach is to localize cerebral activity that co-varied dykinesia and rigidity were found to correlate with activity in the with differences (between-subjects) in tremor amplitude. This Parkinson’s disease-wide network, but tremor did not (Eidelberg identiﬁed similar areas, namely tremor-related activity in the cere- et al., 1994). A recent PET study combined these approaches, bellum, ventrolateral thalamus and motor cortex (Kassubek et al., describing a tremor-related network consisting of sensorimotor Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3213 Figure 4 Metabolic correlates of Parkinson’s disease tremor. (A) Spatial covariance pattern identiﬁed by ordinal trends canonical variate analysis of FDG PET data from 11 hemispheres of nine patients with tremor-dominant Parkinson’s disease (PD) scanned on and off posterior VL stimulation (labelled ventral intermediate nucleus in the original manuscript). Posterior VL stimulation improved tremor severity and reduced metabolic activity in the primary motor cortex, anterior cerebellum/dorsal pons, and the caudate/putamen. (B) The expression of this Parkinson’s disease tremor-related metabolic pattern (PDTP) was reduced by posterior VL stimulation in 10 of the 11 treated hemispheres. (C) Baseline PDTP expression (i.e. off-stimulation pattern scores) correlated (r = 0.85, P5 0.02) with tremor amplitude, measured with concurrent accelerometry. These data show that metabolic activity in both the cortico-cerebellar circuit and the basal ganglia is related to tremor severity. Reprinted from Mure et al. (2011), with permission from Elsevier. cortex, cerebellum (lobules IV/V and dentate), cingulate cortex These ﬁndings ﬁt with the involvement of the cerebello- and—to a lesser extent—putamen (Mure et al., 2011). Activity thalamo-cortical network in tremor, as shown with functional ima- in this network was correlated with clinical tremor scores, it ging (Deiber et al., 1993; Fukuda et al., 2004). It is unclear how was higher in patients with tremor-dominant than non-tremor increased activation of these areas can translate in both reduced and Parkinson’s disease, it increased with disease progression and it increased grey matter volume. This divergence might be explained was suppressed by both posterior VL and STN-DBS (Fig. 4). by differences in neuroplasticity between brain regions, which—in Importantly, the metabolic effects of posterior VL and STN-DBS the context of skill acquisition—can produce opposite volumetric overlapped in a single region, the motor cortex. This suggests that changes in the cortex and basal ganglia (Kloppel et al., 2010). the basal ganglia and cerebellar tremor circuits converge in the Taken together, these ﬁndings provide evidence for the involve- motor cortex. ment of both the cerebello-thalamo-cortical circuit and the basal ganglia in Parkinson’s disease resting tremor. The arrest of tremor by focused interventions in either of these circuits further conﬁrms Structural imaging that both are causally related to tremor. That is, DBS targeted towards either the basal ganglia [pallidum or STN (Lozano et al., Two MRI studies used voxel-based morphometry to test for struc- 1995; Krack et al., 1997)] or the cerebellar loop [posterior VL tural changes (‘traits’) in tremor-dominant Parkinson’s disease. (Benabid et al., 1991)] reduces tremor severity in Parkinson’s dis- These studies compared tremor-dominant Parkinson’s disease with ease. The efﬁcacy of posterior VL and STN-DBS on Parkinson’s either non-tremor patients with Parkinson’s disease (Benninger disease tremor appears to be comparable (Pollak et al., 2002): et al., 2009) or with controls (Kassubek et al., 2002). UPDRS tremor scores (items 20 and 21, OFF medication) Tremor-dominant patients had reduced grey matter volume in the right cerebellum (Benninger et al., 2009) and increased decreased by 75–84% with STN-DBS (Kumar et al., 1998; Krack grey matter volume in the posterior VL (Kassubek et al., 2002). et al., 2003; Kim et al., 2010) and by 77–88% with posterior 3214 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. VL-DBS (Rehncrona et al., 2003; Hariz et al., 2008). Earlier studies Parkinson’s disease, and the bursts were not coherent with per- found that 58–88% of patients with Parkinson’s disease had a ipheral tremor recordings. Patients with tremor-dominant total suppression of tremor 3–6 months after posterior VL-DBS Parkinson’s disease showed distinct tremor-locked bursts without (Benabid et al., 1991; Koller et al., 1994). There are no studies low-threshold calcium spike bursts characteristics in the posterior directly comparing the effects of these two targets, but one study VL, but not in the anterior VL. These ﬁndings could be taken as reported an additional reduction of tremor scores after STN-DBS in evidence that pathological low-threshold calcium spike bursting is patients with Parkinson’s disease with previous thalamic surgery not related to tremor. Alternatively, thalamic low-threshold cal- (Fraix et al., 2005). cium spike bursts might be transformed into tremor-locked bursts by re-entry properties of the thalamo-cortical circuit (Magnin et al., 2000). Another issue concerns the mechanisms that drive thalamic cells Models explaining the into an oscillatory mode in Parkinson’s disease. In theory, any occurrence of parkinsonian mechanism that engenders membrane hyperpolarization, whether through reduction of excitatory drive (dysfacilitation) or excess resting tremor inhibition, will trigger low-frequency rhythmicity of thalamic neu- Several hypotheses have been put forward to explain the occur- rons (Llinas et al., 2005). Several different mechanisms have been rence of resting tremor in Parkinson’s disease. As outlined above, suggested. First, according to the classical model of Parkinson’s there is evidence that both the basal ganglia and the disease (Albin et al., 1989), the internal globus pallidus sends cerebello-thalamo-cortical circuit are implicated in tremor. increased (inhibitory) output to the thalamus, which may hyper- However, most models are based on detailed recordings in a lim- polarize thalamic neurons and thus trigger oscillations at 5–6 Hz ited set of neurons (e.g. ex vivo preparations) or a limited set of (Llinas et al., 2005). However, this mechanism would predict a structures (e.g. electrophysiological recordings). Therefore, most predominant role for the pallidal thalamus, anterior VL, in models focus on a node in a single circuit and interpret the tremor genesis. This does not ﬁt with ﬁndings from DBS, which changes in other circuits as secondary. Here we will place concur- show that interference with the cerebellar thalamus, posterior VL, rent changes in two separate circuits into perspective. This section is superior for treating tremor (Atkinson et al., 2002), or with the also updates and elaborates on earlier reviews about the patho- ﬁnding that there are more tremor cells in the posterior VL than physiology of parkinsonian tremor (Elble, 1996; Deuschl et al., anterior VL (Magnin et al., 2000). Second, it has recently been 2000; Rodriguez-Oroz et al., 2009). proposed that increased inhibitory input from the zona incerta towards the posterior VL could hyperpolarize these thalamic neu- rons (Plaha et al., 2008). The zona incerta is located in the sub- thalamic region, medially with respect to the STN. In non-human Model 1: the thalamic pacemaker primates, the zona incerta receives projections from the internal hypothesis globus pallidus [although mainly the cognitive division (Sidibe et al., 1997)], and it sends GABA-ergic projections to the posterior This hypothesis (Jahnsen and Llinas, 1984) is based on in vitro VL (Bartho et al., 2002). This makes the zona incerta an interface preparations of guinea pig thalamic neurons, where it was found between the basal ganglia and the cerebello-thalamo-cortical cir- that the intrinsic biophysical properties of thalamic neurons allow cuits, and its involvement in tremor may explain why both circuits them to serve as relay systems and as single cell oscillators at two are related to tremor. In line with this hypothesis, DBS of the zona distinct frequencies, 9–10 and 5–6 Hz. Speciﬁcally, slightly depo- incerta can reduce tremor (Plaha et al., 2006) and low-frequency larized thalamic cells tend to oscillate at 10 Hz, while hyperpolar- stimulation of the zona incerta can induce tremor in patients with ized cells oscillate at 6 Hz (Llinas, 1988). These two frequencies previously non-tremulous Parkinson’s disease (Plaha et al., 2008). coincide with the frequency of physiological tremor and Third, thalamic posterior VL neurons may be hyperpolarized Parkinson’s disease tremor, respectively. The key assumption of through the cerebellum. Moreover, the ﬁnding of disynaptic pro- this model is that (single) thalamic neurons, not the basal ganglia jections from the STN to the cerebellar cortex in non-human pri- circuitry, form the tremor pacemaker. However, in vivo measure- mates (Bostan et al., 2010) opens the possibility that pathological ments in the thalamus of patients with Parkinson’s disease have activity in the basal ganglia produces downstream changes in the questioned the presence of these thalamic pacemaker cells. That cerebellum and cerebellar thalamus (posterior VL). Fourth, it is is, while the 6 Hz oscillatory mode in the animal model is asso- possible that hyperpolarization of thalamic posterior VL neurons ciated with low threshold calcium spike bursts, this pattern was is related to the degeneration of dopaminergic projections from not observed (with rare exception) in the thalamus of patients the midbrain to the posterior VL. Speciﬁcally, both the retrorubral with Parkinson’s disease with tremor (Zirh et al., 1998). In con- area [that is degenerated in tremor-dominant Parkinson’s disease trast, a second study found a convincing low threshold calcium (Hirsch et al., 1992)] and the substantia nigra pars compacta send spike bursts pattern in a larger number of cells in the thalamus sparse dopaminergic projections to the whole thalamus, including (both the anterior and posterior VL) of patients with Parkinson’s disease (Magnin et al., 2000), possibly due to more sensitive pro- the posterior VL (Sanchez-Gonzalez et al., 2005). According to cessing techniques. However, low-threshold calcium spike bursts this hypothesis, basal ganglia dysfunction would not be required were present both in patients with tremor-dominant and akinetic for the hyperpolarization of posterior VL neurons. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3215 basal ganglia circuitry, not the thalamus, forms the tremor pace- Model 2: the thalamic ﬁlter hypothesis maker. In line with this hypothesis, parkinsonian primates show This hypothesis (Pare et al., 1990) is also based on in vitro data less selective neuronal responses to proprioceptive stimulation in and proposes that parkinsonian resting tremor emerges when high- the entire pallido-thalamo-cortical loop (Filion et al., 1988; frequency (12–15 Hz) oscillations in the basal ganglia are trans- Goldberg et al., 2002; Pessiglione et al., 2005). These changes formed into a 4–6 Hz pattern by thalamic anterior VL neurons. were found to be larger in the pallidum of patients with The key feature of this hypothesis is that the tremor pacemaker tremor-dominant than non-tremor Parkinson’s disease (Levy is primarily located in the basal ganglia (pallidum), with et al., 2002), and hence related to tremor. However, as already pallido-thalamic interactions determining the net frequency of the mentioned, the inconsistent coherence between basal ganglia os- tremor. This hypothesis seems to ﬁt with recent data in non-human cillations and tremor (Hurtado et al., 1999; Raz et al., 2000) com- primates, where it was found that 10 Hz pallidal oscillations were plicates a causal link between these phenomena (Zaidel et al., only present in tremor-dominant vervet monkeys but not in 2009). non-tremor macaques (Rivlin-Etzion et al., 2010). In contrast, pal- Taken together, the different models discussed above position lidal oscillations at 5 Hz were present in both species. However, the tremor pacemaker either in the thalamus (Model 1) or in the high-frequency stimulation of the pallidum did not spread to the basal ganglia (Models 2–4). Since the cerebellar (not pallidal) thal- motor cortex (Rivlin-Etzion et al., 2008). This makes it unlikely that amus is primarily involved in parkinsonian tremor, the thalamic high-frequency oscillations in the basal ganglia drive Parkinson’s pacemaker hypothesis does not account for the mechanisms that disease resting tremor (Rivlin-Etzion et al., 2006; Zaidel et al., trigger thalamic oscillations, and it remains unclear whether these 2009). Other work also questions the speciﬁc role of mechanisms have any relationship with basal ganglia dysfunction. high-frequency basal ganglia oscillations in the generation of On the other hand, the basal ganglia pacemaker hypotheses are tremor. That is, dopaminergic treatment reduced the pathologically more directly linked to the core pathophysiological substrate of enhanced 8–35 Hz rhythms in the STN of patients with Parkinson’s Parkinson’s disease, but these models struggle with the fact that disease, but this improved only akinesia and rigidity, not tremor tremor-related oscillations in the basal ganglia are only transient (Kuhn et al., 2006). Therefore, most authors relate the increased and inconsistent in nature. high-frequency (8–35 Hz) oscillations in the basal ganglia of pa- tients with Parkinson’s disease to akinesia, but not to tremor (Rivlin-Etzion et al., 2006; Hammond et al., 2007). The ‘dimmer-switch’ model of parkinsonian resting Model 3: the subthalamic tremor nucleus-external globus Given the well-known role of both the basal ganglia and the pallidus pacemaker hypothesis cerebello-thalamic circuits in tremor, we aimed to construct a This hypothesis (Plenz and Kital, 1999) is again based on in vitro data model that speciﬁes and integrates the role of both circuits in and proposes that the STN and external globus pallidus constitute a tremor (Helmich et al., 2011b). To test this systems-level view central pacemaker that is modulated by striatal inhibition of external on tremor, we used functional MRI to identify cerebral responses globus pallidus neurons. This pacemaker could be responsible for that co-ﬂuctuated with spontaneous variations in tremor ampli- synchronized oscillatory activity in the normal and pathological tude, as measured with EMG during scanning (van Duinen basal ganglia. However, these oscillations occurred at frequencies et al., 2005; van Rootselaar et al., 2008; Helmich et al., between 0.4 and 1.8 Hz, and it is unclear whether they have any 2011b). These abrupt amplitude ﬂuctuations are very characteristic relationship with parkinsonian tremor, given the lack of in vivo of parkinsonian tremor, and they do not occur, for example, in measurements. Thus, it is not possible to test whether these oscilla- essential tremor (Elble and Koller, 1990; Gao, 2004; Ropper and tions are consistently coherent with tremor, and hence this hypoth- Samuels, 2009). This method also allowed us to quantify func- esis suffers from the same critique as Model 2. tional interactions between the basal ganglia and the cerebello-thalamo-cortical circuit. We obtained the following re- sults (Fig. 5): (i) tremor amplitude-related activity was localized to Model 4: the loss-of-segregation the cerebello-thalamo-cortical circuit (posterior VL, cerebellum and hypothesis motor cortex); (ii) cerebral activity time-locked to the onset of This hypothesis (Bergman et al., 1998a) is based on the ﬁnding high-amplitude tremor episodes was localized to the basal ganglia that—in normal primates—the activity of neighbouring pallidal and the cerebello-thalamo-cortical circuit; and (iii) tremor- neurons is completely uncorrelated (Bar-Gad et al., 2003), while dominant patients with Parkinson’s disease had increased parkinsonian primates develop markedly increased correlations be- functional connectivity between the basal ganglia and the cere- tween remotely situated pallidal neurons (Bergman et al., 1998a). bello-thalamo-cortical circuit, compared with non-tremor This could lead to excessive synchronization in the basal ganglia, Parkinson’s disease and healthy controls. On the basis of these possibly because inhibitory collaterals in the pallidum are affected data, we suggest the following model, which is also illustrated in by dopamine depletion (Bevan et al., 1998), resulting in tremor Fig. 6: (i) activity in the basal ganglia triggers tremor-related re- (Deuschl et al., 2000). The key feature of this model is that the sponses in the cerebello-thalamo-cortical circuit, which produces 3216 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Figure 5 Tremor amplitude- and onset-related cerebral activity in Parkinson’s disease. (A) Left: Cerebral regions where activity co-ﬂuctuated with tremor amplitude (19 tremor-dominant patients, P5 0.05 whole-brain corrected). Activity was localized to the motor cortex, thalamus (posterior VL; VLp) and cerebellum (left side = side contralateral to tremor). Right: Regions of interest in the basal ganglia are shown. (B) In the cerebello-thalamo-cortical circuit, we found two separate effects: (i) cerebral activity related to tremor amplitude and (ii) cerebral activity related to changes in tremor amplitude (tremor on/offset). Left: These two tremor-related effects are illustrated for the motor cortex of one patient. Right: These two tremor-related effects are shown for the motor cortex across the whole group (19 tremor-dominant patients), separately for the most- and least-affected hemisphere. Similar effects were found in the posterior VL and cerebellum (not shown). (C) In the basal ganglia, we found cerebral activity related to changes in tremor amplitude (tremor on/offset), but not cerebral activity related to tremor amplitude. Left: This effect is illustrated for the internal globus pallidus of one patient. Right: This effect is shown for the internal globus pallidus (GPi) across the whole group (19 tremor-dominant patients), separately for the most- and least-affected hemisphere. Similar effects were found for the putamen, but not for the caudate (not shown). The line graphs in B and C show three relevant time courses: (i) brain activity (motor cortex in orange, internal globus pallidus in blue); (ii) tremor amplitude of the contralateral hand (in black; EMG regressor convolved with the haemodynamic response function); and (iii) tremor on/offset (in dotted grey, ﬁrst temporal derivative of the tremor amplitude regressor, convolved with the haemodynamic response function). These data suggest distinct contributions of two circuits to tremor: the cerebello-thalamo-cortical circuit controls tremor amplitude, and the striato-pallidal circuit produces changes in tremor amplitude. Reprinted from Helmich et al. (2011b), with permission from John Wiley and Sons. GPe = external globus pallidus. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3217 Figure 6 The dimmer-switch model of parkinsonian resting tremor. In tremor-dominant Parkinson’s disease, dopaminergic cell death in the retrorubral area A8 causes dopamine depletion in the pallidum (in red). Pallidal dopamine depletion leads to emergence of pathological activity in the striato-pallidal circuit, which triggers activity in the cerebello-thalamo-cortical circuit (in blue) through the primary motor cortex (red line between pallidum and primary motor cortex). Thus, the striato-pallidal circuit triggers tremor episodes (analogues to a light switch), while the cerebello-thalamo-cortical circuit produces the tremor and controls its amplitude (analogous to a light dimmer). This model is based on Helmich et al. (2011b). VLp = posterior VL. the tremor; and (ii) these interactions occur in the motor cortex, depletion appears required for developing resting tremor where both circuits converge (Hoover and Strick, 1999). The novel (Deuschl et al., 2000). Indeed, if pallidal (but not striatal) aspect of this model is that it offers a mechanism explaining how dopamine depletion is involved in tremor genesis, this could also the basal ganglia and the cerebello-thalamo-cortical circuits inter- explain why striatal DAT signal is not correlated with tremor act with each other. Given the emphasis on a combination of basal severity. ganglia contributions (that trigger tremor on/offset, analogous to The dimmer-switch model combines several features of the pre- a light switch) and cerebello-thalamo-cortical contributions (that vious hypotheses into a larger explanatory framework. First, loss of modulate tremor intensity, analogous to a light dimmer), we call segregation in the dopamine-depleted pallidum may be a mech- this model the ‘dimmer-switch model’ of Parkinson’s disease rest- anism that explains both the emergence of pathological activity in ing tremor (Fig. 6). the basal ganglia, and the increased connectivity between basal To identify the dopaminergic mechanisms underlying these ganglia and motor cortex (Rivlin-Etzion et al., 2008). Second, changes, we compared striato-pallidal DAT binding between altered basal ganglia output may inﬂuence neurons in the cerebel- tremor-dominant and non-tremor patients with Parkinson’s dis- lar thalamus (posterior VL) via the motor cortex. That is, excitatory ease, using [123I]FP-CIT SPECT (Helmich et al., 2011b). This re- cortico-thalamic projections from motor cortex to ventrolateral vealed that pallidal, but not striatal, dopamine depletion correlates thalamus (Fonnum et al., 1981; Rouiller et al., 1998; Kultas- with the severity of resting tremor. This ﬁnding could solve the Ilinsky et al., 2003) can activate inhibitory intra-thalamic circuits dopaminergic paradox of Parkinson’s disease resting tremor. (Ando et al., 1995; Landisman and Connors, 2007; Cruikshank Speciﬁcally, the pallidum receives distinct dopaminergic projections et al., 2010), leading to low-frequency oscillations within the from the substantia nigra pars compacta (Smith et al., 1989) and thalamo-cortical network (Blumenfeld and McCormick, 2000). the retrorubral area (Jan et al., 2000), but these same mesenceph- This model would explain why basal ganglia oscillations are only alic areas also send separate projections to the striatum [substantia transient and inconsistent, why thalamic oscillations are highly syn- nigra pars compacta (Anden et al., 1964); retrorubral area chronous with the tremor, and thus why both basal ganglia and (Francois et al., 1999)]. This pattern of divergence and conver- the cerebello-thalamo-cortical circuit are causally related to gence makes it unlikely that midbrain pathology can produce tremor. It remains to be shown why posterior VL neurons are either pure striatal or pure pallidal dopamine depletion although more prone to develop tremor oscillations than anterior VL neu- the degree of dopamine depletion in each area may vary between rons, since both regions receive cortico-thalamic projections from patients. Thus, patients with Parkinson’s disease with resting the motor cortex. Hypothetically, the connections between the tremor will generally have some degree of striatal dopamine de- posterior VL and the cerebellum are a prerequisite for the devel- pletion, explaining why the presence of striatal dopamine opment of tremor oscillations. 3218 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. ﬂuctuations into account, but focused on cycle-by-cycle coherence Limitations of the model and between neural and muscular activity, i.e. signals occurring at 4 Hz. These approaches are blind to neural changes at the future research onset of high-amplitude tremor episodes, because neuromuscular coherence at 4 Hz is similar across low- and high-tremor amplitude Role of the subthalamic nucleus (Reck et al., 2009). In a preliminary study in one patient with Parkinson’s disease, the authors recorded local ﬁeld potentials With the methods (functional MRI) employed in our previous from the STN and related them to changes in tremor amplitude, paper (Helmich et al., 2011b), we were not able to reliably as measured with EMG (Wang et al., 2005). They found that beta detect cerebral activity in a small nucleus such as the STN. The suppression in the STN preceded the onset of tremor episodes and presence of tremor oscillations in the STN that are coherent with made way for oscillations at tremor frequency in the STN. If ac- peripheral tremor activity (Levy et al., 2000) and the ability of tivity in the beta band is a way by which the sensorimotor system STN-DBS to reduce tremor (Kumar et al., 1998; Krack et al., maintains the status quo (Gilbertson et al., 2005; Engel and Fries, 2003; Kim et al., 2010) suggest that this nucleus has an important 2010; Jenkinson and Brown, 2011), then beta suppression in the pathophysiological role in tremor. In contrast to the pallidum, the STN before tremor onset could indicate a removal of neural inhib- STN receives direct anatomical projections from the motor cortex ition to establish tremor onset-related activity (trigger). On the (Nambu et al., 2000), and functional connectivity between the other hand, since beta suppression in the cortex (Crone et al., motor cortex and the STN is increased in Parkinson’s disease 1998) and STN (Kuhn et al., 2004) is known to precede voluntary (Baudrexel et al., 2011; Moran et al., 2011). The STN also movements, the ﬁnding of beta suppression prior to tremor could sends disynaptic anatomical projections to the cerebellar cortex (Bostan et al., 2010). Therefore, the STN has both afferent and just reﬂect a more general phenomenon preceding any movement. efferent connections with the cerebello-thalamo-cortical tremor circuit. Whether the STN is part of the basal ganglia trigger, or Role of dopamine in tremor dynamics whether the STN is involved in the cerebello-thalamo-cortical cir- In our model, pallidal activity was related to changes in tremor cuit producing the tremor, remains to be investigated in future amplitude, rather than the amplitude of the tremor itself (Fig. 5). studies using high-resolution MRI in combination with connectivity This raises the question how the severity of pallidal dopamine analyses. depletion could predict clinical tremor severity (Fig. 1C). This likely depends on the effect of dopamine depletion on pallidal Tremor oscillator activity. For example, dopamine depletion may increase the amp- Although our methods (functional MRI) enabled a systems-level litude of tremor onset-related activity in the pallidum. This should view on tremor, we could not detect oscillatory activity at tremor lead to more abrupt tremor changes, but not to increased tremor frequency. Therefore, it remains an open question which brain amplitude. Second, dopamine depletion may increase the rate of region(s) determine the tremor frequency. The cerebello-tha- onset-related activity in the pallidum. More frequent episodes of lamo-cortical tremor network we identiﬁed matches closely the pallidal activity could lead to more frequent tremor episodes, but network identiﬁed in studies that have directly tracked cerebral also, if the bursts of pallidal activity occur shortly after each other, changes occurring at resting-tremor frequency (using magneto- to ampliﬁed activity in the cerebello-thalamo-cortical circuit (and encephalography; Fig. 3). Thus, in our view, it is the hence to increased tremor amplitude). Finally, more severe pallidal cerebello-thalamo-cortical network that is the ultimate tremor dopamine depletion may lead to enhanced connectivity between generator, but as inﬂuenced and triggered by the coupled basal the basal ganglia and the cerebello-thalamo-cortical systems. This ganglia network. Accordingly, a novel DBS paradigm that takes would make the cerebello-thalamo-cortical circuit more susceptible these network properties into account was found to be more suc- to perturbing signals from the basal ganglia, and the increased cessful than standard DBS in reducing both Parkinson’s disease input–output relationship may lead to more severe tremor. To symptoms and tremor oscillations in the internal globus pallidus investigate these possibilities, we are currently testing tremor- (Rosin et al., 2011). This new paradigm, termed closed-loop DBS, dominant Parkinson patients ON and OFF dopaminergic medica- uses a trigger detected in a reference structure (M1) as the input tion using functional MRI. to deliver DBS trains to the stimulated structure (internal globus pallidus). These data show that the interconnectivity between vari- Causality ous participating brain areas plays a crucial role in the emergence of pathological oscillations and clinical symptoms. Using metabolic imaging, several groups have found a correlation between tremor amplitude and cerebral activity in the cerebellum, motor cortex and posterior VL (e.g. Deiber et al., 1993; Helmich Relationship between metabolic and et al., 2011b; Mure et al., 2011). One interpretational problem is oscillatory activity that the limited temporal resolution of these techniques makes it Based on our model, we suspect that the intermittent oscillations difﬁcult to determine whether the cerebral effects are causal or in the basal ganglia (Fig. 1) could be related to tremor