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Tremor: Pathophysiology
Parkinsonism and Related Disorders 20S1 (2014) S118–S122
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Tremor: Pathophysiology Mark Hallett * Human Motor Control Section, NINDS, NIH, Bethesda, MD, USA
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summary
Keywords: Tremor Parkinson’s disease Essential tremor Basal ganglia Cerebellum Inferior olive Ataxia Beta activity Brain networks Oscillators
The precise way that tremors emerge is not well known, but there is some good information and hypotheses. This review will focus on the classic (“rest”) tremor of Parkinson disease and essential tremor. Both have their genesis in central oscillators, which appear to be malfunctioning networks. With classic Parkinson tremor, there appears to be dysfunction of the basal ganglia network and the cerebello– thalamo–cortical network. There is evidence that the basal ganglia network triggers the onset of tremor and the cerebellar network is responsible for the amplitude. Since it is a tremor of stability, the beta activity of the basal ganglia may be the trigger. With essential tremor, the cerebello–thalamo–cortical network itself is dysfunctional and perhaps the inferior olive–cerebellar network as well. This is a tremor of action, and the associated ataxia suggests that delays in motor control processing may set up the oscillation.
1. Introduction Given how common tremor is, it is surprising how little we really understand about its pathophysiology. There are many different types of tremor and the pathophysiologies will certainly differ. This review will begin with a broad theoretical background and then emphasize the most common types of tremor. The motor system attempts to control the position of body parts either at rest, in posture or during certain tasks. The control problem is difficult with many degrees of freedom of each body part and a complex central nervous system controller. The general description of a controller is that there is a motor command for a certain position, a system to implement the command, and feedback to indicate how well the command is being carried out. Feedback is used to modulate the command if the body part does not have the exact desired position. However, feedback takes time and the interaction of the original command and the feedback information might be complicated. This process may well become unstable; such instabilities are often oscillatory and this would generate tremor. Any body part is a physical object with mechanical properties. Two of those properties are its weight and its stiffness. If the object gets some mechanical energy, it will tend to oscillate with a frequency proportional to the square root of the ratio of the stiffness divided by the weight. This defines the resonant frequency of an object. With more weight, for example, the frequency will * Correspondence: Mark Hallett, MD, Chief, Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 7D37, 10 Center Drive, Bethesda, MD 20892–1428, USA. Tel.: +1 301 496 9526; fax: +1 301 480 2286. E-mail address: [email protected] (M. Hallett). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
© 2013 Elsevier Ltd. All rights reserved.
be slower. Thus, any body part will have some tremor depending on its characteristics and the amount of energy. One source of energy in humans comes from cardiac motion. If a body part is unsupported it will oscillate at its resonant frequency. This is the origin of an important component of physiological tremor, the natural low amplitude tremor of all body parts. Physiological tremor can be recognized by its characteristic that it will change frequency depending on weight and stiffness. In the laboratory, weighting a limb will lead to a lower frequency. Each body part is connected to the central nervous system. Muscles get the motor command and feedback returns from a variety of sensory receptors. Some of these sensory afferents feedback immediately on the alpha-motoneurons in the spinal cord, producing short loops. The shortest loop comes from the monosynaptic connection of the Ia spindle afferent on the alpha motoneuron, which is responsible for the tendon reflex and much of the H reflex. There are other short loops as well all within the spinal segment, but there are also longer loops, some to brainstem and others to the cerebellum or all the way back to the motor cortex. Hence there are multiple feedback loops all with different timing, critical for optimal control, but providing considerable opportunity for instability. When the excitability of the short latency spinal feedback loops is enhanced, it can couple with the natural resonance of a body part and produce exaggerated physiological tremor. In this circumstance, the tremor frequency will still change with weighting, but the reflexes will participate as demonstrated by EMG bursting in phase with the tremor. In this situation, the peripheral oscillation is the tremor generator and is augmented by the increased spinal excitability. Another mechanism is responsible for most pathological tremors and that is a central nervous system generator. Central nervous
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system generators can be of two types. One would be an unstable loop circuit within the central nervous system, similar to the peripheral loop described earlier. Another would be a nucleus with spontaneous rhythmicity, the spontaneity arising from ion channels in the membrane of the neurons that lead to repetitive depolarizations, generally following hyperpolarizations. A relevant channel in this regard is a low threshold calcium channel. Such nuclei can participate in recurrent circuits in the brain, so there might be abnormal local rhythmicity that drives an otherwise normal circuit. 2. Classic Parkinson tremor Patients with Parkinson disease can have many tremor types. The most common is often called tremor at rest, but this tremor can reappear in posture after a pause (“re-emergent tremor”). Then it is a type of action tremor. There are also separate types of action tremors that can be seen in Parkinson patients. Hence, this tremor is best referred to as “classic tremor” without the erroneous implication that it is only seen at rest. The tremor can be most annoying, for example, when a patient is holding a newspaper to read. It appears that it might be a tremor that is most prominent in stable states – either rest or an unchanging posture. It tends to go away with kinetic movements, such as going from rest to posture or doing a specific task. There is good evidence that classic tremor is pathophysiologically separate from bradykinesia and rigidity [1]. Clinically, the manifestations are separate, and the response of tremor to dopaminergic agents is less certain than bradykinesia. Putaminal dopamine content, measured with SPECT or PET or even postmortem, does not correlate with tremor. There is a possible dopamine connection, however. One post-mortem study linked dopamine content of the retrorubral area to tremor severity. A more recent study linked dopamine SPECT of the globus pallidus to tremor [2,3]. Hence, if there is a dopamine