dynamics reactive to the tremor. Electrophysiological studies, which have a such as abrupt changes in amplitude, but this remains to be much higher temporal resolution, partly suffer from the same tested. Most previous studies did not take tremor amplitude problem. That is, single-cell recordings in the thalamus, STN and Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3219 internal globus pallidus of patients with Parkinson’s disease show Why does resting tremor that many neurons with tremor-related activity also respond to somatosensory stimulation (Lenz et al., 1994; Magnin et al., stop during voluntary 2000). Therefore, neural activity that leads peripheral tremor ac- tivity might also relate to the preceding tremor beat. Conduction movements? times are not helpful to disentangle cause from effect, given the A characteristic feature of Parkinson’s disease resting tremor is its diverse pathways through which afferent input can reach the basal decrease during voluntary movements (Deuschl et al., 2000). This ganglia and thalamus. Nevertheless, there are also thalamic cells feature is routinely used in clinical practice to distinguish resting that do not respond to somatosensory stimulation, and that show tremor from other tremor forms (Deuschl et al., 1998), for ex- tremulous activity preceding muscular activity (Lenz et al., 1994). ample from dystonic tremor where a decrease with movement is This suggests that the thalamus has a causal role in tremor. Other electrophysiological studies have calculated the oscillatory activity typically absent (Schneider et al., 2007). However, the neural (at tremor or double tremor frequency) of single neurons or larger mechanisms underlying the interaction between voluntary move- groups of neurons, for example using subcortical DBS electrodes ments and resting tremor remain unclear. As outlined above, or cortical magnetoencephalography recordings (Levy et al., 2000; parkinsonian tremor results from altered responses in both the Timmermann et al., 2003). Since oscillations are deﬁned over basal ganglia and the cerebello-thalamo-cortical circuit. This indi- longer temporal windows, this procedure makes it difﬁcult to de- cates that voluntary movements may interact with resting tremor termine whether neural oscillations drive the tremor or vice versa. in either or both of these circuits. Analytical methods including the phase of coherence or Granger causality might help to solve this problem (Timmermann et al., 2003; Van Quyen and Bragin, 2007) although these methods Movement–tremor interactions in are susceptible to noise contamination and volume conduction the cerebello-thalamo-cortical circuit (Albo et al., 2004; Rivlin-Etzion et al., 2006). To reliably disentangle cause from effect, interference studies We recently investigated the cerebral interactions between are helpful. Lesion studies provide strong evidence that activity motor planning and Parkinson’s disease resting tremor. To this in the posterior VL is causally linked to tremor: thalamotomy, pos- end, we used a motor imagery paradigm (as a quantiﬁable terior VL-DBS and thalamic stroke lead to immediate tremor arrest proxy of motor planning) while measuring tremor-related activity (Benabid et al., 1991; Atkinson et al., 2002; Probst-Cousin et al., during functional MRI scanning. This procedure avoids the con- 2003; Choi et al., 2008). The motor cortex is the only region of founding effects of somatosensory reafference associated with the cerebello-thalamo-cortical circuit that has a direct access to the the production of voluntary movements. There were two main spinal cord, and therefore it seems plausible that activity in this ﬁndings: (i) planning- and tremor-related responses overlapped area drives the tremor. Accordingly, interference with M1 activity in the posterior VL, but not in the cerebellum or in the motor using transcranial magnetic stimulation can reset resting tremor in cortex and (ii) tremor amplitude was unaffected by motor im- Parkinson’s disease (Ni et al., 2010). In contrast, transcranial mag- agery (Helmich et al., 2011a). This indicates that motor netic stimulation over the cerebellum did not reset tremor, sug- planning-related activity in the posterior VL does not remove gesting that this region does not directly drive the tremor. Lesion tremor-related responses in this region, possibly because both studies support this idea: cerebellar stroke (Kim et al., 2009) and processes involve (partly) different neuronal populations (Lenz cerebellectomy (Deuschl et al., 1999) did not remove ipsilateral et al., 1994; Magnin et al., 2000). Another study directly as- resting tremor, but transformed it into a Holmes tremor (i.e. a sessed the electrophysiological interactions between motor exe- slow-frequency and combined resting, intention and postural cution and Parkinson’s disease resting tremor (Hallett et al., tremor). Therefore, the role of the cerebellum in tremor may be 1977). The pattern of alternating activity in agonist and antag- modulatory rather than causal. Accordingly, a previous mag- onist muscles seen during Parkinson’s disease resting tremor netoencephalography study showed that oscillatory activity in strongly resembled the activity seen during voluntary ﬂexion of the cerebellum is coherent with thalamic and motor activity, but the arm. Furthermore, in many patients with Parkinson’s disease, not with the tremor itself (Timmermann et al., 2003). This sug- a single ‘beat of tremor’ preceded voluntary movements, even gests that the cerebellum does not have a direct efferent or affer- when there was no clinically noticeable tremor (Fig. 7). This ent relationship with peripheral tremor. This relationship could be suggests that resting tremor and voluntary movement execution different for other tremor pathologies. For example, other than in arise from similar oscillations in the motor cortex, which may Parkinson’s disease, cerebellar stroke can ameliorate ipsilateral explain why they do not occur simultaneously. Finally, the ob- essential tremor (Dupuis et al., 2010). Finally, an approach to servation that resting tremor at movement onset is no longer gain mechanistic insights into the role of altered oscillations in inhibited when the cerebellum is absent (Deuschl et al., 1999) Parkinson’s disease has been to stimulate the basal ganglia or or malfunctioning (Kim et al., 2009) suggests that the thalamus at precisely these frequencies, using implanted DBS elec- cortico-cerebellar activation during voluntary movements sup- trodes. For example, 5–40 Hz stimulation of the STN, zona incerta and ventrolateral thalamus induced tremor in patients with presses the tremor rhythm. Re-emergent tremor can then be Parkinson’s disease (Plaha et al., 2008), suggesting that oscillatory explained by reinitiating the cerebello-thalamo-cortical tremor activity in these regions is causally linked to tremor. circuit through the basal ganglia. 3220 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. 2008), and we will not repeat this here. Levodopa and other dopaminergic drugs are generally less efﬁcacious against tremor than other key features of Parkinson’s disease (Fishman, 2008; Rodriguez-Oroz et al., 2009). This failure to respond to dopamin- ergic treatment is difﬁcult to reconcile with most models, which assume that tremor is triggered by dopamine depletion. One pos- sibility is that non-dopaminergic neurotransmitters play a role. For example, patients with Parkinson’s disease have 27% lower sero- Figure 7 A beat of tremor preceding movement in Parkinson’s tonin binding in the raphe than controls, and tremor was the only disease. Fast ﬂexion patterns in patients with Parkinson’s symptom that correlated with the amount of serotonin depletion disease. In many patients with Parkinson’s disease (17 arms of (Doder et al., 2003). In humans, there are serotonergic projections 15 patients), although resting tremor was not continuously from the raphe to the basal ganglia, including the pallidum present, a single ‘beat of tremor’ occasionally occurred before (Wallman et al., 2011). If both serotonergic and dopaminergic the pattern that moved the limb. This is illustrated for one patient. Adapted from Hallett et al. (1977) with permission changes can produce tremor, then this may explain why some from BMJ Publishing Group Ltd. patients fail to respond to dopaminergic therapy. Another specu- lative possibility is that there are crucial temporal windows during disease progression in which the tremor is responsive to dopamin- ergic treatment. For example, basal ganglia signals might be Movement–tremor interactions in required for driving the cerebello-thalamo-cortical circuit into the basal ganglia tremor only during the early phases of the disease. Later in the According to our model, transient activity in the pallidum and disease, perhaps due to depletion of inhibitory neurotransmitters in the tremor circuit, oscillations in the cerebello-thalamo-cortical cir- putamen can trigger tremor-related activity in the cerebello-tha- cuit might not need to be triggered by basal ganglia signals. This lamo-cortical circuit. The pallidum is also activated during volun- would predict that the response of tremor to dopaminergic ther- tary movement planning (Owen et al., 1998; Helmich et al., apy is modulated by disease duration. Finally, one report investi- 2009). Movement-related activity may replace tremor-related ac- gated the effect of dopaminergic treatment on the oscillatory tivity in the pallidum, and this could interfere with tremor in two tremor network in Parkinson’s disease (Pollok et al., 2009). They ways. First, the absence of intermittent ‘triggers’ from the pallidum found that levodopa speciﬁcally reduced thalamo-cortical cou- could cause the tremor to fade out. However, this mechanism pling. This suggests that the thalamo-cortical axis has a central does not explain why tremor is immediately reduced at the role in tremor genesis, but that dopaminergic areas (such as the onset of voluntary movements, which suggests an active (instead basal ganglia) control the emergence of tremor-related oscillations of a passive) disturbance of the cerebello-thalamo-cortical tremor in this circuit. circuit. Second, the pallidum may actively inhibit the motor cortex during voluntary movements. The pallidum supports action selec- tion by exciting desired motor programmes, while inhibiting all others [centre-surround inhibition (Mink, 1996; Beck and Hallett, Why does tremor indicate a 2011)]. Inhibition of motor representations in the motor cortex benign Parkinson’s disease during voluntary movement selection could actively interfere with tremor-related ﬁring in the cerebello-thalamo-cortical circuit, subtype? causing an immediate arrest of the tremor. This concept may also We have reviewed and discussed several clinical and pathophysio- explain why resting tremor re-emerges during ﬁxed postural hold- logical differences between tremor-dominant and non-tremor ing (Jankovic et al., 1999). That is, while the basal ganglia are Parkinson’s disease subtypes. We suggest that pallidal dopamine strongly involved in changing movement set, they are not involved depletion is related to tremor, while other pathophysiological mar- in maintaining a ﬁxed posture (Cools et al., 1984; Hayes et al., kers could explain a more benign disease course. First, there is 1998; Helmich et al., 2009). Thus, Parkinson’s disease tremor may converging evidence from post-mortem and nuclear imaging stu- emerge not necessarily in the absence of movement (rest), but dies that patients with tremor-dominant Parkinson’s disease have rather in the absence of selection demands (including maintaining relatively benign nigrostriatal degeneration. This may explain why a posture when no other posture needs to be selected to satisfy other features of Parkinson’s disease also take a more benign the current task context). course in tremor-dominant patients. Second, there is post-mortem evidence that patients with non-tremor Parkinson’s disease have more cortical lesions than patients with tremor-dominant Why does tremor have a Parkinson’s disease, and this may explain the worse cognitive dys- variable response to function of patients with non-tremor Parkinson’s disease. Appearance of such cortical lesions with advancing disease may dopaminergic treatment? also explain why tremor can diminish or even disappear after sev- Previous work has extensively reviewed the response of tremor to eral years in some patients, because the cerebello-thalamo-cortical different pharmacological preparations (Elble, 2002; Fishman, circuit now becomes damaged. Finally, resting tremor may emerge Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3221 as a collateral effect of cerebral mechanisms that compensate for Lewy bodies, cortical amyloid-beta plaques, and cerebral amyloid pathophysiological changes producing akinesia (Hallett and angiopathy (Selikhova et al., 2009). Also, the cognitive deterior- Khoshbin, 1980; Rivlin-Etzion et al., 2006). Voluntary movement ation occurring in non-tremor Parkinson’s disease [i.e. in the PIGD arises in phase with the tremor, suggesting that the tremor may subtype (Williams-Gray et al., 2007)] was associated with cortical facilitate the ability to initiate movement in the face of akinesia Lewy body pathology instead of cortico-striatal dysfunction (Hallett et al., 1977). This possibility ﬁnds support in the fact (Williams-Gray et al., 2009). These studies indicate that progress- that—in MPTP primate models of Parkinson’s disease—tremor ing cortical Lewy body pathology may stop tremor and introduce usually appears several days after akinesia and rigidity (Zaidel dementia-like cognitive dysfunction. Genetic variations between et al., 2009), i.e. its appearance coincides with the time when patients, for instance in the tau gene (microtubule-associated pro- compensatory mechanisms are presumably being activated. This tein tau; MAPT), may determine whether patients develop these does not yet prove any causal relationship, but one possibility is pathologies or not (Williams-Gray et al., 2009). Finally, as outlined that such compensatory changes—for example in the motor in the previous paragraph, patients with tremor-dominant cortex and cerebellum—may render these regions more suscep- Parkinson’s disease might have increased cerebral compensation. tible to pathological inﬂuences (tremor triggers) from the basal This concept would offer an explanation how failure of compen- ganglia. For example, a study that used transcranial magnetic satory mechanisms in later stages of the disease will lead to grad- stimulation pulses to probe the excitability of the primary motor ual disappearance of tremor, possibly because the (previously cortex showed that, when tested at rest, the slope of the input– healthy) brain areas involved in compensation now become af- output relationship between stimulus intensity and response size is fected by neurodegeneration as well. steeper in patients with Parkinson’s disease than in controls (Valls-Sole et al., 1994). Although this could be the result of a primary basal ganglia deﬁcit (loss of normal inhibition), it could Conclusion also reﬂect an attempt to cortically compensate for the slow re- We propose that Parkinson’s disease resting tremor involves both cruitment of commands to move, by making it easier to recruit the basal ganglia and the cerebello-thalamo-cortical circuit. activity from a resting state (Berardelli et al., 2001). Similarly, Previous models of tremor have largely focused on localizing the increased activity of the cerebellum during movements has been tremor pacemaker in either one of these two distinct circuits. observed frequently in Parkinson’s disease—perhaps to compen- These models have provided valuable information about the sate for dysfunction of dopamine-dependent circuits (Rascol et al., neural mechanisms underlying tremor oscillations in these circuits, 1997; Yu et al., 2007; Wu et al., 2010b). The increased cerebellar but they were unable to solve one crucial paradox of Parkinson’s activity may sensitize the cerebello-thalamo-cortical circuit to per- disease resting tremor: why is tremor produced by the turbing inﬂuences from the basal ganglia, resulting in tremor. This cerebello-thalamo-cortical circuit, but only in the presence of suggests that a combination of basal ganglia pathology (i.e. palli- striato-pallidal dopaminergic dysfunction? A systems-level view dal dopamine depletion) and compensation in the on tremor is necessary to answer this question. We have sug- cerebello-thalamo-cortical circuit leads to tremor, explaining why gested a new ‘dimmer-switch model’ of parkinsonian tremor tremor and a benign disease course are seen in the same patients. (Helmich et al., 2011b): depletion of pallidal dopamine (and pos- sibly serotonin) causes pathological activity in the striato-pallidal circuit that triggers—through the motor cortex—tremor-related Why does resting tremor activity in the cerebello-thalamo-cortical circuit. This striato-pallidal decrease with disease activity can only emerge under motorically static conditions when the basal ganglia are not involved in voluntary motor behaviour, progression? explaining why classical Parkinson’s disease tremor is seen both at rest and during ﬁxed postural holding (re-emergent tremor). Parkinsonian resting tremor has a puzzling feature that distin- Future electrophysiological studies may validate this model by guishes it from other Parkinson’s disease symptoms: in some pa- focusing on oscillatory phenomena time-locked to changes in tients, tremor severity tends to decrease instead of worsen during disease progression (Toth et al., 2004; Lees, 2007). One study tremor amplitude. found that tremor was lost in 9% of patients late in the disease Our model may have clinical implications for the treatment of (Hughes et al., 1993). Accordingly, patients with Parkinson’s dis- tremor: if the basal ganglia are only transiently involved at the ease of tremor-dominant subtype in the early phases of their dis- onset of tremor episodes, then DBS of the STN or pallidum may ease can convert to a non-tremor subtype later on, with PIGD be applied more selectively in an ‘event-related’ manner, inter- symptoms replacing the tremor (Alves et al., 2006). This suggests rupting activity in these regions only when required. For this ap- that the progression of cerebral dysfunction in Parkinson’s disease proach to work, one has to be able to accurately predict the onset may at some point disrupt the ability of brain regions to produce of tremor episodes. This may be done by using the DBS electrodes tremor. Post-mortem work has shown that the primary motor to identify tremor-related signals that typically precede tremor epi- cortex becomes affected in later stages of Parkinson’s disease sodes (Wu et al., 2010a), for example, desynchronization in the (Braak et al., 2003). Furthermore, post-mortem work revealed beta band (Wang et al., 2005). Demand-based DBS may also an association between a non-tremor Parkinson’s disease pheno- prolong the life span of implanted batteries. Finally, a similar type, cognitive disability and pathological lesions including cortical systems-level approach as adopted here could be used to 3222 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Benamer HT, Patterson J, Wyper DJ, Hadley DM, Macphee GJ, investigate other tremors occurring in Parkinson’s disease, as well Grosset DG. Correlation of Parkinson’s disease severity and duration as different tremor pathologies such as essential tremor. with 123I-FP-CIT SPECT striatal uptake. Mov Disord 2000; 15: 692–8. Benninger DH, Thees S, Kollias SS, Bassetti CL, Waldvogel D. Morphological differences in Parkinson’s disease with and without rest tremor. J Neurol 2009; 256: 256–63. Funding Berardelli A, Rothwell JC, Thompson PD, Hallett M. Pathophysiology of bradykinesia in Parkinson’s disease. Brain 2001; 124: 2131–46. The Alkemade-Keuls Foundation (to B.R.B.); the Netherlands Bergman H, Feingold A, Nini A, Raz A, Slovin H, Abeles M, Vaadia E. Organisation for Scientiﬁc Research (NWO; VIDI grant No. Physiological aspects of information processing in the basal ganglia 016.076.352 to B.R.B.; VIDI grant No. 452-03-339 to I.T.; Brain & of normal and parkinsonian primates. Trends Neurosci 1998a; 21: 32–8. Cognition grant No. 433-09-248 to I.T.); the German Research Bergman H, Raz A, Feingold A, Nini A, Nelken I, Hansel D, Ben Pazi H, Reches A. Physiology of MPTP tremor. Mov Disord 1998b; 13 Council (SFB 855 to G.D.) and the NIH Intramural Program (to M.H.). (Suppl 3): 29–34. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci References 1973; 20: 415–55. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence Bevan MD, Booth PA, Eaton SA, Bolam JP. Selective innervation of and characteristics of dementia in Parkinson disease: an 8-year pro- neostriatal interneurons by a subclass of neuron in the globus pallidus spective study. Arch Neurol 2003; 60: 387–92. of the rat. J Neurosci 1998; 18: 9438–52. Abdo WF, van de Warrenburg BP, Burn DJ, Quinn NP, Bloem BR. The Blumenfeld H, McCormick DA. Corticothalamic inputs control the pat- clinical approach to movement disorders. Nat Rev Neurol 2010; 6: tern of activity generated in thalamocortical networks. J Neurosci 29–37. 2000; 20: 5153–62. Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia Bostan AC, Dum RP, Strick PL. The basal ganglia communicate with the disorders. Trends Neurosci 1989; 12: 366–75. cerebellum. Proc Natl Acad Sci U S A 2010; 107: 8452–56. Albo Z, Di Prisco GV, Chen YH, Rangarajan G, Truccolo W, Feng JF, Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Vertes RP, Ding MZ. Is partial coherence a viable technique for iden- Staging of brain pathology related to sporadic Parkinson’s disease. tifying generators of neural oscillations? Biol Cybernet 2004; 90: Neurobiol Aging 2003; 24: 197–211. 318–26. Burn DJ, Rowan EN, Allan LM, Molloy S, O’Brien JT, McKeith IG. Motor Alves G, Larsen JP, Emre M, Wentzel-Larsen T, Aarsland D. Changes in subtype and cognitive decline in Parkinson’s disease, Parkinson’s dis- motor subtype and risk for incident dementia in Parkinson’s disease. ease with dementia, and dementia with Lewy bodies. J Neurol Mov Disord 2006; 21: 1123–30. Neurosurg Psychiatry 2006; 77: 585–9. Anden NE, Carlsson A, Dahlstroem A, Fuxe K, Hillarp NA, Larsson K. Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. A Demonstration and mapping out of nigro-neostriatal dopamine neu- primate model of parkinsonism: selective destruction of dopaminergic rons. Life Sci 1964; 3: 523–30. neurons in the pars compacta of the substantia nigra by Ando N, Izawa Y, Shinoda Y. Relative contributions of thalamic reticular N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U nucleus neurons and intrinsic interneurons to inhibition of thalamic S A 1983; 80: 4546–50. neurons projecting to the motor cortex. J Neurophysiol 1995; 73: Caretti V, Stoffers D, Winogrodzka A, Isaias IU, Costantino G, Pezzoli G, 2470–85. Ferrarese C, Antonini A, Wolters EC, Booij J. Loss of thalamic serotonin Antonini A, Moeller JR, Nakamura T, Spetsieris P, Dhawan V, transporters in early drug-naı¨ve Parkinson’s disease patients is asso- Eidelberg D. The metabolic anatomy of tremor in Parkinson’s disease. ciated with tremor: an [123I]b-CIT SPECT study. J Neural Transm Neurology 1998; 51: 803–10. 2008; 115: 721–9. Atkinson JD, Collins DL, Bertrand G, Peters TM, Pike GB, Sadikot AF. Choi SM, Lee SH, Park MS, Kim BC, Kim MK, Cho KH. Disappearance of Optimal location of thalamotomy lesions for tremor associated with resting tremor after thalamic stroke involving the territory of the tuber- Parkinson disease: a probabilistic analysis based on postoperative mag- othalamic artery. Parkinsonism Relat Disord 2008; 14: 373–5. netic resonance imaging and an integrated digital atlas. J Neurosurg Cools AR, van den Bercken JH, Horstink MW, van Spaendonck KP, 2002; 96: 854–66. Berger HJ. Cognitive and motor shifting aptitude disorder Bar-Gad I, Heimer G, Ritov Y, Bergman H. Functional correlations be- in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1984; 47: tween neighboring neurons in the primate globus pallidus are weak or 443–53. Crone NE, Miglioretti DL, Gordon B, Sieracki JM, Wilson MT, Uematsu S, nonexistent. J Neurosci 2003; 23: 4012–6. Bartho P, Freund TF, Acsady L. Selective GABAergic innervation of thal- Lesser RP. Functional mapping of human sensorimotor cortex with amic nuclei from zona incerta. Eur J Neurosci 2002; 16: 999–1014. electrocorticographic spectral analysis - I. Alpha and beta event-related Baudrexel S, Witte T, Seifried C, von Wegner F, Beissner F, Klein JC, desynchronization. Brain 1998; 121: 2271–99. Steinmetz H, Deichmann R, Roeper J, Hilker R. Resting state fMRI Cruikshank SJ, Urabe H, Nurmikko AV, Connors BW. Pathway-speciﬁc reveals increased subthalamic nucleus-motor cortex connectivity in feedforward circuits between thalamus and neocortex revealed by Parkinson’s disease. Neuroimage 2011; 55: 1728–38. selective optical stimulation of axons. Neuron 2010; 65: 230–45. Beck S, Hallett M. Surround inhibition in the motor system. Exp Brain Res Deiber MP, Pollak P, Passingham R, Landais P, Gervason C, Cinotti L, 2011; 210: 165–72. Friston K, Frackowiak R, Mauguiere F, Benabid AL. Thalamic stimula- Benabid AL, Pollak P, Gervason C, Hoffmann D, Gao DM, Hommel M, tion and suppression of parkinsonian tremor. Evidence of a cerebellar Perret JE, de Rougemont J. Long-term suppression of tremor by deactivation using positron emission tomography. Brain 1993; 116 chronic stimulation of the ventral intermediate thalamic nucleus. (Pt 1): 267–79. Lancet 1991; 337: 403–6. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Benamer HT, Oertel WH, Patterson J, Hadley DM, Pogarell O, Disorder Society on Tremor. Ad Hoc Scientiﬁc Committee. Mov Hoffken H, Gerstner A, Grosset DG. Prospective study of presynaptic Disord 1998; 13 (Suppl 3): 2–23. dopaminergic imaging in patients with mild parkinsonism and tremor Deuschl G, Raethjen J, Baron R, Lindemann M, Wilms H, Krack P. The disorders: part 1. Baseline and 3-month observations. Mov Disord pathophysiology of parkinsonian tremor: a review. J Neurol 2000; 247 2003; 18: 977–84. (Suppl 5): V33–V48. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3223 Deuschl G, Wilms H, Krack P, Wurker M, Heiss WD. Function of the Gilbertson T, Lalo E, Doyle L, Di Lazzaro V, Cioni B, Brown P. Existing cerebellum in Parkinsonian rest tremor and Holmes’ tremor. Ann motor state is favored at the expense of new movement during 13-35 Neurol 1999; 46: 126–8. Hz oscillatory synchrony in the human corticospinal system. J Neurosci Deutch AY, Elsworth JD, Goldstein M, FUXE K, Redmond DE Jr, 2005; 25: 7771–9. Sladek JR Jr, Roth RH. Preferential vulnerability of A8 dopamine neu- Goldberg JA, Boraud T, Maraton S, Haber SN, Vaadia E, Bergman H. rons in the primate to the neurotoxin 1-methyl-4-phenyl-1,2,3,6- Enhanced synchrony among primary motor cortex neurons in the tetrahydropyridine. Neurosci Lett 1986; 68: 51–6. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ. Tremor in Parkinson’s disease. J Neurosci 2002; 22: 4639–53. Parkinson’s disease and serotonergic dysfunction: an 11C-WAY Hallett M, Khoshbin S. A physiological mechanism of bradykinesia. Brain 100635 PET study. Neurology 2003; 60: 601–5. 1980; 103: 301–14. Dupuis MJ, Evrard FL, Jacquerye PG, Picard GR, Lermen OG. Hallett M, Shahani BT, Young RR. Analysis of stereotyped voluntary Disappearance of essential tremor after stroke. Mov Disord 2010; movements at the elbow in patients with Parkinson’s disease. 25: 2884–2887. J Neurol Neurosurg Psychiatry 1977; 40: 1129–35. Eggers C, Kahraman D, Fink GR, Schmidt M, Timmermann L. Hammond C, Bergman H, Brown P. Pathological synchronization in Akinetic-rigid and tremor-dominant Parkinson’s disease patients show Parkinson’s disease: networks, models and treatments. Trends different patterns of FP-CIT single photon emission computed tomog- Neurosci 2007; 30: 357–64. raphy. Mov Disord 2011; 26: 416–23. Hariz MI, Krack P, Alesch F, Augustinsson LE, Bosch A, Ekberg R, Eidelberg D, Moeller JR, Dhawan V, Spetsieris P, Takikawa S, Ishikawa T, Johansson F, Johnels B, Meyerson BA, N’Guyen JP, Pinter M, Chaly T, Robeson W, Margouleff D, Przedborski S. The metabolic Pollak P, von Raison F, Rehncrona S, Speelman JD, Sydow O, topography of parkinsonism. J Cereb Blood Flow Metab 1994; 14: Benabid AL. Multicentre European study of thalamic stimulation for 783–801. parkinsonian tremor: a 6 year follow-up. J Neurol Neurosurg Elble R, Koller W. Tremor. Baltimore, United States: Johns Hopkins Psychiatry 2008; 79: 694–9. University Press; 1990. Hayes AE, Davidson MC, Keele SW, Rafal RD. Toward a functional ana- Elble RJ. Central mechanisms of tremor. J Clin Neurophysiol 1996; 13: lysis of the basal ganglia. J Cogn Neurosci 1998; 10: 178–98. 133–44. Helmich RC, Aarts E, de Lange FP, Bloem BR, Toni I. Increased depend- Elble RJ. Tremor and dopamine agonists. Neurology 2002; 58: S57–S62. ence of action selection on recent motor history in Parkinson’s disease. Engel AK, Fries P. Beta-band oscillations - signalling the status quo? Curr J Neurosci 2009; 29: 6105–13. Opin Neurobiol 2010; 20: 156–65. Helmich RC, Bloem BR, Toni I. Motor imagery evokes increased somato- Fahn S. Classiﬁcation of movement disorders. Mov Disord 2011; 26: sensory activity in parkinson’s disease patients with tremor. Hum 947–57. Brain Mapp 2011a. Advance Access published on June 14, 2011, Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra doi:10.1002/hbm.21318. regional selectivity. Brain 1991; 114 (Pt 5): 2283–301. Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunc- Filion M, Tremblay L, Bedard PJ. Abnormal inﬂuences of passive limb tion drives a cerebellothalamic circuit into Parkinson tremor. Ann movement on the activity of globus pallidus neurons in parkinsonian Neurol 2011b; 69: 269–81. monkeys. Brain Res 1988; 444: 165–76. Hirai T, Jones EG. A new parcellation of the human thalamus on the basis Fishman PS. Paradoxical aspects of parkinsonian tremor. Mov Disord of histochemical staining. Brain Res Brain Res Rev 1989; 14: 1–34. 2008; 23: 168–73. Hirsch EC, Mouatt A, Faucheux B, Bonnet AM, Javoy-Agid F, Fonnum F, Stormmathisen J, Divac I. Biochemical-evidence for glutamate Graybiel AM, Agid Y. Dopamine, tremor, and Parkinson’s disease. as neurotransmitter in corticostriatal and corticothalamic ﬁbers in Lancet 1992; 340: 125–6. rat-brain. Neuroscience 1981; 6: 863–73. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Forsaa EB, Larsen JP, Wentzel-Larsen T, Alves G. What predicts mortality Neurology 1967; 17: 427–42. in Parkinson disease?: a prospective population-based long-term study. Homberg V, Hefter H, Reiners K, Freund HJ. Differential effects Neurology 2010; 75: 1270–76. of changes in mechanical limb properties on physiological and Fraix V, Pollak P, Moro E, Chabardes S, Xie J, Ardouin C, Benabid AL. pathological tremor. J Neurol Neurosurg Psychiatry 1987; 50: Subthalamic nucleus stimulation in tremor dominant parkinsonian pa- 568–79. tients with previous thalamic surgery. J Neurol Neurosurg Psychiatry Hoover JE, Strick PL. The organization of cerebellar and basal ganglia 2005; 76: 246–8. outputs to primary motor cortex as revealed by retrograde transneur- Francois C, Savy C, Jan C, Tande D, Hirsch EC, Yelnik J. Dopaminergic onal transport of herpes simplex virus type 1. J Neurosci 1999; 19: innervation of the subthalamic nucleus in the normal state, in 1446–163. MPTP-treated monkeys, and in Parkinson’s disease patients. J Comp Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic study of Neurol 2000; 425: 121–9. 100 cases of Parkinson’s disease. Arch Neurol 1993; 50: 140–8. Francois C, Yelnik J, Tande D, Agid Y, Hirsch EC. Dopaminergic cell Hurtado JM, Gray CM, Tamas LB, Sigvardt KA. Dynamics of group A8 in the monkey: anatomical organization and projections to tremor-related oscillations in the human globus pallidus: a single case the striatum. J Comp Neurol 1999; 414: 334–47. study. Proc Natl Acad Sci U S A 1999; 96: 1674–79. Fukuda M, Barnes A, Simon ES, Holmes A, Dhawan V, Giladi N, Hurtado JM, Lachaux JP, Beckley DJ, Gray CM, Sigvardt KA. Inter- and Fodstad H, Ma Y, Eidelberg D. Thalamic stimulation for parkinsonian intralimb oscillator coupling in parkinsonian tremor. Mov Disord 2000; tremor: correlation between regional cerebral blood ﬂow and physio- 15: 683–91. logical tremor characteristics. Neuroimage 2004; 21: 608–15. Isaias IU, Benti R, Cilia R, Canesi M, Marotta G, Gerundini P, Pezzoli G, Gao JB. Analysis of amplitude and frequency variations of essential and Antonini A. [123I]FP-CIT striatal binding in early Parkinson’s disease Parkinsonian tremors. Med Biol Eng Comput 2004; 42: 345–9. patients with tremor vs. akinetic-rigid onset. Neuroreport 2007; 18: German DC, Dubach M, Askari S, Speciale SG, Bowden DM. 1499–502. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian Jahnsen H, Llinas R. Ionic basis for the electro-responsiveness and oscil- syndrome in Macaca fascicularis: which midbrain dopaminergic neu- latory properties of guinea-pig thalamic neurones in vitro. J Physiol rons are lost? Neuroscience 1988; 24: 161–74. 1984; 349: 227–47. Ghaemi M, Raethjen J, Hilker R, Rudolf J, Sobesky J, Deuschl G, Jan C, Francois C, Tande D, Yelnik J, Tremblay L, Agid Y, Hirsch E. Heiss WD. Monosymptomatic resting tremor and Parkinson’s disease: Dopaminergic innervation of the pallidum in the normal state, in a multitracer positron emission tomographic study. Mov Disord 2002; MPTP-treated monkeys and in parkinsonian patients. Eur J Neurosci 17: 782–8. 2000; 12: 4525–35. 3224 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Jankovic J, Kapadia AS. Functional decline in Parkinson disease. Arch Landisman CE, Connors BW. VPM and PoM nuclei of the rat somato- Neurol 2001; 58: 1611–5. sensory thalamus: intrinsic neuronal properties and corticothalamic Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, feedback. Cereb Cortex 2007; 17: 2853–65. Huber S, Koller W, Olanow C, Shoulson I. Variable expression of Lee RG, Stein RB. Resetting of tremor by mechanical perturbations: a Parkinson’s disease: a base-line analysis of the DATATOP cohort. comparison of essential tremor and parkinsonian tremor. Ann Neurol The Parkinson Study Group. Neurology 1990; 40: 1529–34. 1981; 10: 523–31. Jankovic J, Schwartz KS, Ondo W. Re-emergent tremor of Parkinson’s Lees AJ. Unresolved issues relating to the shaking palsy on the celebra- disease. J Neurol Neurosurg Psychiatry 1999; 67: 646–50. tion of James Parkinson’s 250th birthday. Mov Disord 2007; 22 (Suppl Jellinger KA. Post mortem studies in Parkinson’s disease—is it possible to 17): S327–34. detect brain areas for speciﬁc symptoms? J Neural Transm 1999; 56 Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009; 373: (Suppl): 1–29. 2055–66. Jenkinson N, Brown P. New insights into the relationship between dopa- Lenz FA, Kwan HC, Martin RL, Tasker RR, Dostrovsky JO, Lenz YE. mine, beta oscillations and motor function. Trends Neurosci 2011; 34 Single unit analysis of the human ventral thalamic nuclear group. (12): 611–8. Tremor-related activity in functionally identiﬁed cells. Brain 1994; Kassubek J, Juengling FD, Hellwig B, Knauff M, Spreer J, Lucking CH. 117 (Pt 3): 531–43. Hypermetabolism in the ventrolateral thalamus in unilateral Lenz FA, Tasker RR, Kwan HC, Schnider S, Kwong R, Murayama Y, Parkinsonian resting tremor: a positron emission tomography study. Dostrovsky JO, Murphy JT. Single unit analysis of the human ventral Neurosci Lett 2001; 304: 17–20. thalamic nuclear group: correlation of thalamic "tremor cells" with the Kassubek J, Juengling FD, Hellwig B, Spreer J, Lucking CH. Thalamic gray 3-6 Hz component of parkinsonian tremor. J Neurosci 1988; 8: matter changes in unilateral Parkinsonian resting tremor: a voxel-based 754–64. morphometric analysis of 3-dimensional magnetic resonance imaging. Leu-Semenescu S, Roze E, Vidailhet M, Legrand AP, Trocello JM, Neurosci Lett 2002; 323: 29–32. Cochen V, Sangla S, Apartis E. Myoclonus or tremor in orthostatism: Kim DG, Koo YH, Kim OJ, Oh SH. Development of Holmes’ tremor in a an under-recognized cause of unsteadiness in Parkinson’s disease. Mov patient with Parkinson’s disease following acute cerebellar infarction. Disord 2007; 22: 2063–9. Mov Disord 2009; 24: 463–4. Levy R, Hutchison WD, Lozano AM, Dostrovsky JO. High-frequency Kim HJ, Jeon BS, Paek SH, Lee JY, Kim HJ, Kim CK, Kim DG. Bilateral synchronization of neuronal activity in the subthalamic nucleus subthalamic deep brain stimulation in Parkinson disease patients with of parkinsonian patients with limb tremor. J Neurosci 2000; 20: severe tremor. Neurosurgery 2010; 67: 626–32. 7766–75. Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss Levy R, Hutchison WD, Lozano AM, Dostrovsky JO. Synchronized neur- in the striatum of patients with idiopathic Parkinson’s disease. onal discharge in the basal ganglia of parkinsonian patients is limited Pathophysiologic and clinical implications. N Engl J Med 1988; 318: to oscillatory activity. J Neurosci 2002; 22: 2855–61. 876–80. Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Kloppel S, Mangin JF, Vongerichten A, Frackowiak RSJ, Siebner HR. Heterogeneity of Parkinson’s disease in the early clinical stages using a Nurture versus nature: long-term impact of forced right-handedness data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343–8. on structure of pericentral cortex and basal ganglia. J Neurosci 2010; Llinas R, Urbano FJ, Leznik E, Ramirez RR, van Marle HJ. Rhythmic and 30: 3271–75. dysrhythmic thalamocortical dynamics: GABA systems and the edge Koh SB, Kwon DY, Seo WK, Kim JH, Kim JH, Lee SH, Oh K, Kim BJ, effect. Trends Neurosci 2005; 28: 325–33. Park KW. Dissociation of cardinal motor signs in Parkinson’s disease Llinas RR. The intrinsic electrophysiological properties of mammalian patients. Eur Neurol 2010; 63: 307–10. neurons: insights into central nervous system function. Science 1988; Koller WC, Busenbark K, Miner K. The relationship of essential tremor to 242: 1654–64. other movement disorders: report on 678 patients. Essential Tremor Lo RY, Tanner CM, Albers KB, Leimpeter AD, Fross RD, Bernstein AL, Study Group. Ann Neurol 1994; 35: 717–23. McGuire V, Quesenberry CP, Nelson LM, Van Den Eeden SK. Clinical Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, features in early Parkinson disease and survival. Arch Neurol 2009; 66: Koudsie A, Limousin PD, Benazzouz A, LeBas JF, Benabid AL, 1353–8. Pollak P. Five-year follow-up of bilateral stimulation of the subthalamic Louis ED, Frucht SJ. Prevalence of essential tremor in patients with nucleus in advanced Parkinson’s disease. N Engl J Med 2003; 349: Parkinson’s disease vs. Parkinson-plus syndromes. Mov Disord 2007; 1925–34. 22: 1402–7. Krack P, Dostrovsky J, Ilinsky I, Kultas-Ilinsky K, Lenz F, Lozano A, Louis ED, Levy G, Cote LJ, Mejia H, Fahn S, Marder K. Clinical correlates Vitek J. Surgery of the motor thalamus: problems with the present of action tremor in Parkinson disease. Arch Neurol 2001; 58: 1630–4. nomenclatures. Mov Disord 2002; 17 (Suppl 3): S2–S8. Louis ED, Pullman SL, Eidelberg D, Dhawan V. Re-emergent tremor Krack P, Pollak P, Limousin P, Benazzouz A, Benabid AL. Stimulation of without accompanying rest tremor in Parkinson’s disease. Can J subthalamic nucleus alleviates tremor in Parkinson’s disease. Lancet Neurol Sci 2008; 35: 513–5. 1997; 350: 1675. Louis ED, Tang MX, Cote L, Alfaro B, Mejia H, Marder K. Progression Kuhn AA, Kupsch A, Schneider GH, Brown P. Reduction in sub- of parkinsonian signs in Parkinson disease. Arch Neurol 1999; 56: thalamic 8-35 Hz oscillatory activity correlates with clinical 334–7. improvement in Parkinson’s disease. Eur J Neurosci 2006; 23: Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, 1956–60. Hutchinson WD, Dostrovsky JO. Effect of GPi pallidotomy on motor Kuhn AA, Williams D, Kupsch A, Limousin P, Hariz M, Schneider GH, function in Parkinson’s disease. Lancet 1995; 346: 1383–7. Yarrow K, Brown P. Event-related beta desynchronization in human Magnin M, Morel A, Jeanmonod D. Single-unit analysis of the pallidum, subthalamic nucleus correlates with motor performance. Brain 2004; thalamus and subthalamic nucleus in parkinsonian patients. 127: 735–46. Neuroscience 2000; 96: 549–64. Kultas-Ilinsky K, Sivan-Loukianova E, Ilinsky IA. Reevaluation of the pri- McAuley JH, Marsden CD. Physiological and pathological tremors and mary motor cortex connections with the thalamus in primates. J Comp rhythmic central motor control. Brain 2000; 123 (Pt 8): 1545–67. Neurol 2003; 457: 133–58. Mink JW. The basal ganglia: focused selection and inhibition of compet- Kumar R, Lozano AM, Kim YJ, Hutchison WD, Sime E, Halket E, ing motor programs. Prog Neurobiol 1996; 50: 381–425. Lang AE. Double-blind evaluation of subthalamic nucleus deep brain Moran A, Bergman H, Israel Z, Bar-Gad I. Subthalamic nucleus functional stimulation in advanced Parkinson’s disease. Neurology 1998; 51: organization revealed by parkinsonian neuronal oscillations and syn- 850–5. chrony. Brain 2008; 131: 3395–409. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3225 Moran RJ, Mallet N, Litvak V, Dolan RJ, Magill PJ, Friston KJ, Brown P. Rajput AH, Pahwa R, Pahwa P, Rajput A. Prognostic signiﬁcance of the Alterations in brain connectivity underlying beta oscillations in onset mode in parkinsonism. Neurology 1993; 43: 829–30. Rajput AH, Sitte HH, Rajput A, Fenton ME, Piﬂ C, Hornykiewicz O. Parkinsonism. Plos Comput Biol 2011; 7: e1002124. Mounayar S, Boulet S, Tande D, Jan C, Pessiglione M, Hirsch EC, Feger J, Globus pallidus dopamine and Parkinson motor subtypes: clinical and Savasta M, Francois C, Tremblay L. A new model to study compen- brain biochemical correlation. Neurology 2008; 70: 1403–10. satory mechanisms in MPTP-treated monkeys exhibiting recovery. Rajput AH, Voll A, Rajput ML, Robinson CA, Rajput A. Course in Brain 2007; 130: 2898–914. Parkinson disease subtypes: a 39-year clinicopathologic study. Mure H, Hirano S, Tang CC, Isaias IU, Antonini A, Ma Y, Dhawan V, Neurology 2009; 73: 206–12. Eidelberg D. Parkinson’s disease tremor-related metabolic network: Rascol O, Sabatini U, Fabre N, Brefel C, Loubinoux I, Celsis P, characterization, progression, and treatment effects. Neuroimage Senard JM, Montastruc JL, Chollet F. The ipsilateral cerebellar hemi- 2011; 54: 1244–53. sphere is overactive during hand movements in akinetic parkinsonian Nambu A, Tokuno H, Hamada I, Kita H, Imanishi M, Akazawa T, patients. Brain 1997; 120: 103–10. Ikeuchi Y, Hasegawa N. Excitatory cortical inputs to pallidal neurons Raz A, Vaadia E, Bergman H. Firing patterns and correlations of spon- via the subthalamic nucleus in the monkey. J Neurophysiol 2000; 84: taneous discharge of pallidal neurons in the normal and the tremulous 289–300. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine vervet model of parkin- Ni Z, Pinto AD, Lang AE, Chen R. Involvement of the cerebello- sonism. J Neurosci 2000; 20: 8559–71. thalamocortical pathway in Parkinson disease. Ann Neurol 2010; 68: Reck C, Florin E, Wojtecki L, Krause H, Groiss S, Voges J, Maarouf M, 816–24. Sturm V, Schnitzler A, Timmermann L. Characterisation of Ohye C, Shibazaki T, Hirai T, Wada H, Hirato M, Kawashima Y. Further tremor-associated local ﬁeld potentials in the subthalamic nucleus in Physiological observations on the ventralis intermedius neurons in the Parkinson’s disease. Eur J Neurosci 2009; 29: 599–612. human thalamus. J Neurophysiol 1989; 61: 488–500. Rehncrona S, Johnels B, Widner H, Tornqvist AL, Hariz M, Sydow O. Oiwa Y, Eberling JL, Nagy D, Pivirotto P, Emborg ME, Bankiewicz KS. Long-term efﬁcacy of thalamic deep brain stimulation for tremor: Overlesioned hemiparkinsonian non human primate model: correlation double-blind assessments. Mov Disord 2003; 18: 163–70. between clinical, neurochemical and histochemical changes. Front Remy P, de Recondo A, Defer G, Loc’h C, Amarenco P, Plante- Biosci 2003; 8: a155–66. Bordeneuve V, Dao-Castellana MH, Bendriem B, Crouzel C, Owen AM, Doyon J, Dagher A, Sadikot A, Evans AC. Abnormal basal Clanet M. Peduncular ’rubral’ tremor and dopaminergic denervation: ganglia outﬂow in Parkinson’s disease identiﬁed with PET. Implications a PET study. Neurology 1995; 45: 472–7. for higher cortical functions. Brain 1998; 121 (Pt 5): 949–65. Rivlin-Etzion M, Elias S, Heimer G, Bergman H. Computational physi- Pare D, Curro’Dossi R, Steriade M. Neuronal basis of the parkinsonian ology of the basal ganglia in Parkinson’s disease. Prog Brain Res resting tremor: a hypothesis and its implications for treatment. 2010; 183: 259–73. Neuroscience 1990; 35: 217–26. Rivlin-Etzion M, Marmor O, Heimer G, Raz A, Nini A, Bergman H. Basal Paulus W, Jellinger K. The neuropathologic basis of different clinical sub- ganglia oscillations and pathophysiology of movement disorders. Curr groups of Parkinson’s disease. J Neuropathol Exp Neurol 1991; 50: Opin Neurobiol 2006; 16: 629–37. 743–55. Rivlin-Etzion M, Marmor O, Saban G, Rosin B, Haber SN, Vaadia E, Percheron G, Francois C, Talbi B, Yelnik J, Fenelon G. The primate motor Prut Y, Bergman H. Low-pass ﬁlter properties of basal ganglia cortical thalamus. Brain Res Brain Res Rev 1996; 22: 93–181. muscle loops in the normal and MPTP primate model of parkinsonism. Pessiglione M, Guehl D, Rolland AS, Francois C, Hirsch EC, Feger J, J Neurosci 2008; 28: 633–49. Tremblay L. Thalamic neuronal activity in dopamine-depleted primates: Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, evidence for a loss of functional segregation within basal ganglia cir- Bezard E, Obeso JA. Initial clinical manifestations of Parkinson’s dis- cuits. J Neurosci 2005; 25: 1523–31. ease: features and pathophysiological mechanisms. Lancet Neurol Pirker W. Correlation of dopamine transporter imaging with parkinsonian 2009; 8: 1128–39. motor handicap: how close is it? Mov Disord 2003; 18 (Suppl 7): Ropper AH, Samuels MA. Adams & Victor’s principles of neurology. S43–S51. 9 edn. McGraw-Hill Medical; 2009. p. 93. Plaha P, Ben Shlomo Y, Patel NK, Gill SS. Stimulation of the caudal zona Rosin B, Slovik M, Mitelman R, Rivlin-Etzion M, Haber SN, Israel Z, incerta is superior to stimulation of the subthalamic nucleus in improv- Vaadia E, Bergman H. Closed-loop deep brain stimulation is superior in ameliorating parkinsonism. Neuron 2011; 72: 370–84. ing contralateral parkinsonism. Brain 2006; 129: 1732–47. Rossi C, Frosini D, Volterrani D, De Feo P, Unti E, Nicoletti V, Kiferle L, Plaha P, Filipovic S, Gill SS. Induction of parkinsonian resting tremor by Bonuccelli U, Ceravolo R. Differences in nigro-striatal impairment in stimulation of the caudal zona incerta nucleus: a clinical study. clinical variants of early Parkinson’s disease: evidence from a FP-CIT J Neurol Neurosurg Psychiatry 2008; 79: 514–21. Plenz D, Kital ST. A basal ganglia pacemaker formed by the subthalamic SPECT study. Eur J Neurol 2010; 17: 626–30. Rouiller EM, Tanne J, Moret V, Kermadi I, Boussaoud D, Welker E. Dual nucleus and external globus pallidus. Nature 1999; 400: 677–82. Pollak P, Krack P, Fraix V, Mendes A, Moro E, Chabardes S, morphology and topography of the corticothalamic terminals originat- Benabid AL. Intraoperative micro- and macrostimulation of the ing from the primary, supplementary motor, and dorsal premotor cor- subthalamic nucleus in Parkinson’s disease. Mov Disord 2002; 17 tical areas in macaque monkeys. J Comparative Neurol 1998; 396: (Suppl 3): S155–61. 169–85. Pollock LJ, Davis L. Muscle tone in parkinsonian states. Arch Neurol Sanchez-Gonzalez MA, Garcia-Cabezas MA, Rico B, Cavada C. The pri- Psychiatry 1930; 23: 303–19. mate thalamus is a key target for brain dopamine. J Neurosci 2005; Pollok B, Makhlouﬁ H, Butz M, Gross J, Timmermann L, Wojtecki L, 25: 6076–83. Schnitzler A. Levodopa affects functional brain networks in parkinso- Schiess MC, Zheng H, Soukup VM, Bonnen JG, Nauta HJ. Parkinson’s nian resting tremor. Mov Disord 2009; 24: 91–8. disease subtypes: clinical classiﬁcation and ventricular cerebrospinal Probst-Cousin S, Druschky A, Neundorfer B. Disappearance of resting ﬂuid analysis. Parkinsonism Relat Disord 2000; 6: 69–76. tremor after "stereotaxic" thalamic stroke. Neurology 2003; 61: Schneider SA, Edwards MJ, Mir P, Cordivari C, Hooker J, Dickson J, 1013–4. Quinn N, Bhatia KP. Patients with adult-onset dystonic tremor resem- Rack PM, Ross HF. The role of reﬂexes in the resting tremor of bling parkinsonian tremor have scans without evidence of dopamin- Parkinson’s disease. Brain 1986; 109 (Pt 1): 115–41. ergic deﬁcit (SWEDDs). Mov Disord 2007; 22: 2210–5. Raethjen J, Lindemann M, Schmaljohann H, Wenzelburger R, Pﬁster G, Seidel S, Kasprian G, Leutmezer F, Prayer D, Auff E. Disruption of nigros- Deuschl G. Multiple oscillators are causing parkinsonian and essential triatal and cerebellothalamic pathways in dopamine responsive tremor. Mov Disord 2000; 15: 84–94. Holmes’ tremor. J Neurol Neurosurg Psychiatry 2009; 80: 921–3. 3226 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Selikhova M, Williams DR, Kempster PA, Holton JL, Revesz T, Lees AJ. A Vidailhet M, Dupel C, Lehericy S, Remy P, Dormont D, Serdaru M, clinico-pathological study of subtypes in Parkinson’s disease. Brain Jedynak P, Veber H, Samson Y, Marsault C, Agid Y. Dopaminergic 2009; 132: 2947–57. dysfunction in midbrain dystonia: anatomoclinical study using Sidibe M, Bevan MD, Bolam JP, Smith Y. Efferent connections of the 3-dimensional magnetic resonance imaging and ﬂuorodopa F 18 posi- internal globus pallidus in the squirrel monkey: I. Topography and tron emission tomography. Arch Neurol 1999; 56: 982–9. synaptic organization of the pallidothalamic projection. J Comp Wallman MJ, Gagnon D, Parent M. Serotonin innervation of human Neurol 1997; 382: 323–47. basal ganglia. Eur J Neurosci 2011; 33: 1519–32. Smith Y, Lavoie B, Dumas J, Parent A. Evidence for a distinct nigropallidal Walshe FMR. Observations on the nature of muscular rigidity of paralysis dopaminergic projection in the squirrel monkey. Brain Res 1989; 482: agitans, and on its relationship to tremor. Brain 1924; 47: 159–77. 381–6. Wang SY, Aziz TZ, Stein JF, Liu X. Time-frequency analysis of transient Spiegel J, Hellwig D, Samnick S, Jost W, Mollers MO, Fassbender K, neuromuscular events: dynamic changes in activity of the subthalamic Kirsch CM, Dillmann U. Striatal FP-CIT uptake differs in the nucleus and forearm muscles related to the intermittent resting tremor. subtypes of early Parkinson’s disease. J Neural Transm 2007; 114: J Neurosci Methods 2005; 145: 151–8. 331–5. Williams-Gray CH, Evans JR, Goris A, Foltynie T, Ban M, Robbins TW, Sung YF, Hsu YD, Huang WS. (99m)Tc-TRODAT-1 SPECT study in Brayne C, Kolachana BS, Weinberger DR, Sawcer SJ, Barker RA. The evaluation of Holmes tremor after thalamic hemorrhage. Ann Nucl distinct cognitive syndromes of Parkinson’s disease: 5 year follow-up Med 2009; 23: 605–8. of the CamPaIGN cohort. Brain 2009; 132: 2958–69. Timmermann L, Gross J, Dirks M, Volkmann J, Freund HJ, Schnitzler A. Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. The cerebral oscillatory network of parkinsonian resting tremor. Brain Evolution of cognitive dysfunction in an incident Parkinson’s disease 2003; 126: 199–212. cohort. Brain 2007; 130: 1787–98. Toth C, Rajput M, Rajput AH. Anomalies of asymmetry of clinical signs in Wu D, Warwick K, Ma Z, Gasson MN, Burgess JG, Pan S, Aziz TZ. parkinsonism. Mov Disord 2004; 19: 151–7. Prediction of Parkinson’s disease tremor onset using a radial basis Vakil E, Herishanu-Naaman S. Declarative and procedural learning in function neural network based on particle swarm optimization. Int J Parkinson’s disease patients having tremor or bradykinesia as the pre- Neural Syst 2010a; 20: 109–116. dominant symptom. Cortex 1998; 34: 611–20. Wu T, Wang LA, Hallett M, Li KC, Chan P. Neural correlates of bimanual Valls-Sole J, Pascualleone A, Brasilneto JP, Cammarota A, Mcshane L, anti-phase and in-phase movements in Parkinson’s disease. Brain Hallett M. Abnormal facilitation of the response to transcranial mag- 2010b; 133: 2394–409. netic stimulation in patients with Parkinsons-disease. Neurology 1994; Yu H, Sternad D, Corcos DM, Vaillancourt DE. Role of hyperactive cere- 44: 735–41. bellum and motor cortex in Parkinson’s disease. Neuroimage 2007; 35: van Duinen H, Zijdewind I, Hoogduin H, Maurits N. Surface EMG meas- 222–33. urements during fMRI at 3T: accurate EMG recordings after artifact Zaidel A, Arkadir D, Israel Z, Bergman H. Akineto-rigid vs. tremor syn- correction. Neuroimage 2005; 27: 240–6. dromes in Parkinsonism. Curr Opin Neurol 2009; 22: 387–93. Van Quyen M, Bragin A. Analysis of dynamic brain oscillations: meth- Zetusky WJ, Jankovic J, Pirozzolo FJ. The heterogeneity of Parkinson’s odological advances. Trends Neurosci 2007; 30: 365–73. disease: clinical and prognostic implications. Neurology 1985; 35: van Rootselaar AF, Maurits NM, Renken R, Koelman JH, Hoogduin JM, 522–6. Leenders KL, Tijssen MA. Simultaneous EMG-functional MRI record- Zirh TA, Lenz FA, Reich SG, Dougherty PM. Patterns of bursting occur- ings can directly relate hyperkinetic movements to brain activity. Hum ring in thalamic cells during parkinsonian tremor. Neuroscience 1998; Brain Mapp 2008; 29: 1430–41. 83: 107–21. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Pubmed Central http://www.deepdyve.com/lp/pubmed-central/cerebral-causes-and-consequences-of-parkinsonian-resting-tremor-a-tale-gsAwcczPwa

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References (197)

J. Hurtado, J. Lachaux, D. Beckley, C. Gray, K. Sigvardt (2000)
Inter‐ and intralimb oscillator coupling in Parkinsonian tremor
Movement Disorders, 15
E. Louis, S. Pullman, D. Eidelberg, V. Dhawan (2008)
Re-Emergent Tremor without Accompanying Rest Tremor in Parkinson’s Disease
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 35
M. Schiess, H. Zheng, V. Soukup, J. Bonnen, H. Nauta (2000)
Parkinson's disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis.
Parkinsonism & related disorders, 6 2
G. Percheron, C. François, B. Talbi, J. Yelnik, G. Fénelon (1996)
The primate motor thalamus
Brain Research Reviews, 22
C. Williams-Gray, T. Foltynie, C. Brayne, T. Robbins, R. Barker (2007)
Evolution of cognitive dysfunction in an incident Parkinson's disease cohort.
Brain : a journal of neurology, 130 Pt 7
P. Plaha, Saša Filipović, Steven Gill (2007)
Induction of parkinsonian resting tremor by stimulation of the caudal zona incerta nucleus: a clinical study
Journal of Neurology, Neurosurgery, and Psychiatry, 79
A. Kühn, David Williams, A. Kupsch, P. Limousin, M. Hariz, G. Schneider, K. Yarrow, P. Brown (2004)
Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance.
Brain : a journal of neurology, 127 Pt 4
R. Elble (2002)
Tremor and dopamine agonists
Neurology, 58
(2009)
Parkinson's disease
Lancet, 373
C. Toth, Michelle Rajput, A. Rajput (2004)
Anomalies of asymmetry of clinical signs in parkinsonism
Movement Disorders, 19
R. Lo, C. Tanner, K. Albers, A. Leimpeter, R. Fross, A. Bernstein, V. Mcguire, C. Quesenberry, Lorene Nelson, S. Eeden (2009)
Clinical features in early Parkinson disease and survival.
Archives of neurology, 66 11
D. Eidelberg, J. Moeller, V. Dhawan, P. Spetsieris, S. Takikawa, T. Ishikawa, T. Chaly, W. Robeson, D. Margouleff, S. Przedborski, S. Fahn (1994)
The Metabolic Topography of Parkinsonism
Journal of Cerebral Blood Flow & Metabolism, 14
A. Engel, P. Fries (2010)
Beta-band oscillations—signalling the status quo?
Current Opinion in Neurobiology, 20
P. Fishman (2008)
Paradoxical aspects of parkinsonian tremor
Movement Disorders, 23
E. Louis, Gilberto Levy, L. Cote, H. Mejia, S. Fahn, K. Marder (2001)
Clinical correlates of action tremor in Parkinson disease.
Archives of neurology, 58 10
S. Starkstein, G. Petracca, E. Chemerinski, A. Tesón, L. Sabe, M. Merello, R. Leiguarda (1998)
Depression in classic versus akinetic‐rigid Parkinson's disease
Movement Disorders, 13
J. Fearnley, A. Lees (1991)
Ageing and Parkinson's disease: substantia nigra regional selectivity.
Brain : a journal of neurology, 114 ( Pt 5)
P. Krack, P. Pollak, P. Limousin, A. Benazzouz, A. Benabid (1997)
Stimulation of subthalamic nucleus alleviates tremor in Parkinson's disease
The Lancet, 350
J. Gao (2004)
Analysis of amplitude and frequency variations of essential and Parkinsonian tremors
Medical and Biological Engineering and Computing, 42
P. Plaha, Y. Ben-Shlomo, N. Patel, S. Gill (2006)
Stimulation of the caudal zona incerta is superior to stimulation of the subthalamic nucleus in improving contralateral parkinsonism.
Brain : a journal of neurology, 129 Pt 7
G. Deuschl, P. Bain, M. Brin (2008)
Consensus Statement of the Movement Disorder Society on Tremor
Movement Disorders, 13
H. Duinen, I. Zijdewind, J. Hoogduin, N. Maurits (2005)
Surface EMG measurements during fMRI at 3T: Accurate EMG recordings after artifact correction
NeuroImage, 27
J. Jankovic, A. Kapadia (2001)
Functional decline in Parkinson disease.
Archives of neurology, 58 10
A. Antonini, J. Moeller, T. Nakamura, P. Spetsieris, V. Dhawan, D. Eidelberg (1998)
The metabolic anatomy of tremor in Parkinson's disease
Neurology, 51
H. Blumenfeld, D. McCormick (2000)
Corticothalamic Inputs Control the Pattern of Activity Generated in Thalamocortical Networks
The Journal of Neuroscience, 20
C. Hammond, H. Bergman, P. Brown (2007)
Pathological synchronization in Parkinson's disease: networks, models and treatments
Trends in Neurosciences, 30
J. Kassubek, Freimut Jüngling, B. Hellwig, J. Spreer, C. Lücking (2002)
Thalamic gray matter changes in unilateral Parkinsonian resting tremor: a voxel-based morphometric analysis of 3-dimensional magnetic resonance imaging
Neuroscience Letters, 323
J. Hoover, P. Strick (1999)
The Organization of Cerebellar and Basal Ganglia Outputs to Primary Motor Cortex as Revealed by Retrograde Transneuronal Transport of Herpes Simplex Virus Type 1
The Journal of Neuroscience, 19
A. Hayes, M. Davidson, S. Keele, R. Rafal (1998)
Toward a Functional Analysis of the Basal Ganglia
Journal of Cognitive Neuroscience, 10
Denis Paré, R. CurróDossi, M. Steriade (1990)
Neuronal basis of the parkinsonian resting tremor: A hypothesis and its implications for treatment
Neuroscience, 35
D. Plenz, Stephen Kital (1999)
A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus
Nature, 400
A. Moran, H. Bergman, Z. Israel, I. Bar-Gad (2008)
Subthalamic nucleus functional organization revealed by parkinsonian neuronal oscillations and synchrony.
Brain : a journal of neurology, 131 Pt 12
C. Jan, C. François, Dominique Tandé, J. Yelnik, L. Tremblay, Y. Agid, E. Hirsch (2000)
Dopaminergic innervation of the pallidum in the normal state, in MPTP‐treated monkeys and in parkinsonian patients
European Journal of Neuroscience, 12
N. Crone, Diana Miglioretti, B. Gordon, J. Sieracki, Michael Wilson, S. Uematsu, R. Lesser (1998)
Functional mapping of human sensorimotor cortex with electrocorticographic spectral analysis. I. Alpha and beta event-related desynchronization.
Brain : a journal of neurology, 121 ( Pt 12)
M. Rodriguez-Oroz, M. Jahanshahi, P. Krack, I. Litvan, R. Macias, E. Bézard, J. Obeso (2009)
Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms
The Lancet Neurology, 8
F. Fonnum, J. Storm-Mathisen, I. Divac (1981)
Biochemical evidence for glutamate as neurotransmitter in corticostriatal and corticothalamic fibres in rat brain
Neuroscience, 6
A. Ropper, M. Samuels (2009)
Comprar Adams and Victor's Principles of Neurology | Allan Ropper | 9780071499927 | Mcgraw-Hill Education
Shouyan Wang, T. Aziz, J. Stein, Xuguang Liu (2005)
Time–frequency analysis of transient neuromuscular events: dynamic changes in activity of the subthalamic nucleus and forearm muscles related to the intermittent resting tremor
Journal of Neuroscience Methods, 145
S. Koh, D. Kwon, W. Seo, Ji Kim, Jong Kim, Seung-Hwan Lee, Kyungmi Oh, Byung‐Jo Kim, Kun-Woo Park (2010)
Dissociation of Cardinal Motor Signs in Parkinson’s Disease Patients
European Neurology, 63
A. Deutch, J. Elsworth, M. Goldstein, K. Fuxe, D. Redmond, J. Sladek, R. Roth (1986)
Preferential vulnerability of A8 dopamine neurons in the primate to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Neuroscience Letters, 68
A. Benabid, P. Pollak, D. Hoffmann, Gervason Cl, M. Hommel, Jean Perret, J. Rougemont, D. Gao (1991)
Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus
The Lancet, 337
N. Jenkinson, P. Brown (2011)
New insights into the relationship between dopamine, beta oscillations and motor function
Trends in Neurosciences, 34
C. François, J. Yelnik, Dominique Tandé, Y. Agid, E. Hirsch (1999)
Dopaminergic cell group A8 in the monkey: Anatomical organization and projections to the striatum
Journal of Comparative Neurology, 414
Defeng Wu, K. Warwick, Zi Ma, M. Gasson, Jonathan Burgess, Song Pan, T. Aziz (2010)
Prediction of Parkinson's Disease tremor Onset Using a Radial Basis Function Neural Network Based on Particle Swarm Optimization
International journal of neural systems, 20 2
A. Lees, J. Hardy, T. Révész (2009)
Parkinson's disease (vol 373, pg 2055, 2009)
The Lancet
V. Caretti, D. Stoffers, A. Winogrodzka, I. Isaias, G. Costantino, G. Pezzoli, C. Ferrarese, A. Antonini, E. Wolters, J. Booij (2008)
Loss of thalamic serotonin transporters in early drug-naïve Parkinson’s disease patients is associated with tremor: an [123I]β-CIT SPECT study
Journal of Neural Transmission, 115
Byhenrik Jahnsen, Rodolfo Llinás (1984)
Ionic basis for the electro‐responsiveness and oscillatory properties of guinea‐pig thalamic neurones in vitro.
The Journal of Physiology, 349
C. Williams-Gray, J. Evans, A. Goris, T. Foltynie, M. Ban, T. Robbins, C. Brayne, B. Kolachana, D. Weinberger, S. Sawcer, R. Barker (2009)
The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort.
Brain : a journal of neurology, 132 Pt 11
A. Raz, E. Vaadia, H. Bergman (2000)
Firing Patterns and Correlations of Spontaneous Discharge of Pallidal Neurons in the Normal and the Tremulous 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Vervet Model of Parkinsonism
The Journal of Neuroscience, 20
W. Nacimiento (2006)
Parkinson-plus-Syndrome
Fortschritte der Neurologie · Psychiatrie, 74
(1999)
Re-emergent tremor of Parkinson's disease
J Neurol Neurosurg Psychiatry, 67
E. Forsaa, Jan Larsen, Tore Wentzel-Larsen, Guido Alves (2010)
What predicts mortality in Parkinson disease?
Neurology, 75
P. Pollak, P. Krack, V. Fraix, A. Mendes, E. Moro, S. Chabardès, A. Benabid (2002)
Intraoperative micro‐ and macrostimulation of the subthalamic nucleus in Parkinson's disease
Movement Disorders, 17
S. Beck, M. Hallett (2011)
Surround inhibition in the motor system
Experimental Brain Research, 210
J. Spiegel, D. Hellwig, S. Samnick, W. Jost, M. Möllers, K. Fassbender, C. Kirsch, U. Dillmann (2007)
Striatal FP-CIT uptake differs in the subtypes of early Parkinson’s disease
Journal of Neural Transmission, 114
T. Hirai, Edward Jones (1989)
A new parcellation of the human thalamus on the basis of histochemical staining
Brain Research Reviews, 14
Hong Yu, D. Sternad, D. Corcos, D. Vaillancourt (2007)
Role of hyperactive cerebellum and motor cortex in Parkinson's disease
NeuroImage, 35
S. Rehncrona, B. Johnels, H. Widner, A. Törnqvist, M. Hariz, O. Sydow (2003)
Long‐term efficacy of thalamic deep brain stimulation for tremor: Double‐blind assessments
Movement Disorders, 18
J. Jankovic, M. Mcdermott, J. Carter, S. Gauthier, C. Goetz, L. Golbe, S. Huber, W. Koller, C. Olanow, I. Shoulson, M. Stern, C. Tanner, W. Weiner (1990)
Variable expression of Parkinson's disease
Neurology, 40
R. Helmich, Marcel Janssen, W. Oyen, B. Bloem, I. Toni (2011)
Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor
Annals of Neurology, 69
D. Aarsland, K. Andersen, J. Larsen, A. Lolk, P. Kragh‐Sørensen (2003)
Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study.
Archives of neurology, 60 3
S. Kish, K. Shannak, O. Hornykiewicz (1988)
Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications.
The New England journal of medicine, 318 14
M. Selikhova, David Williams, David Williams, P. Kempster, P. Kempster, J. Holton, T. Révész, A. Lees (2009)
A clinico-pathological study of subtypes in Parkinson's disease.
Brain : a journal of neurology, 132 Pt 11
H. Bergman, A. Raz, Ariela Feingold, A. Nini, Israel Nelken, Ben‐Pazi Hilla, D. Hansel, A. Reches (2008)
Physiology of MPTP Tremor
Movement Disorders, 13
W. Paulus, K. Jellinger (1991)
The Neuropathologic Basis of Different Clinical Subgroups of Parkinson's Disease
Journal of Neuropathology and Experimental Neurology, 50
C. Davie (1998)
The role of spectroscopy in parkinsonism
Movement Disorders, 13
W. Zetusky, J. Jankovic, F. Pirozzolo (1985)
The heterogeneity of Parkinson's disease
Neurology, 35
(2006)
Basal ganglia oscillations and pathophysiology of movement disorders
Curr Opin Neurobiol, 16
P. Krack, A. Batir, N. Blercom, S. Chabardès, V. Fraix, C. Ardouin, A. Koudsié, P. Limousin, A. Benazzouz, J. Lebas, A. Benabid, P. Pollak (2003)
Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease.
The New England journal of medicine, 349 20
G. Alves, J. Larsen, M. Emre, T. Wentzel‐Larsen, D. Aarsland (2006)
Changes in motor subtype and risk for incident dementia in Parkinson's disease
Movement Disorders, 21
S. Probst‐Cousin, A. Druschky, B. Neundörfer (2003)
Disappearance of resting tremor after “stereotaxic” thalamic stroke
Neurology, 61
J. Mink (1996)
THE BASAL GANGLIA: FOCUSED SELECTION AND INHIBITION OF COMPETING MOTOR PROGRAMS
Progress in Neurobiology, 50
Y. Oiwa, J. Eberling, D. Nagy, P. Pivirotto, M. Emborg, K. Bankiewicz (2003)
Overlesioned hemiparkinsonian non human primate model: correlation between clinical, neurochemical and histochemical changes.
Frontiers in bioscience : a journal and virtual library, 8
M. Ghaemi, J. Raethjen, R. Hilker, J. Rudolf, J. Sobesky, G. Deuschl, W. Heiss (2002)
Monosymptomatic resting tremor and Parkinson's disease: A multitracer positron emission tomographic study
Movement Disorders, 17
E. Louis, S. Frucht (2007)
Prevalence of essential tremor in patients with Parkinson's disease vs. Parkinson‐plus syndromes
Movement Disorders, 22
J. Raethjen, Michael Lindemann, Holger Schmaljohann, R. Wenzelburger, G. Pfister, G. Deuschl (2000)
Multiple oscillators are causing parkinsonian and essential tremor
Movement Disorders, 15
L. Timmermann, J. Gross, M. Dirks, J. Volkmann, H. Freund, A. Schnitzler (2003)
The cerebral oscillatory network of parkinsonian resting tremor.
Brain : a journal of neurology, 126 Pt 1
M. Sidibé, M. Bevan, J. Bolam, Y. Smith (1997)
Efferent connections of the internal globus pallidus in the squirrel monkey: I. topography and synaptic organization of the pallidothalamic projection
Journal of Comparative Neurology, 382
M. Sánchez-González, M. García-Cabezas, B. Rico, C. Cavada (2005)
The Primate Thalamus Is a Key Target for Brain Dopamine
The Journal of Neuroscience, 25
Jeffrey, D., Atkinson, Louis Collins, G. Bertrand, Terry, M., Peters, G., Bruce Pike, Abbas, F., Sadikot (2002)
Optimal location of thalamotomy lesions for tremor associated with Parkinson disease: a probabilistic analysis based on postoperative magnetic resonance imaging and an integrated digital atlas.
Journal of neurosurgery, 96 5
R. Helmich, E. Aarts, Floris Lange, B. Bloem, I. Toni (2009)
Increased Dependence of Action Selection on Recent Motor History in Parkinson's Disease
The Journal of Neuroscience, 29
Houeto Jean-Luc (2022)
[Parkinson's disease].
La Revue du praticien, 55 10
A. Lees (2007)
Unresolved issues relating to the Shaking Palsy on the celebration of James Parkinson's 250th birthday
Movement Disorders, 22
R. Albin, A. Young, J. Penney (1989)
The functional anatomy of basal ganglia disorders
Trends in Neurosciences, 12
M. Hoehn, M. Yahr (1967)
Parkinsonism
Neurology, 17
M. Hallett, B. Shahani, R. Young (1977)
Analysis of stereotyped voluntary movements at the elbow in patients with Parkinson's disease.
Journal of Neurology, Neurosurgery & Psychiatry, 40
A. Rootselaar, N. Maurits, R. Renken, J. Koelman, J. Hoogduin, K. Leenders, M. Tijssen (2008)
Simultaneous EMG‐functional MRI recordings can directly relate hyperkinetic movements to brain activity
Human Brain Mapping, 29
H. Benamer, W. Oertel, J. Patterson, D. Hadley, O. Pogarell, H. Höffken, A. Gerstner, D. Grosset (2003)
Prospective study of presynaptic dopaminergic imaging in patients with mild parkinsonism and tremor disorders: Part 1. Baseline and 3‐month observations
Movement Disorders, 18
Y. Smith, B. Lavoie, J. Dumas, A. Parent (1989)
Evidence for a distinct nigropallidal dopaminergic projection in the squirrel monkey
Brain Research, 482
M. Rivlin-Etzion, O. Marmor, Guy Saban, B. Rosin, S. Haber, E. Vaadia, Y. Prut, H. Bergman (2008)
Low-Pass Filter Properties of Basal Ganglia–Cortical–Muscle Loops in the Normal and MPTP Primate Model of Parkinsonism
The Journal of Neuroscience, 28
Frederick Lenz, Hon Kwan, R. Martin, Ronald Tasker, J. Dostrovsky, Y. Lenz (1994)
Single unit analysis of the human ventral thalamic nuclear group. Tremor-related activity in functionally identified cells.
Brain : a journal of neurology, 117 ( Pt 3)
K. Kultas‐ilinsky, E. Sivan‐Loukianova, I. Ilinsky (2003)
Reevaluation of the primary motor cortex connections with the thalamus in primates
Journal of Comparative Neurology, 457
Seong-Min Choi, Seung-Han Lee, Man-Seok Park, Byeong-Chae Kim, Myeong-Kyu Kim, Ki-Hyun Cho (2008)
Disappearance of resting tremor after thalamic stroke involving the territory of the tuberothalamic artery.
Parkinsonism & related disorders, 14 4
J. Goldberg, T. Boraud, Sharon Maraton, S. Haber, E. Vaadia, H. Bergman (2002)
Enhanced Synchrony among Primary Motor Cortex Neurons in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Primate Model of Parkinson's Disease
The Journal of Neuroscience, 22
N. Ando, Y. Izawa, Y. Shinoda (1995)
Relative contributions of thalamic reticular nucleus neurons and intrinsic interneurons to inhibition of thalamic neurons projecting to the motor cortex.
Journal of neurophysiology, 73 6
H. Braak, K. Tredici, U. Rüb, R. Vos, Ernst Steur, E. Braak (2003)
Staging of brain pathology related to sporadic Parkinson’s disease
Neurobiology of Aging, 24
W. Koller, K. Busenbark, Kevin Miner (1994)
The relationship of essential tremor to other movement disorders: Report on 678 patients
Annals of Neurology, 35
J. Valls-Solé, Á. Pascual-Leone, J. Brasil-Neto, Á. Cammarota, L. McShane, M. Hallett (1994)
Abnormal facilitation of the response to transcranial magnetic stimulation in patients with Parkinson's disease
Neurology, 44
(1930)
Muscle tone in parkinsonian states
Arch Neurol Psychiatry, 23
A. Moore (2010)
Classification of movement disorders.
Neuroimaging clinics of North America, 20 1
J. McAuley, C. Marsden (2000)
Physiological and pathological tremors and rhythmic central motor control.
Brain : a journal of neurology, 123 ( Pt 8)
I. Isaias, R. Benti, R. Cilia, M. Canesi, G. Marotta, P. Gerundini, G. Pezzoli, A. Antonini (2007)
[123I]FP-CIT striatal binding in early Parkinson's disease patients with tremor vs. akinetic-rigid onset
NeuroReport, 18
A. Hughes, S. Daniel, S. Blankson, A. Lees (1993)
A clinicopathologic study of 100 cases of Parkinson's disease.
Archives of neurology, 50 2
K. Jellinger (1999)
Post mortem studies in Parkinson's disease--is it possible to detect brain areas for specific symptoms?
Journal of neural transmission. Supplementum, 56
A. Lozano, A. Lang, N. Gálvez-Jiménez, J. Miyasaki, J. Duff, W. Hutchison, J. Dostrovsky (1995)
Effect of GPi pallidotomy on motor function in Parkinson's disease
The Lancet, 346
(2009)
Course in Parkinson disease subtypes: a 39-year clinicopathologic study
M. Magnin, A. Morel, D. Jeanmonod (2000)
Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients
Neuroscience, 96
A. Androulidakis, L. Doyle, T. Gilbertson, P. Brown (2006)
Corrective movements in response to displacements in visual feedback are more effective during periods of 13–35 Hz oscillatory synchrony in the human corticospinal system
European Journal of Neuroscience, 24
R. Llinás (1988)
The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function.
Science, 242 4886
E. Vakil, Sigal Herishanu-Naaman (1998)
Declarative and Procedural Learning in Parkinson's Disease Patients Having Tremor or Bradykinesia as the Predominant Symptom
Cortex, 34
C. Eggers, D. Kahraman, G. Fink, Matthias Schmidt, L. Timmermann (2011)
Akinetic‐rigid and tremor‐dominant Parkinson's disease patients show different patterns of FP‐CIT Single photon emission computed tomography
Movement Disorders, 26
B. Pollok, Houssain Makhloufi, M. Butz, J. Gross, L. Timmermann, L. Wojtecki, A. Schnitzler (2009)
Levodopa affects functional brain networks in parkinsonian resting tremor
Movement Disorders, 24
F. Walshe (1924)
OBSERVATIONS ON THE NATURE OF THE MUSCULAR RIGIDITY OF PARALYSIS AGITANS, AND ON ITS RELATIONSHIP TO TREMOR
Brain, 47
Y. Sung, Y. Hsu, Wen-Sheng Huang (2009)
99mTc-TRODAT-1 SPECT study in evaluation of Holmes tremor after thalamic hemorrhage
Annals of Nuclear Medicine, 23
M. Filion, L. Tremblay, P. Bédard (1988)
Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys
Brain Research, 444
A. Zaidel, D. Arkadir, Z. Israel, H. Bergman (2009)
Akineto-rigid vs. tremor syndromes in Parkinsonism
Current Opinion in Neurology, 22
M. Rivlin-Etzion, S. Elias, G. Heimer, H. Bergman (2010)
Computational physiology of the basal ganglia in Parkinson's disease.
Progress in brain research, 183
R. Levy, W. Hutchison, A. Lozano, J. Dostrovsky (2000)
High-frequency Synchronization of Neuronal Activity in the Subthalamic Nucleus of Parkinsonian Patients with Limb Tremor
The Journal of Neuroscience, 20
G. Deuschl, J. Raethjen, R. Baron, Michael Lindemann, H. Wilms, P. Krack (2000)
The pathophysiology of parkinsonian tremor: a review
Journal of Neurology, 247
A. Rajput, Harald Sitte, A. Rajput, Mark Fenton, C. Pifl, O. Hornykiewicz (2008)
Globus pallidus dopamine and Parkinson motor subtypes
Neurology, 70
Mark Hallett, Shahram Khoshbin (1980)
A physiological mechanism of bradykinesia.
Brain : a journal of neurology, 103 2
T. Zirh, F. Lenz, S. Reich, P. Dougherty (1998)
Patterns of bursting occurring in thalamic cells during parkinsonian tremor
Neuroscience, 83
A. Cools, Jhlvan Bercken, M. Horstink, K. Spaendonck, H. Berger (1984)
Cognitive and motor shifting aptitude disorder in Parkinson's disease.
Journal of Neurology, Neurosurgery & Psychiatry, 47
Dong-gun Kim, Young-Ho Koo, O. Kim, Seung-Hun Oh (2009)
Development of Holmes' tremor in a patient with Parkinson's disease following acute cerebellar infarction
Movement Disorders, 24
S. Lewis, T. Foltynie, A. Blackwell, T. Robbins, A. Owen, R. Barker (2005)
Heterogeneity of Parkinson’s disease in the early clinical stages using a data driven approach
Journal of Neurology, Neurosurgery & Psychiatry, 76
R. Levy, W. Hutchison, A. Lozano, J. Dostrovsky (2002)
Synchronized Neuronal Discharge in the Basal Ganglia of Parkinsonian Patients Is Limited to Oscillatory Activity
The Journal of Neuroscience, 22
C. Rossi, D. Frosini, D. Volterrani, P. Feo, E. Unti, V. Nicoletti, L. Kiferle, U. Bonuccelli, Roberto Ceravolo (2010)
Differences in nigro‐striatal impairment in clinical variants of early Parkinson’s disease: evidence from a FP‐CIT SPECT study
European Journal of Neurology, 17
Tao Wu, Liang Wang, M. Hallett, Kuncheng Li, P. Chan (2010)
Neural correlates of bimanual anti-phase and in-phase movements in Parkinson's disease.
Brain : a journal of neurology, 133 Pt 8
Andreea Bostan, R. Dum, P. Strick (2010)
The basal ganglia communicate with the cerebellum
Proceedings of the National Academy of Sciences, 107
M. Pessiglione, D. Guehl, Anne‐Sophie Rolland, C. François, E. Hirsch, J. Féger, L. Tremblay (2005)
Thalamic Neuronal Activity in Dopamine-Depleted Primates: Evidence for a Loss of Functional Segregation within Basal Ganglia Circuits
The Journal of Neuroscience, 25
V. Fraix, P. Pollak, E. Moro, S. Chabardès, J. Xie, C. Ardouin, A. Benabid (2005)
Subthalamic nucleus stimulation in tremor dominant parkinsonian patients with previous thalamic surgery
Journal of Neurology, Neurosurgery & Psychiatry, 76
G. Deuschl, H. Wilms, P. Krack, M. Würker, Wolf-Dieter Heiss (1999)
Function of the cerebellum in parkinsonian rest tremor and Holmes' tremor
Annals of Neurology, 46
A. Kühn, A. Kupsch, G. Schneider, P. Brown (2006)
Reduction in subthalamic 8–35 Hz oscillatory activity correlates with clinical improvement in Parkinson's disease
European Journal of Neuroscience, 23
R. Elble (1996)
Central mechanisms of tremor.
Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society, 13 2
M. Quyen, A. Bragin (2007)
Analysis of dynamic brain oscillations: methodological advances
Trends in Neurosciences, 30
O. Rascol, U. Sabatini, N. Fabre, C. Brefel, I. Loubinoux, P. Celsis, J. Sénard, J. Montastruc, F. Chollet (1997)
The ipsilateral cerebellar hemisphere is overactive during hand movements in akinetic parkinsonian patients.
Brain : a journal of neurology, 120 ( Pt 1)
R. Llinás, F. Urbano, E. Leznik, R. Ramírez, H. Marle (2005)
Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect
Trends in Neurosciences, 28
A. Rajput, R. Pahwa, P. Pahwa, A. Rajput (1993)
Prognostic significance of the onset mode in parkinsonism
Neurology, 43
José Hurtado, C. Gray, L. Tamas, K. Sigvardt (1999)
Dynamics of tremor-related oscillations in the human globus pallidus: a single case study.
Proceedings of the National Academy of Sciences of the United States of America, 96 4
P. Remy, A. Recondo, G. Defer, C. Loc'h, P. Amarenco, V. Planté-Bordeneuve, M. Dao-Castellana, B. Bendriem, C. Crouzel, M. Clanet, P. Rondot, Y. Samson (1995)
Peduncular 'Rubral' Tremor and Dopaminergic Denervation
Neurology, 45
H. Benamer, J. Patterson, D. Wyper, D. Hadley, G. Macphee, D. Grosset (2000)
Correlation of Parkinson's disease severity and duration with 123I‐FP‐CIT SPECT striatal uptake
Movement Disorders, 15
Stéphanie Mounayar, S. Boulet, Dominique Tandé, C. Jan, M. Pessiglione, E. Hirsch, J. Féger, M. Savasta, C. François, L. Tremblay (2007)
A new model to study compensatory mechanisms in MPTP-treated monkeys exhibiting recovery.
Brain : a journal of neurology, 130 Pt 11
I. Bar-Gad, G. Heimer, Y. Ritov, H. Bergman (2003)
Functional Correlations between Neighboring Neurons in the Primate Globus Pallidus Are Weak or Nonexistent
The Journal of Neuroscience, 23
A. Nambu, H. Tokuno, I. Hamada, H. Kita, M. Imanishi, T. Akazawa, Yoko Ikeuchi, N. Hasegawa (2000)
Excitatory Cortical Inputs to Pallidal Neurons Via the Subthalamic Nucleus in the Monkey
Journal of Neurophysiology, 84
David Benninger, Sebastian Thees, S. Kollias, Claudio Bassetti, D. Waldvogel (2009)
Morphological differences in Parkinson’s disease with and without rest tremor
Journal of Neurology, 256
M. Hariz, P. Krack, F. Alesch, L. Augustinsson, A. Bosch, R. Ekberg, F. Johansson, B. Johnels, B. Meyerson, J. N'guyen, M. Pinter, P. Pollak, F. Raison, S. Rehncrona, J. Speelman, O. Sydow, A. Benabid (2007)
Multicentre European study of thalamic stimulation for parkinsonian tremor: a 6 year follow-up
Journal of Neurology, Neurosurgery, and Psychiatry, 79
Scott Cruikshank, H. Urabe, A. Nurmikko, B. Connors (2010)
Pathway-Specific Feedforward Circuits between Thalamus and Neocortex Revealed by Selective Optical Stimulation of Axons
Neuron, 65
S. Baudrexel, T. Witte, C. Seifried, F. Wegner, F. Beissner, J. Klein, H. Steinmetz, R. Deichmann, J. Roeper, R. Hilker (2011)
Resting state fMRI reveals increased subthalamic nucleus–motor cortex connectivity in Parkinson's disease
NeuroImage, 55
C. Reck, E. Florin, L. Wojtecki, H. Krause, S. Groiss, J. Voges, M. Maarouf, V. Sturm, A. Schnitzler, L. Timmermann (2009)
Characterisation of tremor‐associated local field potentials in the subthalamic nucleus in Parkinson’s disease
European Journal of Neuroscience, 29
M. Vidailhet, C. Dupel, S. Lehéricy, P. Remy, D. Dormont, M. Serdaru, P. Jedynak, Hugues Veber, Y. Samson, C. Marsault, Y. Agid (1999)
Dopaminergic dysfunction in midbrain dystonia: anatomoclinical study using 3-dimensional magnetic resonance imaging and fluorodopa F 18 positron emission tomography.
Archives of neurology, 56 8
S. Schneider, M. Edwards, P. Mir, C. Cordivari, J. Hooker, J. Dickson, N. Quinn, K. Bhatia (2007)
Patients with adult‐onset dystonic tremor resembling parkinsonian tremor have scans without evidence of dopaminergic deficit (SWEDDs)
Movement Disorders, 22
B. Rosin, M. Slovik, R. Mitelman, M. Rivlin-Etzion, S. Haber, Z. Israel, E. Vaadia, H. Bergman (2011)
Closed-Loop Deep Brain Stimulation Is Superior in Ameliorating Parkinsonism
Neuron, 72
C. François, C. Savy, C. Jan, Dominique Tandé, E. Hirsch, J. Yelnik (2000)
Dopaminergic innervation of the subthalamic nucleus in the normal state, in MPTP‐treated monkeys, and in Parkinson's disease patients
Journal of Comparative Neurology, 425
P. Krack, J. Dostrovsky, I. Ilinsky, K. Kultas‐ilinsky, F. Lenz, A. Lozano, J. Vitek (2002)
Surgery of the motor thalamus: Problems with the present nomenclatures
Movement Disorders, 17
Stefan Seidel, G. Kasprian, F. Leutmezer, D. Prayer, E. Auff (2008)
Disruption of nigrostriatal and cerebellothalamic pathways in dopamine responsive Holmes’ tremor
Journal of Neurology, Neurosurgery, and Psychiatry, 80
E. Rouiller, Judith Tanné, V. Moret, I. Kermadi, D. Boussaoud, E. Welker (1998)
Dual morphology and topography of the corticothalamic terminals originating from the primary, supplementary motor, and dorsal premotor cortical areas in Macaque monkeys
Journal of Comparative Neurology, 396
C. Ohye, T. Shibazaki, T. Hirai, H. Wada, M. Hirato, Y. Kawashima (1989)
Further physiological observations on the ventralis intermedius neurons in the human thalamus.
Journal of neurophysiology, 61 3
V. Hömberg, H. Hefter, K. Reiners, H. Freund (1987)
Differential effects of changes in mechanical limb properties on physiological and pathological tremor.
Journal of Neurology, Neurosurgery & Psychiatry, 50
W. Abdo, B. Warrenburg, D. Burn, N. Quinn, B. Bloem (2010)
The clinical approach to movement disorders
Nature Reviews Neurology, 6
F. Lenz, R. Tasker, H. Kwan, S. Schnider, R. Kwong, Y. Murayama, J. Dostrovsky, J. Murphy (1988)
Single unit analysis of the human ventral thalamic nuclear group: correlation of thalamic "tremor cells" with the 3-6 Hz component of parkinsonian tremor
, 8
S. Klöppel, J. Mangin, A. Vongerichten, Richard Frackowiak, H. Siebner (2010)
Nurture versus Nature: Long-Term Impact of Forced Right-Handedness on Structure of Pericentral Cortex and Basal Ganglia
The Journal of Neuroscience, 30
M. Dupuis, F. Evrard, P. Jacquerye, G. Picard, O. Lermen (2010)
Disappearance of essential tremor after stroke
Movement Disorders, 25
T. Gilbertson, Elodie Lalo, L. Doyle, V. Lazzaro, B. Cioni, P. Brown (2005)
Existing Motor State Is Favored at the Expense of New Movement during 13-35 Hz Oscillatory Synchrony in the Human Corticospinal System
The Journal of Neuroscience, 25
H. Bernheimer, W. Birkmayer, O. Hornykiewicz, K. Jellinger, F. Seitelberger (1973)
Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations.
Journal of the neurological sciences, 20 4
M. Bevan, Philip Booth, Sean Eaton, J. Bolam (1998)
Selective Innervation of Neostriatal Interneurons by a Subclass of Neuron in the Globus Pallidus of the Rat
The Journal of Neuroscience, 18
Zimbul Albo, G. Prisco, Yonghong Chen, G. Rangarajan, W. Truccolo, Jianfeng Feng, R. Vertes, M. Ding (2004)
Is partial coherence a viable technique for identifying generators of neural oscillations?
Biological Cybernetics, 90
A. Owen, J. Doyon, A. Dagher, A. Sadikot, Alan Evans (1998)
Abnormal basal ganglia outflow in Parkinson's disease identified with PET. Implications for higher cortical functions.
Brain : a journal of neurology, 121 ( Pt 5)
A. Berardelli, J. Rothwell, P. Thompson, M. Hallett (2001)
Pathophysiology of bradykinesia in Parkinson's disease.
Brain : a journal of neurology, 124 Pt 11
P. Amarenco, S. Parikh, Kim Neurologic (2003)
Tremor in Parkinson's disease and serotonergic dysfunction An 11 C-WAY 100635 PET study
(2011)
Classification of movement disorders
Mov Disord, 26
Rajeev Kumar, A. Lozano, Y. Kim, W. Hutchison, E. Sime, E. Halket, A. Lang (1998)
Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease
Neurology, 51
L. Pollock, L. Davis (1930)
MUSCLE TONE IN PARKINSONIAN STATES
Journal of Nervous and Mental Disease, 23
Z. Ni, Andrew Pinto, A. Lang, Robert Chen (2010)
Involvement of the cerebellothalamocortical pathway in Parkinson disease
Annals of Neurology, 68
Han-Joon Kim, B. Jeon, S. Paek, Jee-Young Lee, Hee-Jin Kim, C. Kim, D. Kim (2010)
Bilateral Subthalamic Deep Brain Stimulation in Parkinson Disease Patients With Severe Tremor
Neurosurgery, 67
M. Wallman, D. Gagnon, M. Parent (2011)
Serotonin innervation of human basal ganglia
European Journal of Neuroscience, 33
(1990)
Tremor
M. Fukuda, A. Barnes, E. Simon, A. Holmes, V. Dhawan, Nir Giladi, H. Fodstad, Yilong Ma, D. Eidelberg (2004)
Thalamic stimulation for parkinsonian tremor: correlation between regional cerebral blood flow and physiological tremor characteristics
NeuroImage, 21
E. Hirsch, A. Mouatt, B. Faucheux, A. Bonnet, F. Javoy‐Agid, A. Graybiel, Y. Agid (1992)
Dopamine, tremor, and Parkinson's disease
The Lancet, 340
R. Moran, N. Mallet, V. Litvak, R. Dolan, P. Magill, Karl Friston, P. Brown (2011)
Alterations in Brain Connectivity Underlying Beta Oscillations in Parkinsonism
PLoS Computational Biology, 7
P. Rack, H. Ross (1986)
The role of reflexes in the resting tremor of Parkinson's disease.
Brain : a journal of neurology, 109 ( Pt 1)
R. Lee, R. Stein (1981)
Resetting of tremor by mechanical perturbations: A comparison of essential tremor and parkinsonian tremor
Annals of Neurology, 10
N. Andén, A. Carlsson, A. Dahlström, K. Fuxe, N. Hillarp, Kjell Larsson (1964)
DEMONSTRATION AND MAPPING OUT OF NIGRO-NEOSTRIATAL DOPAMINE NEURONS.
Life sciences, 3
J. Kassubek, F. Juengling, B. Hellwig, M. Knauff, J. Spreer, C. Lücking (2001)
Hypermetabolism in the ventrolateral thalamus in unilateral Parkinsonian resting tremor: a positron emission tomography study
Neuroscience Letters, 304
M. Deiber, P. Pollak, R. Passingham, Patricia Landais, C. Gervason, L. Cinotti, Karl Friston, Richard Frackowiak, Françcois Mauguière, A. Benabid (1993)
Thalamic stimulation and suppression of parkinsonian tremor. Evidence of a cerebellar deactivation using positron emission tomography.
Brain : a journal of neurology, 116 ( Pt 1)
S. Leu-Semenescu, E. Roze, M. Vidailhet, A. Legrand, J. Trocello, V. Cochen, S. Sangla, E. Apartis (2007)
Myoclonus or tremor in orthostatism: An under‐recognized cause of unsteadiness in Parkinson's disease
Movement Disorders, 22
R. Helmich, B. Bloem, I. Toni (2012)
Motor imagery evokes increased somatosensory activity in parkinson's disease patients with tremor
Human Brain Mapping, 33
W. Pirker (2003)
Correlation of dopamine transporter imaging with parkinsonian motor handicap: How close is it?
Movement Disorders, 18
D. Burn, E. Rowan, L. Allan, S. Molloy, J. O'Brien, I. McKeith (2006)
Motor subtype and cognitive decline in Parkinson’s disease, Parkinson’s disease with dementia, and dementia with Lewy bodies
Journal of Neurology, Neurosurgery & Psychiatry, 77
D. German, M. Dubach, S. Askari, S. Speciale, D. Bowden (1988)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonian syndrome in Macaca fascicularis: Which midbrain dopaminergic neurons are lost?
Neuroscience, 24
A. Sillitti, G. Succi, Stefano Panfilis
Non-commercial Research and Educational Use including without Limitation Use in Instruction at Your Institution, Sending It to Specific Colleagues That You Know, and Providing a Copy to Your Institution's Administrator. All Other Uses, Reproduction and Distribution, including without Limitation Comm
Burns Rs, C. Chiueh, S. Markey, M. Ebert, D. Jacobowitz, I. Kopin (1983)
A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Proceedings of the National Academy of Sciences of the United States of America, 80 14
Elan Louis, Ming Tang, L. Cote, B. Alfaro, H. Mejia, K. Marder (1999)
Progression of parkinsonian signs in Parkinson disease.
Archives of neurology, 56 3
Parkinson tremor: causes and consequences
H. Bergman, Ariela Feingold, A. Nini, A. Raz, Hamutal Slovin, M. Abeles, E. Vaadia (1998)
Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates
Trends in Neurosciences, 21
P. Barthó, T. Freund, L. Acsády (2002)
Selective GABAergic innervation of thalamic nuclei from zona incerta
European Journal of Neuroscience, 16
C. Landisman, B. Connors (2007)
VPM and PoM nuclei of the rat somatosensory thalamus: intrinsic neuronal properties and corticothalamic feedback.
Cerebral cortex, 17 12
H. Mure, S. Hirano, C. Tang, I. Isaias, A. Antonini, Yilong Ma, V. Dhawan, D. Eidelberg (2011)
Parkinson's disease tremor-related metabolic network: Characterization, progression, and treatment effects
NeuroImage, 54

Publisher: Pubmed Central
Copyright: © The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain.
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eISSN: 1460-2156
DOI: 10.1093/brain/aws023
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Abstract

doi:10.1093/brain/aws023 Brain 2012: 135; 3206–3226 | 3206 BRAIN A JOURNAL OF NEUROLOGY REVIEW ARTICLE Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? 1,2 3 4 1 2 Rick C. Helmich, Mark Hallett, Gu ¨ nther Deuschl, Ivan Toni and Bastiaan R. Bloem 1 Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands 2 Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology and Parkinson Centre Nijmegen (ParC), 6500 HB Nijmegen 3 Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA 4 Department of Neurology, Christian-Albrechts-University, 24118 Kiel, Germany Correspondence to: Dr. Rick C. Helmich, Radboud University Nijmegen Medical Centre, Neurology Department (HP 935), PO BOX 9101, 6500 HB Nijmegen, The Netherlands E-mail: [email protected] Tremor in Parkinson’s disease has several mysterious features. Clinically, tremor is seen in only three out of four patients with Parkinson’s disease, and tremor-dominant patients generally follow a more benign disease course than non-tremor patients. Pathophysiologically, tremor is linked to altered activity in not one, but two distinct circuits: the basal ganglia, which are primarily affected by dopamine depletion in Parkinson’s disease, and the cerebello-thalamo-cortical circuit, which is also involved in many other tremors. The purpose of this review is to integrate these clinical and pathophysiological features of tremor in Parkinson’s disease. We ﬁrst describe clinical and pathological differences between tremor-dominant and non-tremor Parkinson’s disease subtypes, and then summarize recent studies on the pathophysiology of tremor. We also discuss a newly proposed ‘dimmer-switch model’ that explains tremor as resulting from the combined actions of two circuits: the basal ganglia that trigger tremor episodes and the cerebello-thalamo-cortical circuit that produces the tremor. Finally, we address several important open questions: why resting tremor stops during voluntary movements, why it has a variable response to dopaminergic treatment, why it indicates a benign Parkinson’s disease subtype and why its expression decreases with disease progression. Keywords: Parkinson’s disease; tremor; basal ganglia; cerebellum, thalamus Abbreviations: DBS = deep brain stimulation; PIGD = postural instability and gait disability; STN = subthalamic nucleus; UPDRS = Uniﬁed Parkinson’s Disease Rating Scale; VL = ventral lateral thalamus between patients. This review focuses on the occurrence of Introduction tremor, a striking example of this phenotypic heterogeneity. Parkinson’s disease is a surprisingly heterogeneous neurodegenera- While some patients with Parkinson’s disease have a prominent tive disorder. The classical triad of motor symptoms includes rest- and disabling tremor, others never develop this symptom (Hoehn and Yahr, 1967). This observation formed the basis for classifying ing tremor, akinesia and rigidity (Lees et al., 2009). However, the patients with Parkinson’s disease into tremor-dominant and expression of these cardinal motor symptoms varies markedly Received October 10, 2011. Revised November 28, 2011. Accepted December 14, 2011. Advance Access publication March 1, 2012 The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3207 non-tremor subtypes (Zetusky et al., 1985; Jankovic et al., 1990; re-emerge during postural holding, making it difﬁcult to clinically Rajput et al., 1993; Lewis et al., 2005; Burn et al., 2006). distinguish it from essential tremor. This distinction can be made by focusing on the delay between adopting a posture and the Moreover, patients with Parkinson’s disease can manifest different emergence of tremor: in essential tremor there is no delay, while types of tremor: at rest, with action or postural, including ortho- Parkinson’s disease resting tremor re-emerges after a few seconds static. The reason for this marked phenotypic heterogeneity re- (on average 10 s) (Jankovic et al., 1999). Since the frequency of mains unclear. A better understanding of the mechanisms re-emergent and resting tremor can be similar, it has been underlying the expression of tremor could help clarify tremor hypothesized that both tremors share a similar pathophysiological pathophysiology, and as such offer potential new avenues for mechanism. One interesting patient with Parkinson’s disease had symptomatic treatment. Here, we will review some salient clinical no resting tremor, but a marked 3–6 Hz postural tremor that features of tremor in Parkinson’s disease, discuss recent studies on occurred after a delay of 2–4 s following postural holding (Louis the pathophysiology of tremor and review a newly proposed et al., 2008), thus resembling re-emergent tremor. Such observa- model (Helmich et al., 2011b) to explain the cerebral mechanisms tions point to heterogeneity in the circumstances under which the involved in generating resting tremor in Parkinson’s disease. classical Parkinson’s disease ‘resting’ tremor occurs. In the following sections, we will mainly focus on the classic resting tremor in Parkinson’s disease. We will ﬁrst describe the The tremors of Parkinson’s clinical and cerebral differences between patients with tremor- dominant and non-tremor Parkinson’s disease. Then we will disease detail how these differences may inform us about the causes Tremor is characterized clinically by involuntary, rhythmic and alter- and consequences of Parkinson’s disease resting tremor. nating movements of one or more body parts (Abdo et al., 2010). Parkinson’s disease harbours many different tremors. These tremors can vary according to the circumstances under which they occur, the The clinical phenotype of body part that is involved and the frequency at which the tremor occurs. For example, tremor may occur at rest, during postural tremor-dominant Parkinson’s holding or during voluntary movements; it can be seen in the disease hands, feet or other body parts; and tremor frequency can vary from low (4–5 Hz) to high (8–10 Hz). A consensus statement of The classiﬁcation of patients with Parkinson’s disease into tremor- the Movement Disorder Society includes a parallel classiﬁcation dominant and non-tremor subtypes is well established. Different scheme that categorizes three tremor syndromes associated with taxonomies have been used to deﬁne these two subtypes. First, Parkinson’s disease (Deuschl et al., 1998). This classiﬁcation is still tremor-dominant Parkinson’s disease has been contrasted with used widely today (Fahn, 2011). First, the most common or classical a form of Parkinson’s disease dominated by axial symptoms, i.e. Parkinson’s disease tremor is deﬁned as a resting tremor, or rest and postural instability and gait disability (the PIGD subtype) (Zetusky postural/kinetic tremor with the same frequency. This tremor is in- et al., 1985; Jankovic et al., 1990). This distinction is based on the hibited during movement and may reoccur with the same frequency relative expression of tremor and PIGD, using subscores of the when adopting a posture or even when moving. When recurring Uniﬁed Parkinson’s Disease Rating Scale (UPDRS). Second, with posture, it has been called re-emergent tremor. Second, some tremor-dominant Parkinson’s disease has been contrasted with a patients with Parkinson’s disease develop rest and postural/kinetic Parkinson’s disease subtype dominated by bradykinesia and rigid- tremors of different frequencies, with the postural/kinetic tremor ity (Rajput et al., 1993; Schiess et al., 2000), again using UPDRS displaying a higher (41.5 Hz) and non-harmonically related fre- subscores. A third, data-driven approach has identiﬁed Parkinson’s quency to the resting tremor. This form occurs in 510% of patients disease subtypes by applying clustering algorithms to several clin- with Parkinson’s disease. Some consider it to be an incidental com- ical parameters such as symptom severity, disease onset and clin- bination of an essential tremor with Parkinson’s disease (Louis and ical progression (Lewis et al., 2005). The latter approach again Frucht, 2007), but it appears more plausible that postural tremor is a produced tremor-dominant and non-tremor clusters of patients, manifestation of Parkinson’s disease. Third, isolated postural and together with a young-onset form and a rapid progression group. kinetic tremors do occur in Parkinson’s disease. The frequency of these tremors may vary between 4 and 9 Hz. A speciﬁc form of Tremor is an independent symptom (position-dependent) postural tremor is orthostatic tremor, which may occur in Parkinson’s disease at different frequencies (4–6, 8–9 Tremor may have a pathophysiology different from most other or 13–18 Hz), with or without co-existent resting tremor (Leu- Parkinson’s disease symptoms. First, tremor does not progress at Semenescu et al., 2007). Since this tremor type occurs at a higher the same rate as bradykinesia, rigidity, gait and balance (Louis age of onset than primary orthostatic tremor, and since it may et al., 1999). Second, tremor severity does not correlate with respond to dopaminergic treatment, it has been argued that it is a other motor symptoms (Louis et al., 2001). Third, tremor can manifestation of Parkinson’s disease rather than a chance association occur on the body side contralaterally to the otherwise most af- of two tremor syndromes (Leu-Semenescu et al., 2007). fected side, i.e. where bradykinesia and rigidity are most promin- The distinction between these different tremors is not always ent. This so-called wrong-sided tremor is seen in 4% of patients visible to the naked eye. For example, resting tremor can with Parkinson’s disease (Koh et al., 2010). Finally, tremor 3208 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. responds less well to dopaminergic treatment than bradykinesia particularly the lateral ventral tier (Fearnley and Lees, 1991). and rigidity (Koller et al., 1994; Fishman, 2008). This leads to dopamine depletion in the striatum, particularly in the dorsolateral putamen (Kish et al., 1988). These changes are strongly linked to bradykinesia (Albin et al., 1989), but their rele- Tremor is a marker of benign vance to resting tremor remains unclear (Rodriguez-Oroz et al., Parkinson’s disease 2009). Here, we will discuss data from post-mortem and nuclear imaging studies that examined whether resting tremor has a dopa- Clinical and behavioural differences between patients with minergic basis. tremor-dominant and non-tremor Parkinson’s disease suggest that tremor is a marker of benign Parkinson’s disease. For in- stance, there are indications that patients with tremor-dominant Post-mortem studies Parkinson’s disease have a relatively slow disease progression. This Patients with tremor-dominant Parkinson’s disease have milder idea was ﬁrst proposed by Hoehn and Yahr (1967), who found a cell loss in the substantia nigra pars compacta (particularly in the greater proportion of death and disability in patients with lateral portion) and in the locus coeruleus than patients with Parkinson’s disease with a non-tremor onset mode, at least non-tremor Parkinson’s disease (Paulus and Jellinger, 1991; during the ﬁrst 10 years of the disease. Other studies conﬁrmed Jellinger, 1999). This suggests that patients with tremor-dominant this: compared to patients with Parkinson’s disease with a Parkinson’s disease have less dopaminergic (and possibly also less tremor-dominant subtype, patients with Parkinson’s disease with nor-adrenergic) dysfunction than non-tremor patients. This could a PIGD subtype had a larger annual increase in symptom severity explain some of the clinical advantages that are associated with (Jankovic and Kapadia, 2001) and a shorter survival (Lo et al., tremor. On the other hand, patients with tremor-dominant 2009; Forsaa et al., 2010). Furthermore, a post-mortem study Parkinson’s disease have considerably more cell loss in the retro- showed that patients with tremor-dominant Parkinson’s disease rubral area of the midbrain, as assessed in a post-mortem study progressed more slowly to Hoehn and Yahr grade 4 than comparing six patients with tremulous Parkinson’s disease to ﬁve patients with akinetic-rigid dominant Parkinson’s disease (Rajput patients with non-tremor Parkinson’s disease (Hirsch et al., 1992). et al., 2009), using the subtyping scheme by Rajput et al. (1993). The small sample size in this study warrants caution although con- Another post-mortem study found that patients with ﬁrmatory evidence came from animal work. In non-human pri- tremor-dominant Parkinson’s disease had a lower degree of dis- mates, the retrorubral area contains 10% of the mesencephalic ability (Hoehn and Yahr grade) than tremor-dominant patients at dopaminergic neurons, compared with 76% in the substantia 5 and 8 years (Selikhova et al., 2009), using the subtyping scheme nigra pars compacta and 14% in the ventral tegmental area discussed earlier (Lewis et al., 2005). However, tremor-dominant (Francois et al., 1999). Injection of 1-methyl-4-phenyl-1,2,3,6- and non-tremor patients with Parkinson’s disease had similar dis- tetrahydropyridine (MPTP) destroys these dopaminergic neurons ease duration at the time of death. This led to their conclusion that (Burns et al., 1983), but with marked differences between species. tremor alone does not predict a signiﬁcantly longer survival: pa- Clinically, rhesus (Macaca mulatta) monkeys develop infrequent tients with tremor-dominant Parkinson’s disease progress more and brief episodes of high-frequency tremor, whereas vervet slowly during the initial course of the disease, but lose this relative (African green) monkeys frequently have prolonged episodes of advantage later on (Selikhova et al., 2009). Finally, patients with low-frequency resting tremor (Bergman et al., 1998b). Both spe- tremor-dominant Parkinson’s disease have better cognitive per- cies develop akinesia, rigidity and severe postural instability. Thus, formance than non-tremor patients with Parkinson’s disease vervet monkeys resemble the tremulous Parkinson’s disease sub- (Vakil and Herishanu-Naaman, 1998; Lewis et al., 2005; Burn type, while rhesus monkeys resemble the non-tremor Parkinson’s et al., 2006) and are less likely to develop dementia (Aarsland disease subtype (Rivlin-Etzion et al., 2010). There are no studies et al., 2003; Williams-Gray et al., 2007). To distinguish between directly comparing the spatial topography of MPTP-induced neural tremor-dominant and non-tremor Parkinson’s disease subtypes, all damage between these species, but in vervet monkeys, the retro- of the studies reviewed above used a combined resting and pos- rubral area (A8) is preferentially damaged (Deutch et al., 1986), tural/action tremor score on the UPDRS. Therefore, it remains while in rhesus monkeys, the substantia nigra pars compacta (A9) unclear which of these tremors best predicts the clinical advan- is more affected (German et al., 1988; Oiwa et al., 2003). tages associated with the tremor-dominant subtype. Since postural Although circumstantial, these observations lend further support and action tremors frequently occur in the akinetic-rigid subtype to the idea that tremor is related to—and possibly caused by— (Deuschl et al., 2000; Helmich et al., 2011b), it could be argued dopaminergic cell loss in the retrorubral area (Jellinger, 1999). The that the presence of resting tremor is the best predictor of clinical retrorubral area could produce tremor via its dopaminergic projec- progression. This remains to be tested. tions to, among other regions, the subthalamic region (Francois et al., 2000) and the pallidum (Jan et al., 2000). Accordingly, a study in parkinsonian vervet monkeys found that tremor The neurochemical basis of severity correlated exclusively with dopaminergic ﬁbres in the external globus pallidus (Mounayar et al., 2007). Similarly, a parkinsonian resting tremor post-mortem study in patients with Parkinson’s disease The core pathological process in Parkinson’s disease involves showed that clinical tremor severity was correlated exclusively dopaminergic cell loss in the substantia nigra pars compacta, with concentrations of the dopamine metabolite homovanillic Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3209 acid in the pallidum (Bernheimer et al., 1973). Taken together, patients with tremor-dominant Parkinson’s disease had lower levels of thalamic serotonin transporters than non-tremor patients these data suggest that tremor might result from pallidal dysfunc- (Caretti et al., 2008). This opens the possibility that abnormalities tion, triggered by a speciﬁc loss of dopaminergic projections from in the serotonergic system are involved in generating resting the retrorubral area. Note that not all ﬁndings consistently point in tremor in Parkinson’s disease although this hypothesis remains to this direction: a recent post-mortem study showed higher dopa- be tested in post-mortem studies. mine levels in the ventral internal globus pallidus of patients with These ﬁndings suggest that tremor severity does not depend on tremor-dominant than non-tremor Parkinson’s disease (Rajput the amount of nigrostriatal dopamine depletion. On the other et al., 2008). However, only few data points were measured hand, it has been argued that the expression of resting tremor is (a single hemisphere of two tremor-dominant patients), which conditional upon dopaminergic denervation in the midbrain limit the interpretation of these results. New imaging techniques (Deuschl et al., 2000). Indeed, many disorders with resting may conﬁrm the role of the retrorubral area in tremor in vivo, for tremor show a form of nigrostriatal dopamine depletion, e.g. example by measuring N-acetyl-aspartate (a marker of neuronal mono-symptomatic resting tremor (Ghaemi et al., 2002), dystonic viability) in the retrorubral area with magnetic resonance spectros- resting tremor after mesencephalic lesions (Vidailhet et al., 1999) copy or by measuring connectivity between the retrorubral area and Holmes’ tremor (formerly called rubral or midbrain tremor) and the basal ganglia using diffusion tensor imaging and func- (Remy et al., 1995; Seidel et al., 2009; Sung et al., 2009). tional MRI. Thus, we are left with the paradox that nigrostriatal dopamine depletion may be a prerequisite for developing resting tremor, In vivo dopaminergic and serotonergic but the level of tremor expression is independent of nigrostriatal degeneration. How these ﬁndings can be reconciled will be dis- imaging cussed later in this paper. Five [123I]FP-CIT SPECT studies have described neurochemical differences between patients with tremor-dominant and non-tremor Parkinson’s disease (Fig. 1). Three of these found Thalamic nomenclature that patients with tremor-dominant Parkinson’s disease had less The thalamus is one of the key regions involved in tremor. The striatal dopamine depletion than those with non-tremor nomenclature of the thalamic subregions is diverse and often con- Parkinson’s disease (Spiegel et al., 2007; Rossi et al., 2010; fusing. Here we will follow the nomenclature proposed by Jones Helmich et al., 2011b). These differences were spatially localized (Hirai and Jones, 1989). Using acetylcholinesterase and Nissl stain- to the putamen in one report (Rossi et al., 2010) and extended to ing on post-mortem thalamic sections in humans, Jones divided the caudate in the other studies (Spiegel et al., 2007; Helmich the ventral lateral (VL) thalamus into anterior and posterior nuclei. et al., 2011b). These ﬁndings ﬁt with the milder nigral pathology These two nuclei have clearly corresponding areas in the primate of tremor-dominant patients noted earlier (Paulus and Jellinger, thalamus, where information about the connectivity of these areas 1991; Jellinger, 1999). The fourth SPECT study found the opposite is available. Thus, according to Jones, the anterior VL receives pattern (Isaias et al., 2007), perhaps because of a different deﬁn- input from the pallidum, and the posterior VL receives input ition of Parkinson’s disease subgroups, or because only 10 from the cerebellum. Many clinicians, on the other hand, use tremor-dominant patients with Parkinson’s disease were included, the thalamic nomenclature by Hassler, because of its widespread whereas the other studies included 16–24 tremor-dominant pa- use in the deep brain stimulation (DBS) literature. The most tients (Spiegel et al., 2007; Rossi et al., 2010; Helmich et al., common thalamic target for tremor relief is Hassler’s ventral inter- 2011b). The ﬁfth study found different spatial distributions of mediate nucleus, which is localized during surgery based on the dopamine depletion in tremor-dominant and non-tremor presence of tremor-synchronous bursts and kinaesthetic cells, an- Parkinson’s disease subtypes. Speciﬁcally, non-tremor patients terior to cutaneous receptive cells (Krack et al., 2002). It is gen- showed pronounced dopamine depletion in the posterior striatum, erally agreed that interference with this region relieves tremor by while tremor-dominant patients had severe dopamine depletion in deafferenting the thalamus from cerebellar projections (Percheron the lateral putamen (Eggers et al., 2011). Finally, several SPECT et al., 1996; Krack et al., 2002). Therefore, the neurosurgeon’s studies have correlated the amount of striatal dopamine depletion ventral intermediate nucleus is thought to correspond to (part of) with the severity of individual symptoms. These studies consist- Jones’ posterior VL (Krack et al., 2002). To maintain a uniform ently show that, unlike other Parkinson’s disease symptoms, rest- nomenclature throughout this paper, we will refer to the ventral ing tremor does not correlate with nigrostriatal dopamine intermediate nucleus as posterior VL although it must be borne in depletion (Benamer et al., 2000, 2003; Pirker, 2003; Isaias mind that this analogy is not a strict one. et al., 2007; Spiegel et al., 2007). The weight of the evidence therefore suggests milder nigral pathology in tremor-dominant pa- tients, possibly with a different spatial distribution as well. This Neural mechanisms underlying raises the question whether other neurotransmitters could be involved in generating tremor. Two imaging studies indicate a parkinsonian resting tremor role for serotonin: one study found an association between reduced midbrain raphe 5-HT1A binding and increased tremor Parkinsonian tremor is caused mainly by central, rather than per- severity (Doder et al., 2003), and another study found that ipheral mechanisms (Elble, 1996; Deuschl et al., 2000; McAuley 3210 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Figure 1 Neurochemical correlates of Parkinson’s disease tremor. (A) Correlation between age-normalized striatal [123] I beta-CIT binding and UPDRS motor subscores for speech, facial expression, tremor (rest and action tremor), rigidity, bradykinesia, and posture and gait (n = 59). Reprinted from Pirker (2003), with permission from John Wiley and Sons. (B) Correlation between C-WAY 100635 PET in the raphe and total UPDRS tremor score (r = 0529; P5 0.01; n = 23). Reprinted from Doder et al. (2003), with permission from Wolters Kluwer. (C) Correlation between pallidal [I-123] FP-CIT binding and resting tremor severity [tremor rating scale (TRS); r = 0.57; P = 0.023], using within-patient difference scores (between most-affected and least-affected sides). This procedure controls for non-speciﬁc differences between patients. Reprinted from Helmich et al. (2011b), with permission from John Wiley and Sons. These data show that tremor severity is correlated with dopamine depletion in the pallidum (C), but not the striatum (A), and also with serotonin depletion in the raphe (B). and Marsden, 2000). Evidence for this view comes from work tremor although peripheral reﬂexes (muscle stretch) may interact showing that peripheral deafferentation (Pollock and Davis, with central oscillations (Rack and Ross, 1986). 1930), peripheral anaesthesia of tremulous muscles (Walshe, Several electrophysiological and metabolic investigations have 1924) and mechanical perturbations (Lee and Stein, 1981; studied the cerebral basis of tremor production. Methodological Homberg et al., 1987) have little effect on Parkinson’s disease differences between these studies must be considered for Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3211 Figure 2 Neuronal correlates of Parkinson’s disease tremor. (A) Simultaneous recording of thalamic posterior VL (VLp) single-unit activity and peripheral EMG during tremor in a parkinsonian patient. These data show continuous synchronization between internal globus pallidus activity and peripheral EMG. Reprinted from Lenz et al. (1988), with permission from the Society for Neuroscience. (B) Simultaneous recording of internal globus pallidus (GPi) multi-unit activity and peripheral EMG during tremor in a patient with Parkinson’s disease (PD). The two plots illustrate the raw signals of two epochs of data sampled 5 min apart. Note that in the left trace the peaks in the spike density function coincide with the EMG bursts, whereas in the right trace the oscillations in the spike density function occur at a lower frequency than the EMG. These data show that synchronization between neuronal activity in internal globus pallidus and peripheral EMG is transient in nature. Reprinted from Hurtado et al. (1999). Copyright (2011) National Academy of Sciences, USA. interpreting their results. First, different experimental designs have ganglia-cortical circuit, tremor activity is organized in parallel and been used: (i) an ‘event-related’ design, where tremor character- partly segregated subloops: intra-operative recording of local ﬁeld istics (such as ﬂuctuations in tremor amplitude) were directly potentials in the STN of patients with tremor-dominant Parkinson’s related to cerebral activity and (ii) a ‘trait’ design, where baseline disease revealed clusters of tremor-associated coupling between characteristics (such as cerebral perfusion or grey matter density) STN and tremor EMG that were spatially distinct for different were compared between tremor-dominant and non-tremor muscles (Reck et al., 2009). Another study using intra-operative Parkinson’s disease subgroups. With this latter approach, differ- STN recordings in patients with tremor-dominant Parkinson’s ences between subgroups might be related to tremor, but also disease found that neurons (episodically) oscillating at tremor fre- to other factors. Second, different recording techniques have quency were locally surrounded by non-oscillating or out-of- phase neurons, while larger populations of neurons continuously been used: (i) electrophysiological studies tried to relate cycle-to- cycle oscillations in tremor (typically 4 Hz) to neural oscillations oscillated at 8–20 Hz (Moran et al., 2008). Given the known with the same frequency as the tremor. The spatial resolution of somatotopic organization of the posterior VL (Ohye et al., such studies was limited to a group of neurons (e.g. studies in 1989), a similar organization of tremor in subloops may apply to patients with deep electrodes) or to a shallow portion of the cor- the cerebello-thalamo-cortical circuit. These ﬁndings explain why tical mantle (e.g. studies using magnetoencephalography) and (ii) tremor in different limbs is generally not coherent with each other (Hurtado et al., 2000; Raethjen et al., 2000). Importantly, the metabolic imaging methods such as PET and functional MRI are blind to the rapid cycle-to-cycle changes in neural activity, but are synchronicity of basal ganglia and thalamic activity to tremor sensitive to episodic changes in tremor output, and offer a view of varies between regions. Pallidal neurons are only transiently and the whole brain. In the following section, we brieﬂy review these inconsistently coherent with tremor (Hurtado et al., 1999; Raz studies, taking these methodological considerations into account. et al., 2000), while posterior VL neurons are highly synchronous Electrophysiological studies have identiﬁed cells ﬁring at tremor with tremor (Lenz et al., 1994) (Fig. 2). These ﬁndings suggest frequency both in the basal ganglia [subthalamic nucleus (STN) that the basal ganglia cannot be the driving force behind resting and pallidum (Levy et al., 2000; Raz et al., 2000)] and the pos- tremor (Zaidel et al., 2009). Magnetoencephalography work sup- terior VL (Lenz et al., 1994; Magnin et al., 2000). Within the basal ports this view, showing that a cerebello-thalamo-cortical circuit, 3212 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Figure 3 Oscillatory correlates of Parkinson’s disease tremor. This ﬁgure shows statistical parametric (SPM) maps of spatially normalized cerebro-muscular and cerebro-cerebral coherence of four patients with right-sided rest tremor. Cerebral activity was measured with magnetoencephalography and muscular activity with EMG. (A) Cerebro-muscular coherence at double tremor frequency is located in the contralateral primary motor cortex (M1). (B) This plot shows the coherence between M1 activity and the tremor EMG for one patient with Parkinson’s disease. The dashed line indicates the 99% conﬁdence level. (C) Cerebro-cerebral coherence was computed with the reference region in M1 and averaged for all four patients. Areas of consistent coupling with M1 were found in the secondary somatosensory cortex (S2), posterior parietal cortex (PPC), cingulate motor area (CMA)/supplementary motor area (SMA), contralateral diencephalon and ipsilateral cerebellum. Due to the poor coverage by and the large distance to the magnetoencephalography sensors, localization in the latter two areas is not as precise as at the cortical level. These data show a cerebello-thalamo-cortical circuit coupled with tremor on a cycle-by-cycle basis. Reprinted from Timmermann et al. (2003), by permission of Oxford University Press. rather than the basal ganglia, ﬁres in synchrony with ongoing 2001). Other PET studies compared baseline cerebral perfusion resting tremor in Parkinson’s disease (Timmermann et al., 2003) (a ‘trait’) between tremor-dominant and non-tremor patients (Fig. 3). with Parkinson’s disease. They found that tremor-dominant pa- Several metabolic imaging studies (PET) investigated how ‘event- tients had relatively increased perfusion of the thalamus, pons related’ cerebral activity changed after posterior VL-DBS, which and premotor cortex, compared to non-tremor patients (Antonini reduces tremor amplitude. These studies found that posterior VL et al., 1998). Compared to healthy controls, both Parkinson’s dis- stimulation was associated with reduced activity in the cerebellum ease groups had increased pallido–thalamic and pontine activity, (Deiber et al., 1993; Fukuda et al., 2004), motor cortex (Fukuda and reduced activity in premotor cortex, supplementary motor et al., 2004) and medial frontal cortex (Fukuda et al., 2004). area and parietal cortex (Antonini et al., 1998). Accordingly, bra- Another approach is to localize cerebral activity that co-varied dykinesia and rigidity were found to correlate with activity in the with differences (between-subjects) in tremor amplitude. This Parkinson’s disease-wide network, but tremor did not (Eidelberg identiﬁed similar areas, namely tremor-related activity in the cere- et al., 1994). A recent PET study combined these approaches, bellum, ventrolateral thalamus and motor cortex (Kassubek et al., describing a tremor-related network consisting of sensorimotor Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3213 Figure 4 Metabolic correlates of Parkinson’s disease tremor. (A) Spatial covariance pattern identiﬁed by ordinal trends canonical variate analysis of FDG PET data from 11 hemispheres of nine patients with tremor-dominant Parkinson’s disease (PD) scanned on and off posterior VL stimulation (labelled ventral intermediate nucleus in the original manuscript). Posterior VL stimulation improved tremor severity and reduced metabolic activity in the primary motor cortex, anterior cerebellum/dorsal pons, and the caudate/putamen. (B) The expression of this Parkinson’s disease tremor-related metabolic pattern (PDTP) was reduced by posterior VL stimulation in 10 of the 11 treated hemispheres. (C) Baseline PDTP expression (i.e. off-stimulation pattern scores) correlated (r = 0.85, P5 0.02) with tremor amplitude, measured with concurrent accelerometry. These data show that metabolic activity in both the cortico-cerebellar circuit and the basal ganglia is related to tremor severity. Reprinted from Mure et al. (2011), with permission from Elsevier. cortex, cerebellum (lobules IV/V and dentate), cingulate cortex These ﬁndings ﬁt with the involvement of the cerebello- and—to a lesser extent—putamen (Mure et al., 2011). Activity thalamo-cortical network in tremor, as shown with functional ima- in this network was correlated with clinical tremor scores, it ging (Deiber et al., 1993; Fukuda et al., 2004). It is unclear how was higher in patients with tremor-dominant than non-tremor increased activation of these areas can translate in both reduced and Parkinson’s disease, it increased with disease progression and it increased grey matter volume. This divergence might be explained was suppressed by both posterior VL and STN-DBS (Fig. 4). by differences in neuroplasticity between brain regions, which—in Importantly, the metabolic effects of posterior VL and STN-DBS the context of skill acquisition—can produce opposite volumetric overlapped in a single region, the motor cortex. This suggests that changes in the cortex and basal ganglia (Kloppel et al., 2010). the basal ganglia and cerebellar tremor circuits converge in the Taken together, these ﬁndings provide evidence for the involve- motor cortex. ment of both the cerebello-thalamo-cortical circuit and the basal ganglia in Parkinson’s disease resting tremor. The arrest of tremor by focused interventions in either of these circuits further conﬁrms Structural imaging that both are causally related to tremor. That is, DBS targeted towards either the basal ganglia [pallidum or STN (Lozano et al., Two MRI studies used voxel-based morphometry to test for struc- 1995; Krack et al., 1997)] or the cerebellar loop [posterior VL tural changes (‘traits’) in tremor-dominant Parkinson’s disease. (Benabid et al., 1991)] reduces tremor severity in Parkinson’s dis- These studies compared tremor-dominant Parkinson’s disease with ease. The efﬁcacy of posterior VL and STN-DBS on Parkinson’s either non-tremor patients with Parkinson’s disease (Benninger disease tremor appears to be comparable (Pollak et al., 2002): et al., 2009) or with controls (Kassubek et al., 2002). UPDRS tremor scores (items 20 and 21, OFF medication) Tremor-dominant patients had reduced grey matter volume in the right cerebellum (Benninger et al., 2009) and increased decreased by 75–84% with STN-DBS (Kumar et al., 1998; Krack grey matter volume in the posterior VL (Kassubek et al., 2002). et al., 2003; Kim et al., 2010) and by 77–88% with posterior 3214 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. VL-DBS (Rehncrona et al., 2003; Hariz et al., 2008). Earlier studies Parkinson’s disease, and the bursts were not coherent with per- found that 58–88% of patients with Parkinson’s disease had a ipheral tremor recordings. Patients with tremor-dominant total suppression of tremor 3–6 months after posterior VL-DBS Parkinson’s disease showed distinct tremor-locked bursts without (Benabid et al., 1991; Koller et al., 1994). There are no studies low-threshold calcium spike bursts characteristics in the posterior directly comparing the effects of these two targets, but one study VL, but not in the anterior VL. These ﬁndings could be taken as reported an additional reduction of tremor scores after STN-DBS in evidence that pathological low-threshold calcium spike bursting is patients with Parkinson’s disease with previous thalamic surgery not related to tremor. Alternatively, thalamic low-threshold cal- (Fraix et al., 2005). cium spike bursts might be transformed into tremor-locked bursts by re-entry properties of the thalamo-cortical circuit (Magnin et al., 2000). Another issue concerns the mechanisms that drive thalamic cells Models explaining the into an oscillatory mode in Parkinson’s disease. In theory, any occurrence of parkinsonian mechanism that engenders membrane hyperpolarization, whether through reduction of excitatory drive (dysfacilitation) or excess resting tremor inhibition, will trigger low-frequency rhythmicity of thalamic neu- Several hypotheses have been put forward to explain the occur- rons (Llinas et al., 2005). Several different mechanisms have been rence of resting tremor in Parkinson’s disease. As outlined above, suggested. First, according to the classical model of Parkinson’s there is evidence that both the basal ganglia and the disease (Albin et al., 1989), the internal globus pallidus sends cerebello-thalamo-cortical circuit are implicated in tremor. increased (inhibitory) output to the thalamus, which may hyper- However, most models are based on detailed recordings in a lim- polarize thalamic neurons and thus trigger oscillations at 5–6 Hz ited set of neurons (e.g. ex vivo preparations) or a limited set of (Llinas et al., 2005). However, this mechanism would predict a structures (e.g. electrophysiological recordings). Therefore, most predominant role for the pallidal thalamus, anterior VL, in models focus on a node in a single circuit and interpret the tremor genesis. This does not ﬁt with ﬁndings from DBS, which changes in other circuits as secondary. Here we will place concur- show that interference with the cerebellar thalamus, posterior VL, rent changes in two separate circuits into perspective. This section is superior for treating tremor (Atkinson et al., 2002), or with the also updates and elaborates on earlier reviews about the patho- ﬁnding that there are more tremor cells in the posterior VL than physiology of parkinsonian tremor (Elble, 1996; Deuschl et al., anterior VL (Magnin et al., 2000). Second, it has recently been 2000; Rodriguez-Oroz et al., 2009). proposed that increased inhibitory input from the zona incerta towards the posterior VL could hyperpolarize these thalamic neu- rons (Plaha et al., 2008). The zona incerta is located in the sub- thalamic region, medially with respect to the STN. In non-human Model 1: the thalamic pacemaker primates, the zona incerta receives projections from the internal hypothesis globus pallidus [although mainly the cognitive division (Sidibe et al., 1997)], and it sends GABA-ergic projections to the posterior This hypothesis (Jahnsen and Llinas, 1984) is based on in vitro VL (Bartho et al., 2002). This makes the zona incerta an interface preparations of guinea pig thalamic neurons, where it was found between the basal ganglia and the cerebello-thalamo-cortical cir- that the intrinsic biophysical properties of thalamic neurons allow cuits, and its involvement in tremor may explain why both circuits them to serve as relay systems and as single cell oscillators at two are related to tremor. In line with this hypothesis, DBS of the zona distinct frequencies, 9–10 and 5–6 Hz. Speciﬁcally, slightly depo- incerta can reduce tremor (Plaha et al., 2006) and low-frequency larized thalamic cells tend to oscillate at 10 Hz, while hyperpolar- stimulation of the zona incerta can induce tremor in patients with ized cells oscillate at 6 Hz (Llinas, 1988). These two frequencies previously non-tremulous Parkinson’s disease (Plaha et al., 2008). coincide with the frequency of physiological tremor and Third, thalamic posterior VL neurons may be hyperpolarized Parkinson’s disease tremor, respectively. The key assumption of through the cerebellum. Moreover, the ﬁnding of disynaptic pro- this model is that (single) thalamic neurons, not the basal ganglia jections from the STN to the cerebellar cortex in non-human pri- circuitry, form the tremor pacemaker. However, in vivo measure- mates (Bostan et al., 2010) opens the possibility that pathological ments in the thalamus of patients with Parkinson’s disease have activity in the basal ganglia produces downstream changes in the questioned the presence of these thalamic pacemaker cells. That cerebellum and cerebellar thalamus (posterior VL). Fourth, it is is, while the 6 Hz oscillatory mode in the animal model is asso- possible that hyperpolarization of thalamic posterior VL neurons ciated with low threshold calcium spike bursts, this pattern was is related to the degeneration of dopaminergic projections from not observed (with rare exception) in the thalamus of patients the midbrain to the posterior VL. Speciﬁcally, both the retrorubral with Parkinson’s disease with tremor (Zirh et al., 1998). In con- area [that is degenerated in tremor-dominant Parkinson’s disease trast, a second study found a convincing low threshold calcium (Hirsch et al., 1992)] and the substantia nigra pars compacta send spike bursts pattern in a larger number of cells in the thalamus sparse dopaminergic projections to the whole thalamus, including (both the anterior and posterior VL) of patients with Parkinson’s disease (Magnin et al., 2000), possibly due to more sensitive pro- the posterior VL (Sanchez-Gonzalez et al., 2005). According to cessing techniques. However, low-threshold calcium spike bursts this hypothesis, basal ganglia dysfunction would not be required were present both in patients with tremor-dominant and akinetic for the hyperpolarization of posterior VL neurons. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3215 basal ganglia circuitry, not the thalamus, forms the tremor pace- Model 2: the thalamic ﬁlter hypothesis maker. In line with this hypothesis, parkinsonian primates show This hypothesis (Pare et al., 1990) is also based on in vitro data less selective neuronal responses to proprioceptive stimulation in and proposes that parkinsonian resting tremor emerges when high- the entire pallido-thalamo-cortical loop (Filion et al., 1988; frequency (12–15 Hz) oscillations in the basal ganglia are trans- Goldberg et al., 2002; Pessiglione et al., 2005). These changes formed into a 4–6 Hz pattern by thalamic anterior VL neurons. were found to be larger in the pallidum of patients with The key feature of this hypothesis is that the tremor pacemaker tremor-dominant than non-tremor Parkinson’s disease (Levy is primarily located in the basal ganglia (pallidum), with et al., 2002), and hence related to tremor. However, as already pallido-thalamic interactions determining the net frequency of the mentioned, the inconsistent coherence between basal ganglia os- tremor. This hypothesis seems to ﬁt with recent data in non-human cillations and tremor (Hurtado et al., 1999; Raz et al., 2000) com- primates, where it was found that 10 Hz pallidal oscillations were plicates a causal link between these phenomena (Zaidel et al., only present in tremor-dominant vervet monkeys but not in 2009). non-tremor macaques (Rivlin-Etzion et al., 2010). In contrast, pal- Taken together, the different models discussed above position lidal oscillations at 5 Hz were present in both species. However, the tremor pacemaker either in the thalamus (Model 1) or in the high-frequency stimulation of the pallidum did not spread to the basal ganglia (Models 2–4). Since the cerebellar (not pallidal) thal- motor cortex (Rivlin-Etzion et al., 2008). This makes it unlikely that amus is primarily involved in parkinsonian tremor, the thalamic high-frequency oscillations in the basal ganglia drive Parkinson’s pacemaker hypothesis does not account for the mechanisms that disease resting tremor (Rivlin-Etzion et al., 2006; Zaidel et al., trigger thalamic oscillations, and it remains unclear whether these 2009). Other work also questions the speciﬁc role of mechanisms have any relationship with basal ganglia dysfunction. high-frequency basal ganglia oscillations in the generation of On the other hand, the basal ganglia pacemaker hypotheses are tremor. That is, dopaminergic treatment reduced the pathologically more directly linked to the core pathophysiological substrate of enhanced 8–35 Hz rhythms in the STN of patients with Parkinson’s Parkinson’s disease, but these models struggle with the fact that disease, but this improved only akinesia and rigidity, not tremor tremor-related oscillations in the basal ganglia are only transient (Kuhn et al., 2006). Therefore, most authors relate the increased and inconsistent in nature. high-frequency (8–35 Hz) oscillations in the basal ganglia of pa- tients with Parkinson’s disease to akinesia, but not to tremor (Rivlin-Etzion et al., 2006; Hammond et al., 2007). The ‘dimmer-switch’ model of parkinsonian resting Model 3: the subthalamic tremor nucleus-external globus Given the well-known role of both the basal ganglia and the pallidus pacemaker hypothesis cerebello-thalamic circuits in tremor, we aimed to construct a This hypothesis (Plenz and Kital, 1999) is again based on in vitro data model that speciﬁes and integrates the role of both circuits in and proposes that the STN and external globus pallidus constitute a tremor (Helmich et al., 2011b). To test this systems-level view central pacemaker that is modulated by striatal inhibition of external on tremor, we used functional MRI to identify cerebral responses globus pallidus neurons. This pacemaker could be responsible for that co-ﬂuctuated with spontaneous variations in tremor ampli- synchronized oscillatory activity in the normal and pathological tude, as measured with EMG during scanning (van Duinen basal ganglia. However, these oscillations occurred at frequencies et al., 2005; van Rootselaar et al., 2008; Helmich et al., between 0.4 and 1.8 Hz, and it is unclear whether they have any 2011b). These abrupt amplitude ﬂuctuations are very characteristic relationship with parkinsonian tremor, given the lack of in vivo of parkinsonian tremor, and they do not occur, for example, in measurements. Thus, it is not possible to test whether these oscilla- essential tremor (Elble and Koller, 1990; Gao, 2004; Ropper and tions are consistently coherent with tremor, and hence this hypoth- Samuels, 2009). This method also allowed us to quantify func- esis suffers from the same critique as Model 2. tional interactions between the basal ganglia and the cerebello-thalamo-cortical circuit. We obtained the following re- sults (Fig. 5): (i) tremor amplitude-related activity was localized to Model 4: the loss-of-segregation the cerebello-thalamo-cortical circuit (posterior VL, cerebellum and hypothesis motor cortex); (ii) cerebral activity time-locked to the onset of This hypothesis (Bergman et al., 1998a) is based on the ﬁnding high-amplitude tremor episodes was localized to the basal ganglia that—in normal primates—the activity of neighbouring pallidal and the cerebello-thalamo-cortical circuit; and (iii) tremor- neurons is completely uncorrelated (Bar-Gad et al., 2003), while dominant patients with Parkinson’s disease had increased parkinsonian primates develop markedly increased correlations be- functional connectivity between the basal ganglia and the cere- tween remotely situated pallidal neurons (Bergman et al., 1998a). bello-thalamo-cortical circuit, compared with non-tremor This could lead to excessive synchronization in the basal ganglia, Parkinson’s disease and healthy controls. On the basis of these possibly because inhibitory collaterals in the pallidum are affected data, we suggest the following model, which is also illustrated in by dopamine depletion (Bevan et al., 1998), resulting in tremor Fig. 6: (i) activity in the basal ganglia triggers tremor-related re- (Deuschl et al., 2000). The key feature of this model is that the sponses in the cerebello-thalamo-cortical circuit, which produces 3216 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Figure 5 Tremor amplitude- and onset-related cerebral activity in Parkinson’s disease. (A) Left: Cerebral regions where activity co-ﬂuctuated with tremor amplitude (19 tremor-dominant patients, P5 0.05 whole-brain corrected). Activity was localized to the motor cortex, thalamus (posterior VL; VLp) and cerebellum (left side = side contralateral to tremor). Right: Regions of interest in the basal ganglia are shown. (B) In the cerebello-thalamo-cortical circuit, we found two separate effects: (i) cerebral activity related to tremor amplitude and (ii) cerebral activity related to changes in tremor amplitude (tremor on/offset). Left: These two tremor-related effects are illustrated for the motor cortex of one patient. Right: These two tremor-related effects are shown for the motor cortex across the whole group (19 tremor-dominant patients), separately for the most- and least-affected hemisphere. Similar effects were found in the posterior VL and cerebellum (not shown). (C) In the basal ganglia, we found cerebral activity related to changes in tremor amplitude (tremor on/offset), but not cerebral activity related to tremor amplitude. Left: This effect is illustrated for the internal globus pallidus of one patient. Right: This effect is shown for the internal globus pallidus (GPi) across the whole group (19 tremor-dominant patients), separately for the most- and least-affected hemisphere. Similar effects were found for the putamen, but not for the caudate (not shown). The line graphs in B and C show three relevant time courses: (i) brain activity (motor cortex in orange, internal globus pallidus in blue); (ii) tremor amplitude of the contralateral hand (in black; EMG regressor convolved with the haemodynamic response function); and (iii) tremor on/offset (in dotted grey, ﬁrst temporal derivative of the tremor amplitude regressor, convolved with the haemodynamic response function). These data suggest distinct contributions of two circuits to tremor: the cerebello-thalamo-cortical circuit controls tremor amplitude, and the striato-pallidal circuit produces changes in tremor amplitude. Reprinted from Helmich et al. (2011b), with permission from John Wiley and Sons. GPe = external globus pallidus. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3217 Figure 6 The dimmer-switch model of parkinsonian resting tremor. In tremor-dominant Parkinson’s disease, dopaminergic cell death in the retrorubral area A8 causes dopamine depletion in the pallidum (in red). Pallidal dopamine depletion leads to emergence of pathological activity in the striato-pallidal circuit, which triggers activity in the cerebello-thalamo-cortical circuit (in blue) through the primary motor cortex (red line between pallidum and primary motor cortex). Thus, the striato-pallidal circuit triggers tremor episodes (analogues to a light switch), while the cerebello-thalamo-cortical circuit produces the tremor and controls its amplitude (analogous to a light dimmer). This model is based on Helmich et al. (2011b). VLp = posterior VL. the tremor; and (ii) these interactions occur in the motor cortex, depletion appears required for developing resting tremor where both circuits converge (Hoover and Strick, 1999). The novel (Deuschl et al., 2000). Indeed, if pallidal (but not striatal) aspect of this model is that it offers a mechanism explaining how dopamine depletion is involved in tremor genesis, this could also the basal ganglia and the cerebello-thalamo-cortical circuits inter- explain why striatal DAT signal is not correlated with tremor act with each other. Given the emphasis on a combination of basal severity. ganglia contributions (that trigger tremor on/offset, analogous to The dimmer-switch model combines several features of the pre- a light switch) and cerebello-thalamo-cortical contributions (that vious hypotheses into a larger explanatory framework. First, loss of modulate tremor intensity, analogous to a light dimmer), we call segregation in the dopamine-depleted pallidum may be a mech- this model the ‘dimmer-switch model’ of Parkinson’s disease rest- anism that explains both the emergence of pathological activity in ing tremor (Fig. 6). the basal ganglia, and the increased connectivity between basal To identify the dopaminergic mechanisms underlying these ganglia and motor cortex (Rivlin-Etzion et al., 2008). Second, changes, we compared striato-pallidal DAT binding between altered basal ganglia output may inﬂuence neurons in the cerebel- tremor-dominant and non-tremor patients with Parkinson’s dis- lar thalamus (posterior VL) via the motor cortex. That is, excitatory ease, using [123I]FP-CIT SPECT (Helmich et al., 2011b). This re- cortico-thalamic projections from motor cortex to ventrolateral vealed that pallidal, but not striatal, dopamine depletion correlates thalamus (Fonnum et al., 1981; Rouiller et al., 1998; Kultas- with the severity of resting tremor. This ﬁnding could solve the Ilinsky et al., 2003) can activate inhibitory intra-thalamic circuits dopaminergic paradox of Parkinson’s disease resting tremor. (Ando et al., 1995; Landisman and Connors, 2007; Cruikshank Speciﬁcally, the pallidum receives distinct dopaminergic projections et al., 2010), leading to low-frequency oscillations within the from the substantia nigra pars compacta (Smith et al., 1989) and thalamo-cortical network (Blumenfeld and McCormick, 2000). the retrorubral area (Jan et al., 2000), but these same mesenceph- This model would explain why basal ganglia oscillations are only alic areas also send separate projections to the striatum [substantia transient and inconsistent, why thalamic oscillations are highly syn- nigra pars compacta (Anden et al., 1964); retrorubral area chronous with the tremor, and thus why both basal ganglia and (Francois et al., 1999)]. This pattern of divergence and conver- the cerebello-thalamo-cortical circuit are causally related to gence makes it unlikely that midbrain pathology can produce tremor. It remains to be shown why posterior VL neurons are either pure striatal or pure pallidal dopamine depletion although more prone to develop tremor oscillations than anterior VL neu- the degree of dopamine depletion in each area may vary between rons, since both regions receive cortico-thalamic projections from patients. Thus, patients with Parkinson’s disease with resting the motor cortex. Hypothetically, the connections between the tremor will generally have some degree of striatal dopamine de- posterior VL and the cerebellum are a prerequisite for the devel- pletion, explaining why the presence of striatal dopamine opment of tremor oscillations. 3218 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. ﬂuctuations into account, but focused on cycle-by-cycle coherence Limitations of the model and between neural and muscular activity, i.e. signals occurring at 4 Hz. These approaches are blind to neural changes at the future research onset of high-amplitude tremor episodes, because neuromuscular coherence at 4 Hz is similar across low- and high-tremor amplitude Role of the subthalamic nucleus (Reck et al., 2009). In a preliminary study in one patient with Parkinson’s disease, the authors recorded local ﬁeld potentials With the methods (functional MRI) employed in our previous from the STN and related them to changes in tremor amplitude, paper (Helmich et al., 2011b), we were not able to reliably as measured with EMG (Wang et al., 2005). They found that beta detect cerebral activity in a small nucleus such as the STN. The suppression in the STN preceded the onset of tremor episodes and presence of tremor oscillations in the STN that are coherent with made way for oscillations at tremor frequency in the STN. If ac- peripheral tremor activity (Levy et al., 2000) and the ability of tivity in the beta band is a way by which the sensorimotor system STN-DBS to reduce tremor (Kumar et al., 1998; Krack et al., maintains the status quo (Gilbertson et al., 2005; Engel and Fries, 2003; Kim et al., 2010) suggest that this nucleus has an important 2010; Jenkinson and Brown, 2011), then beta suppression in the pathophysiological role in tremor. In contrast to the pallidum, the STN before tremor onset could indicate a removal of neural inhib- STN receives direct anatomical projections from the motor cortex ition to establish tremor onset-related activity (trigger). On the (Nambu et al., 2000), and functional connectivity between the other hand, since beta suppression in the cortex (Crone et al., motor cortex and the STN is increased in Parkinson’s disease 1998) and STN (Kuhn et al., 2004) is known to precede voluntary (Baudrexel et al., 2011; Moran et al., 2011). The STN also movements, the ﬁnding of beta suppression prior to tremor could sends disynaptic anatomical projections to the cerebellar cortex (Bostan et al., 2010). Therefore, the STN has both afferent and just reﬂect a more general phenomenon preceding any movement. efferent connections with the cerebello-thalamo-cortical tremor circuit. Whether the STN is part of the basal ganglia trigger, or Role of dopamine in tremor dynamics whether the STN is involved in the cerebello-thalamo-cortical cir- In our model, pallidal activity was related to changes in tremor cuit producing the tremor, remains to be investigated in future amplitude, rather than the amplitude of the tremor itself (Fig. 5). studies using high-resolution MRI in combination with connectivity This raises the question how the severity of pallidal dopamine analyses. depletion could predict clinical tremor severity (Fig. 1C). This likely depends on the effect of dopamine depletion on pallidal Tremor oscillator activity. For example, dopamine depletion may increase the amp- Although our methods (functional MRI) enabled a systems-level litude of tremor onset-related activity in the pallidum. This should view on tremor, we could not detect oscillatory activity at tremor lead to more abrupt tremor changes, but not to increased tremor frequency. Therefore, it remains an open question which brain amplitude. Second, dopamine depletion may increase the rate of region(s) determine the tremor frequency. The cerebello-tha- onset-related activity in the pallidum. More frequent episodes of lamo-cortical tremor network we identiﬁed matches closely the pallidal activity could lead to more frequent tremor episodes, but network identiﬁed in studies that have directly tracked cerebral also, if the bursts of pallidal activity occur shortly after each other, changes occurring at resting-tremor frequency (using magneto- to ampliﬁed activity in the cerebello-thalamo-cortical circuit (and encephalography; Fig. 3). Thus, in our view, it is the hence to increased tremor amplitude). Finally, more severe pallidal cerebello-thalamo-cortical network that is the ultimate tremor dopamine depletion may lead to enhanced connectivity between generator, but as inﬂuenced and triggered by the coupled basal the basal ganglia and the cerebello-thalamo-cortical systems. This ganglia network. Accordingly, a novel DBS paradigm that takes would make the cerebello-thalamo-cortical circuit more susceptible these network properties into account was found to be more suc- to perturbing signals from the basal ganglia, and the increased cessful than standard DBS in reducing both Parkinson’s disease input–output relationship may lead to more severe tremor. To symptoms and tremor oscillations in the internal globus pallidus investigate these possibilities, we are currently testing tremor- (Rosin et al., 2011). This new paradigm, termed closed-loop DBS, dominant Parkinson patients ON and OFF dopaminergic medica- uses a trigger detected in a reference structure (M1) as the input tion using functional MRI. to deliver DBS trains to the stimulated structure (internal globus pallidus). These data show that the interconnectivity between vari- Causality ous participating brain areas plays a crucial role in the emergence of pathological oscillations and clinical symptoms. Using metabolic imaging, several groups have found a correlation between tremor amplitude and cerebral activity in the cerebellum, motor cortex and posterior VL (e.g. Deiber et al., 1993; Helmich Relationship between metabolic and et al., 2011b; Mure et al., 2011). One interpretational problem is oscillatory activity that the limited temporal resolution of these techniques makes it Based on our model, we suspect that the intermittent oscillations difﬁcult to determine whether the cerebral effects are causal or in the basal ganglia (Fig. 1) could be related to tremor dynamics reactive to the tremor. Electrophysiological studies, which have a such as abrupt changes in amplitude, but this remains to be much higher temporal resolution, partly suffer from the same tested. Most previous studies did not take tremor amplitude problem. That is, single-cell recordings in the thalamus, STN and Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3219 internal globus pallidus of patients with Parkinson’s disease show Why does resting tremor that many neurons with tremor-related activity also respond to somatosensory stimulation (Lenz et al., 1994; Magnin et al., stop during voluntary 2000). Therefore, neural activity that leads peripheral tremor ac- tivity might also relate to the preceding tremor beat. Conduction movements? times are not helpful to disentangle cause from effect, given the A characteristic feature of Parkinson’s disease resting tremor is its diverse pathways through which afferent input can reach the basal decrease during voluntary movements (Deuschl et al., 2000). This ganglia and thalamus. Nevertheless, there are also thalamic cells feature is routinely used in clinical practice to distinguish resting that do not respond to somatosensory stimulation, and that show tremor from other tremor forms (Deuschl et al., 1998), for ex- tremulous activity preceding muscular activity (Lenz et al., 1994). ample from dystonic tremor where a decrease with movement is This suggests that the thalamus has a causal role in tremor. Other electrophysiological studies have calculated the oscillatory activity typically absent (Schneider et al., 2007). However, the neural (at tremor or double tremor frequency) of single neurons or larger mechanisms underlying the interaction between voluntary move- groups of neurons, for example using subcortical DBS electrodes ments and resting tremor remain unclear. As outlined above, or cortical magnetoencephalography recordings (Levy et al., 2000; parkinsonian tremor results from altered responses in both the Timmermann et al., 2003). Since oscillations are deﬁned over basal ganglia and the cerebello-thalamo-cortical circuit. This indi- longer temporal windows, this procedure makes it difﬁcult to de- cates that voluntary movements may interact with resting tremor termine whether neural oscillations drive the tremor or vice versa. in either or both of these circuits. Analytical methods including the phase of coherence or Granger causality might help to solve this problem (Timmermann et al., 2003; Van Quyen and Bragin, 2007) although these methods Movement–tremor interactions in are susceptible to noise contamination and volume conduction the cerebello-thalamo-cortical circuit (Albo et al., 2004; Rivlin-Etzion et al., 2006). To reliably disentangle cause from effect, interference studies We recently investigated the cerebral interactions between are helpful. Lesion studies provide strong evidence that activity motor planning and Parkinson’s disease resting tremor. To this in the posterior VL is causally linked to tremor: thalamotomy, pos- end, we used a motor imagery paradigm (as a quantiﬁable terior VL-DBS and thalamic stroke lead to immediate tremor arrest proxy of motor planning) while measuring tremor-related activity (Benabid et al., 1991; Atkinson et al., 2002; Probst-Cousin et al., during functional MRI scanning. This procedure avoids the con- 2003; Choi et al., 2008). The motor cortex is the only region of founding effects of somatosensory reafference associated with the cerebello-thalamo-cortical circuit that has a direct access to the the production of voluntary movements. There were two main spinal cord, and therefore it seems plausible that activity in this ﬁndings: (i) planning- and tremor-related responses overlapped area drives the tremor. Accordingly, interference with M1 activity in the posterior VL, but not in the cerebellum or in the motor using transcranial magnetic stimulation can reset resting tremor in cortex and (ii) tremor amplitude was unaffected by motor im- Parkinson’s disease (Ni et al., 2010). In contrast, transcranial mag- agery (Helmich et al., 2011a). This indicates that motor netic stimulation over the cerebellum did not reset tremor, sug- planning-related activity in the posterior VL does not remove gesting that this region does not directly drive the tremor. Lesion tremor-related responses in this region, possibly because both studies support this idea: cerebellar stroke (Kim et al., 2009) and processes involve (partly) different neuronal populations (Lenz cerebellectomy (Deuschl et al., 1999) did not remove ipsilateral et al., 1994; Magnin et al., 2000). Another study directly as- resting tremor, but transformed it into a Holmes tremor (i.e. a sessed the electrophysiological interactions between motor exe- slow-frequency and combined resting, intention and postural cution and Parkinson’s disease resting tremor (Hallett et al., tremor). Therefore, the role of the cerebellum in tremor may be 1977). The pattern of alternating activity in agonist and antag- modulatory rather than causal. Accordingly, a previous mag- onist muscles seen during Parkinson’s disease resting tremor netoencephalography study showed that oscillatory activity in strongly resembled the activity seen during voluntary ﬂexion of the cerebellum is coherent with thalamic and motor activity, but the arm. Furthermore, in many patients with Parkinson’s disease, not with the tremor itself (Timmermann et al., 2003). This sug- a single ‘beat of tremor’ preceded voluntary movements, even gests that the cerebellum does not have a direct efferent or affer- when there was no clinically noticeable tremor (Fig. 7). This ent relationship with peripheral tremor. This relationship could be suggests that resting tremor and voluntary movement execution different for other tremor pathologies. For example, other than in arise from similar oscillations in the motor cortex, which may Parkinson’s disease, cerebellar stroke can ameliorate ipsilateral explain why they do not occur simultaneously. Finally, the ob- essential tremor (Dupuis et al., 2010). Finally, an approach to servation that resting tremor at movement onset is no longer gain mechanistic insights into the role of altered oscillations in inhibited when the cerebellum is absent (Deuschl et al., 1999) Parkinson’s disease has been to stimulate the basal ganglia or or malfunctioning (Kim et al., 2009) suggests that the thalamus at precisely these frequencies, using implanted DBS elec- cortico-cerebellar activation during voluntary movements sup- trodes. For example, 5–40 Hz stimulation of the STN, zona incerta and ventrolateral thalamus induced tremor in patients with presses the tremor rhythm. Re-emergent tremor can then be Parkinson’s disease (Plaha et al., 2008), suggesting that oscillatory explained by reinitiating the cerebello-thalamo-cortical tremor activity in these regions is causally linked to tremor. circuit through the basal ganglia. 3220 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. 2008), and we will not repeat this here. Levodopa and other dopaminergic drugs are generally less efﬁcacious against tremor than other key features of Parkinson’s disease (Fishman, 2008; Rodriguez-Oroz et al., 2009). This failure to respond to dopamin- ergic treatment is difﬁcult to reconcile with most models, which assume that tremor is triggered by dopamine depletion. One pos- sibility is that non-dopaminergic neurotransmitters play a role. For example, patients with Parkinson’s disease have 27% lower sero- Figure 7 A beat of tremor preceding movement in Parkinson’s tonin binding in the raphe than controls, and tremor was the only disease. Fast ﬂexion patterns in patients with Parkinson’s symptom that correlated with the amount of serotonin depletion disease. In many patients with Parkinson’s disease (17 arms of (Doder et al., 2003). In humans, there are serotonergic projections 15 patients), although resting tremor was not continuously from the raphe to the basal ganglia, including the pallidum present, a single ‘beat of tremor’ occasionally occurred before (Wallman et al., 2011). If both serotonergic and dopaminergic the pattern that moved the limb. This is illustrated for one patient. Adapted from Hallett et al. (1977) with permission changes can produce tremor, then this may explain why some from BMJ Publishing Group Ltd. patients fail to respond to dopaminergic therapy. Another specu- lative possibility is that there are crucial temporal windows during disease progression in which the tremor is responsive to dopamin- ergic treatment. For example, basal ganglia signals might be Movement–tremor interactions in required for driving the cerebello-thalamo-cortical circuit into the basal ganglia tremor only during the early phases of the disease. Later in the According to our model, transient activity in the pallidum and disease, perhaps due to depletion of inhibitory neurotransmitters in the tremor circuit, oscillations in the cerebello-thalamo-cortical cir- putamen can trigger tremor-related activity in the cerebello-tha- cuit might not need to be triggered by basal ganglia signals. This lamo-cortical circuit. The pallidum is also activated during volun- would predict that the response of tremor to dopaminergic ther- tary movement planning (Owen et al., 1998; Helmich et al., apy is modulated by disease duration. Finally, one report investi- 2009). Movement-related activity may replace tremor-related ac- gated the effect of dopaminergic treatment on the oscillatory tivity in the pallidum, and this could interfere with tremor in two tremor network in Parkinson’s disease (Pollok et al., 2009). They ways. First, the absence of intermittent ‘triggers’ from the pallidum found that levodopa speciﬁcally reduced thalamo-cortical cou- could cause the tremor to fade out. However, this mechanism pling. This suggests that the thalamo-cortical axis has a central does not explain why tremor is immediately reduced at the role in tremor genesis, but that dopaminergic areas (such as the onset of voluntary movements, which suggests an active (instead basal ganglia) control the emergence of tremor-related oscillations of a passive) disturbance of the cerebello-thalamo-cortical tremor in this circuit. circuit. Second, the pallidum may actively inhibit the motor cortex during voluntary movements. The pallidum supports action selec- tion by exciting desired motor programmes, while inhibiting all others [centre-surround inhibition (Mink, 1996; Beck and Hallett, Why does tremor indicate a 2011)]. Inhibition of motor representations in the motor cortex benign Parkinson’s disease during voluntary movement selection could actively interfere with tremor-related ﬁring in the cerebello-thalamo-cortical circuit, subtype? causing an immediate arrest of the tremor. This concept may also We have reviewed and discussed several clinical and pathophysio- explain why resting tremor re-emerges during ﬁxed postural hold- logical differences between tremor-dominant and non-tremor ing (Jankovic et al., 1999). That is, while the basal ganglia are Parkinson’s disease subtypes. We suggest that pallidal dopamine strongly involved in changing movement set, they are not involved depletion is related to tremor, while other pathophysiological mar- in maintaining a ﬁxed posture (Cools et al., 1984; Hayes et al., kers could explain a more benign disease course. First, there is 1998; Helmich et al., 2009). Thus, Parkinson’s disease tremor may converging evidence from post-mortem and nuclear imaging stu- emerge not necessarily in the absence of movement (rest), but dies that patients with tremor-dominant Parkinson’s disease have rather in the absence of selection demands (including maintaining relatively benign nigrostriatal degeneration. This may explain why a posture when no other posture needs to be selected to satisfy other features of Parkinson’s disease also take a more benign the current task context). course in tremor-dominant patients. Second, there is post-mortem evidence that patients with non-tremor Parkinson’s disease have more cortical lesions than patients with tremor-dominant Why does tremor have a Parkinson’s disease, and this may explain the worse cognitive dys- variable response to function of patients with non-tremor Parkinson’s disease. Appearance of such cortical lesions with advancing disease may dopaminergic treatment? also explain why tremor can diminish or even disappear after sev- Previous work has extensively reviewed the response of tremor to eral years in some patients, because the cerebello-thalamo-cortical different pharmacological preparations (Elble, 2002; Fishman, circuit now becomes damaged. Finally, resting tremor may emerge Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3221 as a collateral effect of cerebral mechanisms that compensate for Lewy bodies, cortical amyloid-beta plaques, and cerebral amyloid pathophysiological changes producing akinesia (Hallett and angiopathy (Selikhova et al., 2009). Also, the cognitive deterior- Khoshbin, 1980; Rivlin-Etzion et al., 2006). Voluntary movement ation occurring in non-tremor Parkinson’s disease [i.e. in the PIGD arises in phase with the tremor, suggesting that the tremor may subtype (Williams-Gray et al., 2007)] was associated with cortical facilitate the ability to initiate movement in the face of akinesia Lewy body pathology instead of cortico-striatal dysfunction (Hallett et al., 1977). This possibility ﬁnds support in the fact (Williams-Gray et al., 2009). These studies indicate that progress- that—in MPTP primate models of Parkinson’s disease—tremor ing cortical Lewy body pathology may stop tremor and introduce usually appears several days after akinesia and rigidity (Zaidel dementia-like cognitive dysfunction. Genetic variations between et al., 2009), i.e. its appearance coincides with the time when patients, for instance in the tau gene (microtubule-associated pro- compensatory mechanisms are presumably being activated. This tein tau; MAPT), may determine whether patients develop these does not yet prove any causal relationship, but one possibility is pathologies or not (Williams-Gray et al., 2009). Finally, as outlined that such compensatory changes—for example in the motor in the previous paragraph, patients with tremor-dominant cortex and cerebellum—may render these regions more suscep- Parkinson’s disease might have increased cerebral compensation. tible to pathological inﬂuences (tremor triggers) from the basal This concept would offer an explanation how failure of compen- ganglia. For example, a study that used transcranial magnetic satory mechanisms in later stages of the disease will lead to grad- stimulation pulses to probe the excitability of the primary motor ual disappearance of tremor, possibly because the (previously cortex showed that, when tested at rest, the slope of the input– healthy) brain areas involved in compensation now become af- output relationship between stimulus intensity and response size is fected by neurodegeneration as well. steeper in patients with Parkinson’s disease than in controls (Valls-Sole et al., 1994). Although this could be the result of a primary basal ganglia deﬁcit (loss of normal inhibition), it could Conclusion also reﬂect an attempt to cortically compensate for the slow re- We propose that Parkinson’s disease resting tremor involves both cruitment of commands to move, by making it easier to recruit the basal ganglia and the cerebello-thalamo-cortical circuit. activity from a resting state (Berardelli et al., 2001). Similarly, Previous models of tremor have largely focused on localizing the increased activity of the cerebellum during movements has been tremor pacemaker in either one of these two distinct circuits. observed frequently in Parkinson’s disease—perhaps to compen- These models have provided valuable information about the sate for dysfunction of dopamine-dependent circuits (Rascol et al., neural mechanisms underlying tremor oscillations in these circuits, 1997; Yu et al., 2007; Wu et al., 2010b). The increased cerebellar but they were unable to solve one crucial paradox of Parkinson’s activity may sensitize the cerebello-thalamo-cortical circuit to per- disease resting tremor: why is tremor produced by the turbing inﬂuences from the basal ganglia, resulting in tremor. This cerebello-thalamo-cortical circuit, but only in the presence of suggests that a combination of basal ganglia pathology (i.e. palli- striato-pallidal dopaminergic dysfunction? A systems-level view dal dopamine depletion) and compensation in the on tremor is necessary to answer this question. We have sug- cerebello-thalamo-cortical circuit leads to tremor, explaining why gested a new ‘dimmer-switch model’ of parkinsonian tremor tremor and a benign disease course are seen in the same patients. (Helmich et al., 2011b): depletion of pallidal dopamine (and pos- sibly serotonin) causes pathological activity in the striato-pallidal circuit that triggers—through the motor cortex—tremor-related Why does resting tremor activity in the cerebello-thalamo-cortical circuit. This striato-pallidal decrease with disease activity can only emerge under motorically static conditions when the basal ganglia are not involved in voluntary motor behaviour, progression? explaining why classical Parkinson’s disease tremor is seen both at rest and during ﬁxed postural holding (re-emergent tremor). Parkinsonian resting tremor has a puzzling feature that distin- Future electrophysiological studies may validate this model by guishes it from other Parkinson’s disease symptoms: in some pa- focusing on oscillatory phenomena time-locked to changes in tients, tremor severity tends to decrease instead of worsen during disease progression (Toth et al., 2004; Lees, 2007). One study tremor amplitude. found that tremor was lost in 9% of patients late in the disease Our model may have clinical implications for the treatment of (Hughes et al., 1993). Accordingly, patients with Parkinson’s dis- tremor: if the basal ganglia are only transiently involved at the ease of tremor-dominant subtype in the early phases of their dis- onset of tremor episodes, then DBS of the STN or pallidum may ease can convert to a non-tremor subtype later on, with PIGD be applied more selectively in an ‘event-related’ manner, inter- symptoms replacing the tremor (Alves et al., 2006). This suggests rupting activity in these regions only when required. For this ap- that the progression of cerebral dysfunction in Parkinson’s disease proach to work, one has to be able to accurately predict the onset may at some point disrupt the ability of brain regions to produce of tremor episodes. This may be done by using the DBS electrodes tremor. Post-mortem work has shown that the primary motor to identify tremor-related signals that typically precede tremor epi- cortex becomes affected in later stages of Parkinson’s disease sodes (Wu et al., 2010a), for example, desynchronization in the (Braak et al., 2003). Furthermore, post-mortem work revealed beta band (Wang et al., 2005). Demand-based DBS may also an association between a non-tremor Parkinson’s disease pheno- prolong the life span of implanted batteries. Finally, a similar type, cognitive disability and pathological lesions including cortical systems-level approach as adopted here could be used to 3222 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Benamer HT, Patterson J, Wyper DJ, Hadley DM, Macphee GJ, investigate other tremors occurring in Parkinson’s disease, as well Grosset DG. Correlation of Parkinson’s disease severity and duration as different tremor pathologies such as essential tremor. with 123I-FP-CIT SPECT striatal uptake. Mov Disord 2000; 15: 692–8. Benninger DH, Thees S, Kollias SS, Bassetti CL, Waldvogel D. Morphological differences in Parkinson’s disease with and without rest tremor. J Neurol 2009; 256: 256–63. Funding Berardelli A, Rothwell JC, Thompson PD, Hallett M. Pathophysiology of bradykinesia in Parkinson’s disease. Brain 2001; 124: 2131–46. The Alkemade-Keuls Foundation (to B.R.B.); the Netherlands Bergman H, Feingold A, Nini A, Raz A, Slovin H, Abeles M, Vaadia E. Organisation for Scientiﬁc Research (NWO; VIDI grant No. Physiological aspects of information processing in the basal ganglia 016.076.352 to B.R.B.; VIDI grant No. 452-03-339 to I.T.; Brain & of normal and parkinsonian primates. Trends Neurosci 1998a; 21: 32–8. Cognition grant No. 433-09-248 to I.T.); the German Research Bergman H, Raz A, Feingold A, Nini A, Nelken I, Hansel D, Ben Pazi H, Reches A. Physiology of MPTP tremor. Mov Disord 1998b; 13 Council (SFB 855 to G.D.) and the NIH Intramural Program (to M.H.). (Suppl 3): 29–34. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci References 1973; 20: 415–55. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence Bevan MD, Booth PA, Eaton SA, Bolam JP. Selective innervation of and characteristics of dementia in Parkinson disease: an 8-year pro- neostriatal interneurons by a subclass of neuron in the globus pallidus spective study. Arch Neurol 2003; 60: 387–92. of the rat. J Neurosci 1998; 18: 9438–52. Abdo WF, van de Warrenburg BP, Burn DJ, Quinn NP, Bloem BR. The Blumenfeld H, McCormick DA. Corticothalamic inputs control the pat- clinical approach to movement disorders. Nat Rev Neurol 2010; 6: tern of activity generated in thalamocortical networks. J Neurosci 29–37. 2000; 20: 5153–62. Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia Bostan AC, Dum RP, Strick PL. The basal ganglia communicate with the disorders. Trends Neurosci 1989; 12: 366–75. cerebellum. Proc Natl Acad Sci U S A 2010; 107: 8452–56. Albo Z, Di Prisco GV, Chen YH, Rangarajan G, Truccolo W, Feng JF, Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Vertes RP, Ding MZ. Is partial coherence a viable technique for iden- Staging of brain pathology related to sporadic Parkinson’s disease. tifying generators of neural oscillations? Biol Cybernet 2004; 90: Neurobiol Aging 2003; 24: 197–211. 318–26. Burn DJ, Rowan EN, Allan LM, Molloy S, O’Brien JT, McKeith IG. Motor Alves G, Larsen JP, Emre M, Wentzel-Larsen T, Aarsland D. Changes in subtype and cognitive decline in Parkinson’s disease, Parkinson’s dis- motor subtype and risk for incident dementia in Parkinson’s disease. ease with dementia, and dementia with Lewy bodies. J Neurol Mov Disord 2006; 21: 1123–30. Neurosurg Psychiatry 2006; 77: 585–9. Anden NE, Carlsson A, Dahlstroem A, Fuxe K, Hillarp NA, Larsson K. Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. A Demonstration and mapping out of nigro-neostriatal dopamine neu- primate model of parkinsonism: selective destruction of dopaminergic rons. Life Sci 1964; 3: 523–30. neurons in the pars compacta of the substantia nigra by Ando N, Izawa Y, Shinoda Y. Relative contributions of thalamic reticular N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U nucleus neurons and intrinsic interneurons to inhibition of thalamic S A 1983; 80: 4546–50. neurons projecting to the motor cortex. J Neurophysiol 1995; 73: Caretti V, Stoffers D, Winogrodzka A, Isaias IU, Costantino G, Pezzoli G, 2470–85. Ferrarese C, Antonini A, Wolters EC, Booij J. Loss of thalamic serotonin Antonini A, Moeller JR, Nakamura T, Spetsieris P, Dhawan V, transporters in early drug-naı¨ve Parkinson’s disease patients is asso- Eidelberg D. The metabolic anatomy of tremor in Parkinson’s disease. ciated with tremor: an [123I]b-CIT SPECT study. J Neural Transm Neurology 1998; 51: 803–10. 2008; 115: 721–9. Atkinson JD, Collins DL, Bertrand G, Peters TM, Pike GB, Sadikot AF. Choi SM, Lee SH, Park MS, Kim BC, Kim MK, Cho KH. Disappearance of Optimal location of thalamotomy lesions for tremor associated with resting tremor after thalamic stroke involving the territory of the tuber- Parkinson disease: a probabilistic analysis based on postoperative mag- othalamic artery. Parkinsonism Relat Disord 2008; 14: 373–5. netic resonance imaging and an integrated digital atlas. J Neurosurg Cools AR, van den Bercken JH, Horstink MW, van Spaendonck KP, 2002; 96: 854–66. Berger HJ. Cognitive and motor shifting aptitude disorder Bar-Gad I, Heimer G, Ritov Y, Bergman H. Functional correlations be- in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1984; 47: tween neighboring neurons in the primate globus pallidus are weak or 443–53. Crone NE, Miglioretti DL, Gordon B, Sieracki JM, Wilson MT, Uematsu S, nonexistent. J Neurosci 2003; 23: 4012–6. Bartho P, Freund TF, Acsady L. Selective GABAergic innervation of thal- Lesser RP. Functional mapping of human sensorimotor cortex with amic nuclei from zona incerta. Eur J Neurosci 2002; 16: 999–1014. electrocorticographic spectral analysis - I. Alpha and beta event-related Baudrexel S, Witte T, Seifried C, von Wegner F, Beissner F, Klein JC, desynchronization. Brain 1998; 121: 2271–99. Steinmetz H, Deichmann R, Roeper J, Hilker R. Resting state fMRI Cruikshank SJ, Urabe H, Nurmikko AV, Connors BW. Pathway-speciﬁc reveals increased subthalamic nucleus-motor cortex connectivity in feedforward circuits between thalamus and neocortex revealed by Parkinson’s disease. Neuroimage 2011; 55: 1728–38. selective optical stimulation of axons. Neuron 2010; 65: 230–45. Beck S, Hallett M. Surround inhibition in the motor system. Exp Brain Res Deiber MP, Pollak P, Passingham R, Landais P, Gervason C, Cinotti L, 2011; 210: 165–72. Friston K, Frackowiak R, Mauguiere F, Benabid AL. Thalamic stimula- Benabid AL, Pollak P, Gervason C, Hoffmann D, Gao DM, Hommel M, tion and suppression of parkinsonian tremor. Evidence of a cerebellar Perret JE, de Rougemont J. Long-term suppression of tremor by deactivation using positron emission tomography. Brain 1993; 116 chronic stimulation of the ventral intermediate thalamic nucleus. (Pt 1): 267–79. Lancet 1991; 337: 403–6. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Benamer HT, Oertel WH, Patterson J, Hadley DM, Pogarell O, Disorder Society on Tremor. Ad Hoc Scientiﬁc Committee. Mov Hoffken H, Gerstner A, Grosset DG. Prospective study of presynaptic Disord 1998; 13 (Suppl 3): 2–23. dopaminergic imaging in patients with mild parkinsonism and tremor Deuschl G, Raethjen J, Baron R, Lindemann M, Wilms H, Krack P. The disorders: part 1. Baseline and 3-month observations. Mov Disord pathophysiology of parkinsonian tremor: a review. J Neurol 2000; 247 2003; 18: 977–84. (Suppl 5): V33–V48. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3223 Deuschl G, Wilms H, Krack P, Wurker M, Heiss WD. Function of the Gilbertson T, Lalo E, Doyle L, Di Lazzaro V, Cioni B, Brown P. Existing cerebellum in Parkinsonian rest tremor and Holmes’ tremor. Ann motor state is favored at the expense of new movement during 13-35 Neurol 1999; 46: 126–8. Hz oscillatory synchrony in the human corticospinal system. J Neurosci Deutch AY, Elsworth JD, Goldstein M, FUXE K, Redmond DE Jr, 2005; 25: 7771–9. Sladek JR Jr, Roth RH. Preferential vulnerability of A8 dopamine neu- Goldberg JA, Boraud T, Maraton S, Haber SN, Vaadia E, Bergman H. rons in the primate to the neurotoxin 1-methyl-4-phenyl-1,2,3,6- Enhanced synchrony among primary motor cortex neurons in the tetrahydropyridine. Neurosci Lett 1986; 68: 51–6. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ. Tremor in Parkinson’s disease. J Neurosci 2002; 22: 4639–53. Parkinson’s disease and serotonergic dysfunction: an 11C-WAY Hallett M, Khoshbin S. A physiological mechanism of bradykinesia. Brain 100635 PET study. Neurology 2003; 60: 601–5. 1980; 103: 301–14. Dupuis MJ, Evrard FL, Jacquerye PG, Picard GR, Lermen OG. Hallett M, Shahani BT, Young RR. Analysis of stereotyped voluntary Disappearance of essential tremor after stroke. Mov Disord 2010; movements at the elbow in patients with Parkinson’s disease. 25: 2884–2887. J Neurol Neurosurg Psychiatry 1977; 40: 1129–35. Eggers C, Kahraman D, Fink GR, Schmidt M, Timmermann L. Hammond C, Bergman H, Brown P. Pathological synchronization in Akinetic-rigid and tremor-dominant Parkinson’s disease patients show Parkinson’s disease: networks, models and treatments. Trends different patterns of FP-CIT single photon emission computed tomog- Neurosci 2007; 30: 357–64. raphy. Mov Disord 2011; 26: 416–23. Hariz MI, Krack P, Alesch F, Augustinsson LE, Bosch A, Ekberg R, Eidelberg D, Moeller JR, Dhawan V, Spetsieris P, Takikawa S, Ishikawa T, Johansson F, Johnels B, Meyerson BA, N’Guyen JP, Pinter M, Chaly T, Robeson W, Margouleff D, Przedborski S. The metabolic Pollak P, von Raison F, Rehncrona S, Speelman JD, Sydow O, topography of parkinsonism. J Cereb Blood Flow Metab 1994; 14: Benabid AL. Multicentre European study of thalamic stimulation for 783–801. parkinsonian tremor: a 6 year follow-up. J Neurol Neurosurg Elble R, Koller W. Tremor. Baltimore, United States: Johns Hopkins Psychiatry 2008; 79: 694–9. University Press; 1990. Hayes AE, Davidson MC, Keele SW, Rafal RD. Toward a functional ana- Elble RJ. Central mechanisms of tremor. J Clin Neurophysiol 1996; 13: lysis of the basal ganglia. J Cogn Neurosci 1998; 10: 178–98. 133–44. Helmich RC, Aarts E, de Lange FP, Bloem BR, Toni I. Increased depend- Elble RJ. Tremor and dopamine agonists. Neurology 2002; 58: S57–S62. ence of action selection on recent motor history in Parkinson’s disease. Engel AK, Fries P. Beta-band oscillations - signalling the status quo? Curr J Neurosci 2009; 29: 6105–13. Opin Neurobiol 2010; 20: 156–65. Helmich RC, Bloem BR, Toni I. Motor imagery evokes increased somato- Fahn S. Classiﬁcation of movement disorders. Mov Disord 2011; 26: sensory activity in parkinson’s disease patients with tremor. Hum 947–57. Brain Mapp 2011a. Advance Access published on June 14, 2011, Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra doi:10.1002/hbm.21318. regional selectivity. Brain 1991; 114 (Pt 5): 2283–301. Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunc- Filion M, Tremblay L, Bedard PJ. Abnormal inﬂuences of passive limb tion drives a cerebellothalamic circuit into Parkinson tremor. Ann movement on the activity of globus pallidus neurons in parkinsonian Neurol 2011b; 69: 269–81. monkeys. Brain Res 1988; 444: 165–76. Hirai T, Jones EG. A new parcellation of the human thalamus on the basis Fishman PS. Paradoxical aspects of parkinsonian tremor. Mov Disord of histochemical staining. Brain Res Brain Res Rev 1989; 14: 1–34. 2008; 23: 168–73. Hirsch EC, Mouatt A, Faucheux B, Bonnet AM, Javoy-Agid F, Fonnum F, Stormmathisen J, Divac I. Biochemical-evidence for glutamate Graybiel AM, Agid Y. Dopamine, tremor, and Parkinson’s disease. as neurotransmitter in corticostriatal and corticothalamic ﬁbers in Lancet 1992; 340: 125–6. rat-brain. Neuroscience 1981; 6: 863–73. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Forsaa EB, Larsen JP, Wentzel-Larsen T, Alves G. What predicts mortality Neurology 1967; 17: 427–42. in Parkinson disease?: a prospective population-based long-term study. Homberg V, Hefter H, Reiners K, Freund HJ. Differential effects Neurology 2010; 75: 1270–76. of changes in mechanical limb properties on physiological and Fraix V, Pollak P, Moro E, Chabardes S, Xie J, Ardouin C, Benabid AL. pathological tremor. J Neurol Neurosurg Psychiatry 1987; 50: Subthalamic nucleus stimulation in tremor dominant parkinsonian pa- 568–79. tients with previous thalamic surgery. J Neurol Neurosurg Psychiatry Hoover JE, Strick PL. The organization of cerebellar and basal ganglia 2005; 76: 246–8. outputs to primary motor cortex as revealed by retrograde transneur- Francois C, Savy C, Jan C, Tande D, Hirsch EC, Yelnik J. Dopaminergic onal transport of herpes simplex virus type 1. J Neurosci 1999; 19: innervation of the subthalamic nucleus in the normal state, in 1446–163. MPTP-treated monkeys, and in Parkinson’s disease patients. J Comp Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic study of Neurol 2000; 425: 121–9. 100 cases of Parkinson’s disease. Arch Neurol 1993; 50: 140–8. Francois C, Yelnik J, Tande D, Agid Y, Hirsch EC. Dopaminergic cell Hurtado JM, Gray CM, Tamas LB, Sigvardt KA. Dynamics of group A8 in the monkey: anatomical organization and projections to tremor-related oscillations in the human globus pallidus: a single case the striatum. J Comp Neurol 1999; 414: 334–47. study. Proc Natl Acad Sci U S A 1999; 96: 1674–79. Fukuda M, Barnes A, Simon ES, Holmes A, Dhawan V, Giladi N, Hurtado JM, Lachaux JP, Beckley DJ, Gray CM, Sigvardt KA. Inter- and Fodstad H, Ma Y, Eidelberg D. Thalamic stimulation for parkinsonian intralimb oscillator coupling in parkinsonian tremor. Mov Disord 2000; tremor: correlation between regional cerebral blood ﬂow and physio- 15: 683–91. logical tremor characteristics. Neuroimage 2004; 21: 608–15. Isaias IU, Benti R, Cilia R, Canesi M, Marotta G, Gerundini P, Pezzoli G, Gao JB. Analysis of amplitude and frequency variations of essential and Antonini A. [123I]FP-CIT striatal binding in early Parkinson’s disease Parkinsonian tremors. Med Biol Eng Comput 2004; 42: 345–9. patients with tremor vs. akinetic-rigid onset. Neuroreport 2007; 18: German DC, Dubach M, Askari S, Speciale SG, Bowden DM. 1499–502. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian Jahnsen H, Llinas R. Ionic basis for the electro-responsiveness and oscil- syndrome in Macaca fascicularis: which midbrain dopaminergic neu- latory properties of guinea-pig thalamic neurones in vitro. J Physiol rons are lost? Neuroscience 1988; 24: 161–74. 1984; 349: 227–47. Ghaemi M, Raethjen J, Hilker R, Rudolf J, Sobesky J, Deuschl G, Jan C, Francois C, Tande D, Yelnik J, Tremblay L, Agid Y, Hirsch E. Heiss WD. Monosymptomatic resting tremor and Parkinson’s disease: Dopaminergic innervation of the pallidum in the normal state, in a multitracer positron emission tomographic study. Mov Disord 2002; MPTP-treated monkeys and in parkinsonian patients. Eur J Neurosci 17: 782–8. 2000; 12: 4525–35. 3224 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Jankovic J, Kapadia AS. Functional decline in Parkinson disease. Arch Landisman CE, Connors BW. VPM and PoM nuclei of the rat somato- Neurol 2001; 58: 1611–5. sensory thalamus: intrinsic neuronal properties and corticothalamic Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, feedback. Cereb Cortex 2007; 17: 2853–65. Huber S, Koller W, Olanow C, Shoulson I. Variable expression of Lee RG, Stein RB. Resetting of tremor by mechanical perturbations: a Parkinson’s disease: a base-line analysis of the DATATOP cohort. comparison of essential tremor and parkinsonian tremor. Ann Neurol The Parkinson Study Group. Neurology 1990; 40: 1529–34. 1981; 10: 523–31. Jankovic J, Schwartz KS, Ondo W. Re-emergent tremor of Parkinson’s Lees AJ. Unresolved issues relating to the shaking palsy on the celebra- disease. J Neurol Neurosurg Psychiatry 1999; 67: 646–50. tion of James Parkinson’s 250th birthday. Mov Disord 2007; 22 (Suppl Jellinger KA. Post mortem studies in Parkinson’s disease—is it possible to 17): S327–34. detect brain areas for speciﬁc symptoms? J Neural Transm 1999; 56 Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009; 373: (Suppl): 1–29. 2055–66. Jenkinson N, Brown P. New insights into the relationship between dopa- Lenz FA, Kwan HC, Martin RL, Tasker RR, Dostrovsky JO, Lenz YE. mine, beta oscillations and motor function. Trends Neurosci 2011; 34 Single unit analysis of the human ventral thalamic nuclear group. (12): 611–8. Tremor-related activity in functionally identiﬁed cells. Brain 1994; Kassubek J, Juengling FD, Hellwig B, Knauff M, Spreer J, Lucking CH. 117 (Pt 3): 531–43. Hypermetabolism in the ventrolateral thalamus in unilateral Lenz FA, Tasker RR, Kwan HC, Schnider S, Kwong R, Murayama Y, Parkinsonian resting tremor: a positron emission tomography study. Dostrovsky JO, Murphy JT. Single unit analysis of the human ventral Neurosci Lett 2001; 304: 17–20. thalamic nuclear group: correlation of thalamic "tremor cells" with the Kassubek J, Juengling FD, Hellwig B, Spreer J, Lucking CH. Thalamic gray 3-6 Hz component of parkinsonian tremor. J Neurosci 1988; 8: matter changes in unilateral Parkinsonian resting tremor: a voxel-based 754–64. morphometric analysis of 3-dimensional magnetic resonance imaging. Leu-Semenescu S, Roze E, Vidailhet M, Legrand AP, Trocello JM, Neurosci Lett 2002; 323: 29–32. Cochen V, Sangla S, Apartis E. Myoclonus or tremor in orthostatism: Kim DG, Koo YH, Kim OJ, Oh SH. Development of Holmes’ tremor in a an under-recognized cause of unsteadiness in Parkinson’s disease. Mov patient with Parkinson’s disease following acute cerebellar infarction. Disord 2007; 22: 2063–9. Mov Disord 2009; 24: 463–4. Levy R, Hutchison WD, Lozano AM, Dostrovsky JO. High-frequency Kim HJ, Jeon BS, Paek SH, Lee JY, Kim HJ, Kim CK, Kim DG. Bilateral synchronization of neuronal activity in the subthalamic nucleus subthalamic deep brain stimulation in Parkinson disease patients with of parkinsonian patients with limb tremor. J Neurosci 2000; 20: severe tremor. Neurosurgery 2010; 67: 626–32. 7766–75. Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss Levy R, Hutchison WD, Lozano AM, Dostrovsky JO. Synchronized neur- in the striatum of patients with idiopathic Parkinson’s disease. onal discharge in the basal ganglia of parkinsonian patients is limited Pathophysiologic and clinical implications. N Engl J Med 1988; 318: to oscillatory activity. J Neurosci 2002; 22: 2855–61. 876–80. Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Kloppel S, Mangin JF, Vongerichten A, Frackowiak RSJ, Siebner HR. Heterogeneity of Parkinson’s disease in the early clinical stages using a Nurture versus nature: long-term impact of forced right-handedness data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343–8. on structure of pericentral cortex and basal ganglia. J Neurosci 2010; Llinas R, Urbano FJ, Leznik E, Ramirez RR, van Marle HJ. Rhythmic and 30: 3271–75. dysrhythmic thalamocortical dynamics: GABA systems and the edge Koh SB, Kwon DY, Seo WK, Kim JH, Kim JH, Lee SH, Oh K, Kim BJ, effect. Trends Neurosci 2005; 28: 325–33. Park KW. Dissociation of cardinal motor signs in Parkinson’s disease Llinas RR. The intrinsic electrophysiological properties of mammalian patients. Eur Neurol 2010; 63: 307–10. neurons: insights into central nervous system function. Science 1988; Koller WC, Busenbark K, Miner K. The relationship of essential tremor to 242: 1654–64. other movement disorders: report on 678 patients. Essential Tremor Lo RY, Tanner CM, Albers KB, Leimpeter AD, Fross RD, Bernstein AL, Study Group. Ann Neurol 1994; 35: 717–23. McGuire V, Quesenberry CP, Nelson LM, Van Den Eeden SK. Clinical Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, features in early Parkinson disease and survival. Arch Neurol 2009; 66: Koudsie A, Limousin PD, Benazzouz A, LeBas JF, Benabid AL, 1353–8. Pollak P. Five-year follow-up of bilateral stimulation of the subthalamic Louis ED, Frucht SJ. Prevalence of essential tremor in patients with nucleus in advanced Parkinson’s disease. N Engl J Med 2003; 349: Parkinson’s disease vs. Parkinson-plus syndromes. Mov Disord 2007; 1925–34. 22: 1402–7. Krack P, Dostrovsky J, Ilinsky I, Kultas-Ilinsky K, Lenz F, Lozano A, Louis ED, Levy G, Cote LJ, Mejia H, Fahn S, Marder K. Clinical correlates Vitek J. Surgery of the motor thalamus: problems with the present of action tremor in Parkinson disease. Arch Neurol 2001; 58: 1630–4. nomenclatures. Mov Disord 2002; 17 (Suppl 3): S2–S8. Louis ED, Pullman SL, Eidelberg D, Dhawan V. Re-emergent tremor Krack P, Pollak P, Limousin P, Benazzouz A, Benabid AL. Stimulation of without accompanying rest tremor in Parkinson’s disease. Can J subthalamic nucleus alleviates tremor in Parkinson’s disease. Lancet Neurol Sci 2008; 35: 513–5. 1997; 350: 1675. Louis ED, Tang MX, Cote L, Alfaro B, Mejia H, Marder K. Progression Kuhn AA, Kupsch A, Schneider GH, Brown P. Reduction in sub- of parkinsonian signs in Parkinson disease. Arch Neurol 1999; 56: thalamic 8-35 Hz oscillatory activity correlates with clinical 334–7. improvement in Parkinson’s disease. Eur J Neurosci 2006; 23: Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, 1956–60. Hutchinson WD, Dostrovsky JO. Effect of GPi pallidotomy on motor Kuhn AA, Williams D, Kupsch A, Limousin P, Hariz M, Schneider GH, function in Parkinson’s disease. Lancet 1995; 346: 1383–7. Yarrow K, Brown P. Event-related beta desynchronization in human Magnin M, Morel A, Jeanmonod D. Single-unit analysis of the pallidum, subthalamic nucleus correlates with motor performance. Brain 2004; thalamus and subthalamic nucleus in parkinsonian patients. 127: 735–46. Neuroscience 2000; 96: 549–64. Kultas-Ilinsky K, Sivan-Loukianova E, Ilinsky IA. Reevaluation of the pri- McAuley JH, Marsden CD. Physiological and pathological tremors and mary motor cortex connections with the thalamus in primates. J Comp rhythmic central motor control. Brain 2000; 123 (Pt 8): 1545–67. Neurol 2003; 457: 133–58. Mink JW. The basal ganglia: focused selection and inhibition of compet- Kumar R, Lozano AM, Kim YJ, Hutchison WD, Sime E, Halket E, ing motor programs. Prog Neurobiol 1996; 50: 381–425. Lang AE. Double-blind evaluation of subthalamic nucleus deep brain Moran A, Bergman H, Israel Z, Bar-Gad I. Subthalamic nucleus functional stimulation in advanced Parkinson’s disease. Neurology 1998; 51: organization revealed by parkinsonian neuronal oscillations and syn- 850–5. chrony. Brain 2008; 131: 3395–409. Parkinson tremor: causes and consequences Brain 2012: 135; 3206–3226 | 3225 Moran RJ, Mallet N, Litvak V, Dolan RJ, Magill PJ, Friston KJ, Brown P. Rajput AH, Pahwa R, Pahwa P, Rajput A. Prognostic signiﬁcance of the Alterations in brain connectivity underlying beta oscillations in onset mode in parkinsonism. Neurology 1993; 43: 829–30. Rajput AH, Sitte HH, Rajput A, Fenton ME, Piﬂ C, Hornykiewicz O. Parkinsonism. Plos Comput Biol 2011; 7: e1002124. Mounayar S, Boulet S, Tande D, Jan C, Pessiglione M, Hirsch EC, Feger J, Globus pallidus dopamine and Parkinson motor subtypes: clinical and Savasta M, Francois C, Tremblay L. A new model to study compen- brain biochemical correlation. Neurology 2008; 70: 1403–10. satory mechanisms in MPTP-treated monkeys exhibiting recovery. Rajput AH, Voll A, Rajput ML, Robinson CA, Rajput A. Course in Brain 2007; 130: 2898–914. Parkinson disease subtypes: a 39-year clinicopathologic study. Mure H, Hirano S, Tang CC, Isaias IU, Antonini A, Ma Y, Dhawan V, Neurology 2009; 73: 206–12. Eidelberg D. Parkinson’s disease tremor-related metabolic network: Rascol O, Sabatini U, Fabre N, Brefel C, Loubinoux I, Celsis P, characterization, progression, and treatment effects. Neuroimage Senard JM, Montastruc JL, Chollet F. The ipsilateral cerebellar hemi- 2011; 54: 1244–53. sphere is overactive during hand movements in akinetic parkinsonian Nambu A, Tokuno H, Hamada I, Kita H, Imanishi M, Akazawa T, patients. Brain 1997; 120: 103–10. Ikeuchi Y, Hasegawa N. Excitatory cortical inputs to pallidal neurons Raz A, Vaadia E, Bergman H. Firing patterns and correlations of spon- via the subthalamic nucleus in the monkey. J Neurophysiol 2000; 84: taneous discharge of pallidal neurons in the normal and the tremulous 289–300. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine vervet model of parkin- Ni Z, Pinto AD, Lang AE, Chen R. Involvement of the cerebello- sonism. J Neurosci 2000; 20: 8559–71. thalamocortical pathway in Parkinson disease. Ann Neurol 2010; 68: Reck C, Florin E, Wojtecki L, Krause H, Groiss S, Voges J, Maarouf M, 816–24. Sturm V, Schnitzler A, Timmermann L. Characterisation of Ohye C, Shibazaki T, Hirai T, Wada H, Hirato M, Kawashima Y. Further tremor-associated local ﬁeld potentials in the subthalamic nucleus in Physiological observations on the ventralis intermedius neurons in the Parkinson’s disease. Eur J Neurosci 2009; 29: 599–612. human thalamus. J Neurophysiol 1989; 61: 488–500. Rehncrona S, Johnels B, Widner H, Tornqvist AL, Hariz M, Sydow O. Oiwa Y, Eberling JL, Nagy D, Pivirotto P, Emborg ME, Bankiewicz KS. Long-term efﬁcacy of thalamic deep brain stimulation for tremor: Overlesioned hemiparkinsonian non human primate model: correlation double-blind assessments. Mov Disord 2003; 18: 163–70. between clinical, neurochemical and histochemical changes. Front Remy P, de Recondo A, Defer G, Loc’h C, Amarenco P, Plante- Biosci 2003; 8: a155–66. Bordeneuve V, Dao-Castellana MH, Bendriem B, Crouzel C, Owen AM, Doyon J, Dagher A, Sadikot A, Evans AC. Abnormal basal Clanet M. Peduncular ’rubral’ tremor and dopaminergic denervation: ganglia outﬂow in Parkinson’s disease identiﬁed with PET. Implications a PET study. Neurology 1995; 45: 472–7. for higher cortical functions. Brain 1998; 121 (Pt 5): 949–65. Rivlin-Etzion M, Elias S, Heimer G, Bergman H. Computational physi- Pare D, Curro’Dossi R, Steriade M. Neuronal basis of the parkinsonian ology of the basal ganglia in Parkinson’s disease. Prog Brain Res resting tremor: a hypothesis and its implications for treatment. 2010; 183: 259–73. Neuroscience 1990; 35: 217–26. Rivlin-Etzion M, Marmor O, Heimer G, Raz A, Nini A, Bergman H. Basal Paulus W, Jellinger K. The neuropathologic basis of different clinical sub- ganglia oscillations and pathophysiology of movement disorders. Curr groups of Parkinson’s disease. J Neuropathol Exp Neurol 1991; 50: Opin Neurobiol 2006; 16: 629–37. 743–55. Rivlin-Etzion M, Marmor O, Saban G, Rosin B, Haber SN, Vaadia E, Percheron G, Francois C, Talbi B, Yelnik J, Fenelon G. The primate motor Prut Y, Bergman H. Low-pass ﬁlter properties of basal ganglia cortical thalamus. Brain Res Brain Res Rev 1996; 22: 93–181. muscle loops in the normal and MPTP primate model of parkinsonism. Pessiglione M, Guehl D, Rolland AS, Francois C, Hirsch EC, Feger J, J Neurosci 2008; 28: 633–49. Tremblay L. Thalamic neuronal activity in dopamine-depleted primates: Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, evidence for a loss of functional segregation within basal ganglia cir- Bezard E, Obeso JA. Initial clinical manifestations of Parkinson’s dis- cuits. J Neurosci 2005; 25: 1523–31. ease: features and pathophysiological mechanisms. Lancet Neurol Pirker W. Correlation of dopamine transporter imaging with parkinsonian 2009; 8: 1128–39. motor handicap: how close is it? Mov Disord 2003; 18 (Suppl 7): Ropper AH, Samuels MA. Adams & Victor’s principles of neurology. S43–S51. 9 edn. McGraw-Hill Medical; 2009. p. 93. Plaha P, Ben Shlomo Y, Patel NK, Gill SS. Stimulation of the caudal zona Rosin B, Slovik M, Mitelman R, Rivlin-Etzion M, Haber SN, Israel Z, incerta is superior to stimulation of the subthalamic nucleus in improv- Vaadia E, Bergman H. Closed-loop deep brain stimulation is superior in ameliorating parkinsonism. Neuron 2011; 72: 370–84. ing contralateral parkinsonism. Brain 2006; 129: 1732–47. Rossi C, Frosini D, Volterrani D, De Feo P, Unti E, Nicoletti V, Kiferle L, Plaha P, Filipovic S, Gill SS. Induction of parkinsonian resting tremor by Bonuccelli U, Ceravolo R. Differences in nigro-striatal impairment in stimulation of the caudal zona incerta nucleus: a clinical study. clinical variants of early Parkinson’s disease: evidence from a FP-CIT J Neurol Neurosurg Psychiatry 2008; 79: 514–21. Plenz D, Kital ST. A basal ganglia pacemaker formed by the subthalamic SPECT study. Eur J Neurol 2010; 17: 626–30. Rouiller EM, Tanne J, Moret V, Kermadi I, Boussaoud D, Welker E. Dual nucleus and external globus pallidus. Nature 1999; 400: 677–82. Pollak P, Krack P, Fraix V, Mendes A, Moro E, Chabardes S, morphology and topography of the corticothalamic terminals originat- Benabid AL. Intraoperative micro- and macrostimulation of the ing from the primary, supplementary motor, and dorsal premotor cor- subthalamic nucleus in Parkinson’s disease. Mov Disord 2002; 17 tical areas in macaque monkeys. J Comparative Neurol 1998; 396: (Suppl 3): S155–61. 169–85. Pollock LJ, Davis L. Muscle tone in parkinsonian states. Arch Neurol Sanchez-Gonzalez MA, Garcia-Cabezas MA, Rico B, Cavada C. The pri- Psychiatry 1930; 23: 303–19. mate thalamus is a key target for brain dopamine. J Neurosci 2005; Pollok B, Makhlouﬁ H, Butz M, Gross J, Timmermann L, Wojtecki L, 25: 6076–83. Schnitzler A. Levodopa affects functional brain networks in parkinso- Schiess MC, Zheng H, Soukup VM, Bonnen JG, Nauta HJ. Parkinson’s nian resting tremor. Mov Disord 2009; 24: 91–8. disease subtypes: clinical classiﬁcation and ventricular cerebrospinal Probst-Cousin S, Druschky A, Neundorfer B. Disappearance of resting ﬂuid analysis. Parkinsonism Relat Disord 2000; 6: 69–76. tremor after "stereotaxic" thalamic stroke. Neurology 2003; 61: Schneider SA, Edwards MJ, Mir P, Cordivari C, Hooker J, Dickson J, 1013–4. Quinn N, Bhatia KP. Patients with adult-onset dystonic tremor resem- Rack PM, Ross HF. The role of reﬂexes in the resting tremor of bling parkinsonian tremor have scans without evidence of dopamin- Parkinson’s disease. Brain 1986; 109 (Pt 1): 115–41. ergic deﬁcit (SWEDDs). Mov Disord 2007; 22: 2210–5. Raethjen J, Lindemann M, Schmaljohann H, Wenzelburger R, Pﬁster G, Seidel S, Kasprian G, Leutmezer F, Prayer D, Auff E. Disruption of nigros- Deuschl G. Multiple oscillators are causing parkinsonian and essential triatal and cerebellothalamic pathways in dopamine responsive tremor. Mov Disord 2000; 15: 84–94. Holmes’ tremor. J Neurol Neurosurg Psychiatry 2009; 80: 921–3. 3226 | Brain 2012: 135; 3206–3226 R. C. Helmich et al. Selikhova M, Williams DR, Kempster PA, Holton JL, Revesz T, Lees AJ. A Vidailhet M, Dupel C, Lehericy S, Remy P, Dormont D, Serdaru M, clinico-pathological study of subtypes in Parkinson’s disease. Brain Jedynak P, Veber H, Samson Y, Marsault C, Agid Y. Dopaminergic 2009; 132: 2947–57. dysfunction in midbrain dystonia: anatomoclinical study using Sidibe M, Bevan MD, Bolam JP, Smith Y. Efferent connections of the 3-dimensional magnetic resonance imaging and ﬂuorodopa F 18 posi- internal globus pallidus in the squirrel monkey: I. Topography and tron emission tomography. Arch Neurol 1999; 56: 982–9. synaptic organization of the pallidothalamic projection. J Comp Wallman MJ, Gagnon D, Parent M. Serotonin innervation of human Neurol 1997; 382: 323–47. basal ganglia. Eur J Neurosci 2011; 33: 1519–32. Smith Y, Lavoie B, Dumas J, Parent A. Evidence for a distinct nigropallidal Walshe FMR. Observations on the nature of muscular rigidity of paralysis dopaminergic projection in the squirrel monkey. Brain Res 1989; 482: agitans, and on its relationship to tremor. Brain 1924; 47: 159–77. 381–6. Wang SY, Aziz TZ, Stein JF, Liu X. Time-frequency analysis of transient Spiegel J, Hellwig D, Samnick S, Jost W, Mollers MO, Fassbender K, neuromuscular events: dynamic changes in activity of the subthalamic Kirsch CM, Dillmann U. Striatal FP-CIT uptake differs in the nucleus and forearm muscles related to the intermittent resting tremor. subtypes of early Parkinson’s disease. J Neural Transm 2007; 114: J Neurosci Methods 2005; 145: 151–8. 331–5. Williams-Gray CH, Evans JR, Goris A, Foltynie T, Ban M, Robbins TW, Sung YF, Hsu YD, Huang WS. (99m)Tc-TRODAT-1 SPECT study in Brayne C, Kolachana BS, Weinberger DR, Sawcer SJ, Barker RA. The evaluation of Holmes tremor after thalamic hemorrhage. Ann Nucl distinct cognitive syndromes of Parkinson’s disease: 5 year follow-up Med 2009; 23: 605–8. of the CamPaIGN cohort. Brain 2009; 132: 2958–69. Timmermann L, Gross J, Dirks M, Volkmann J, Freund HJ, Schnitzler A. Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. The cerebral oscillatory network of parkinsonian resting tremor. Brain Evolution of cognitive dysfunction in an incident Parkinson’s disease 2003; 126: 199–212. cohort. Brain 2007; 130: 1787–98. Toth C, Rajput M, Rajput AH. Anomalies of asymmetry of clinical signs in Wu D, Warwick K, Ma Z, Gasson MN, Burgess JG, Pan S, Aziz TZ. parkinsonism. Mov Disord 2004; 19: 151–7. Prediction of Parkinson’s disease tremor onset using a radial basis Vakil E, Herishanu-Naaman S. Declarative and procedural learning in function neural network based on particle swarm optimization. Int J Parkinson’s disease patients having tremor or bradykinesia as the pre- Neural Syst 2010a; 20: 109–116. dominant symptom. Cortex 1998; 34: 611–20. Wu T, Wang LA, Hallett M, Li KC, Chan P. Neural correlates of bimanual Valls-Sole J, Pascualleone A, Brasilneto JP, Cammarota A, Mcshane L, anti-phase and in-phase movements in Parkinson’s disease. Brain Hallett M. Abnormal facilitation of the response to transcranial mag- 2010b; 133: 2394–409. netic stimulation in patients with Parkinsons-disease. Neurology 1994; Yu H, Sternad D, Corcos DM, Vaillancourt DE. Role of hyperactive cere- 44: 735–41. bellum and motor cortex in Parkinson’s disease. Neuroimage 2007; 35: van Duinen H, Zijdewind I, Hoogduin H, Maurits N. Surface EMG meas- 222–33. urements during fMRI at 3T: accurate EMG recordings after artifact Zaidel A, Arkadir D, Israel Z, Bergman H. Akineto-rigid vs. tremor syn- correction. Neuroimage 2005; 27: 240–6. dromes in Parkinsonism. Curr Opin Neurol 2009; 22: 387–93. Van Quyen M, Bragin A. Analysis of dynamic brain oscillations: meth- Zetusky WJ, Jankovic J, Pirozzolo FJ. The heterogeneity of Parkinson’s odological advances. Trends Neurosci 2007; 30: 365–73. disease: clinical and prognostic implications. Neurology 1985; 35: van Rootselaar AF, Maurits NM, Renken R, Koelman JH, Hoogduin JM, 522–6. Leenders KL, Tijssen MA. Simultaneous EMG-functional MRI record- Zirh TA, Lenz FA, Reich SG, Dougherty PM. Patterns of bursting occur- ings can directly relate hyperkinetic movements to brain activity. Hum ring in thalamic cells during parkinsonian tremor. Neuroscience 1998; Brain Mapp 2008; 29: 1430–41. 83: 107–21.

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Brain – Pubmed Central

Published: Mar 1, 2012

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Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits?

Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits?

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Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits?

Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits?

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