connection, it is not the traditional nigrostriatal pathway that is relevant. There is evidence from neuroimaging studies that serotonin might be more relevant than dopamine to classic tremor. A PET study with a ligand that binds to the 5-HT1A receptor indicated that there is more tremor with less binding in the raphe [4]. A more recent study, however, re-evaluating this observation in more detail, indicated that the correlation is more with postural tremor than rest tremor [5]. It has been uncertain what to make of these observations, since, at least so far, manipulating serotonin does not seem to be an influential modulator of tremor. The oscillatory network in the brain that correlates with tremor has been identified with several techniques. A pattern has emerged from FDG PET scans. In a large group of patient scans, the correlate to the amount of tremor included activity in the dentate nucleus and rostral parts of the cerebellum, the putamen and the motor cortex [6]. Using magnetoencephalography during tremor, it is possible to look at the link between brain activity and EMG bursting with corticomuscular coherence and corticocortical coherence [7]. Corticomuscular coherence shows the contralateral primary motor cortex (M1) most strongly indicating that M1 is the main driver of the tremor. Corticocortical coherence reveals those structures oscillating with M1 to be the secondary somatosensory cortex, the posterior parietal cortex, the cingulate and supplementary motor areas, the diencephalon and the cerebellum. In another study, fMRI was used and separately correlated brain activity with the onset of tremor periods and the amplitude of tremor during the tremor periods (Fig. 1) [3]. Correlating with onset is activity in the putamen and both divisions of the globus pallidus. Correlating with amplitude is activity in the cerebellum, VIM nucleus of the thalamus and motor and premotor cortex. While these studies are
Fig. 1. Functional MRI of Parkinson classic tremor. The graphs show activation in the motor cortex on top and in the internal division of the globus pallidus on the bottom. In each part, there are lines for the MRI activity, the tremor amplitude and the tremor on or offset. Note the correlation of tremor amplitude and motor cortex activity and the correlation of tremor on/offset with pallidal activity. Figure modified from [3] with permission.
not completely concordant, some features emerge. M1 is likely the major driver and its network with the cerebellum via the thalamus seems to be the principal circuit for tremor amplitude. The fact that the VIM nucleus is such a good surgical target for tremor is consistent. The clever idea of looking particularly at tremor onset activity reveals a role for an abnormal basal ganglia, and suggests that the basal ganglia triggers the cortical–cerebellar circuit to produce the tremor. The model emerges of coupled oscillators of basal ganglia and cerebellar circuits [2,3]. This idea now has strong support from the relatively new anatomical observations showing bidirectional links between basal ganglia and cerebellum. Where in these circuits is the abnormality that produces the tremor? In Parkinson disease there is the basal ganglia abnormality and, of course, that is an important suspect. The possible neurotransmitter abnormalities noted earlier might be a clue in this regard. Recordings from patients undergoing surgery for Parkinson’s disease demonstrate that there are cells in STN and GPi that burst at tremor frequency and can be demonstrated to be in phase with tremor. It is known that different body parts generally oscillate out of phase with each other and this can be appreciated in the cellular recordings as well, as the cells will be in phase with only certain body parts. The tremor frequency cells are intermixed with cells firing at beta frequency, an abnormal activity related to bradykinesia (Fig. 2) [8]. This finding indicates involvement of the basal ganglia, but does not constitute proof of being the initiating factor. The VIM of the thalamus also has cells bursting in tight phase with tremor and since thalamic cells have a low threshold calcium
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Fig. 2. Neuronal firing patterns in the subthalamic nucleus in a patient with Parkinson’s disease. Part A shows three different neurons with both raw data and extracted times of action potentials. Part B shows interspike interval histograms, and Part C the power density for the same three neurons, respectively. Figure from [8] with permission.
channel, there has been a question as to whether these cells could be the pacemaker. The successive interspike intervals in a burst can be interpreted as to whether the neuron is following a tremor generated elsewhere or whether it itself is spontaneously generating the bursts. The findings from two groups are that tremor bursts are generally following and not initiating the tremor [9,10]. In conclusion, it looks like there is a tremor network involving both basal ganglia and cerebellar circuits, but that a specific generator node in the network is not identified. Perhaps the network goes into oscillation as the result of an instability, such as a delay or asynchrony in one part of the network or perhaps excessive synchrony of local groups of neurons. Increased synchrony of neurons related to the beta rhythm is indeed seen in the monkey MPTP model of Parkinson’s disease, and the strong beta rhythm demonstrable in patients with Parkinson’s disease suggests that this is true also in humans [11]. The network oscillates at rest and in stable posture, but does not when a kinetic movement is made. It appears that the motor commands coming through the network disrupt the tremor oscillations, and, indeed, the beta oscillations diminish with voluntary movement [12]. 3. Essential tremor It is traditional to think of essential tremor as a tremor in posture and kinetic action, commonly involving predominantly both arms, with no other neurological deficits. Tremor can involve other body parts such as the head, rarely can be present at rest, and there can be minor amounts of cerebellar ataxia. Essential tremor can also co-exist with dystonia, and, in this circumstance, the question arises as to whether this is an association between two independent disorders or whether this means the tremor is different in type, and should be called dystonic tremor. There are also tremors that look similar to essential tremor, but are task specific, like primary writing tremor. There are enough variations and overlaps that some authorities even question if there really is a pure essential tremor, but I will take the view here that it does exist and can be studied.
Essential tremor often appears to be autosomal dominant, but for some reason mutations have been very difficult to find. There is some evidence for cerebellar involvement in the basic pathophysiology, and this has some face validity given the ataxic features in the patients. Magnetic resonance spectroscopy shows diminished N-acetylaspartate (NAA) [13], and voxelbased morphometry (VBM) shows cerebellar atrophy [14]. Some pathological studies show loss of Purkinje cells and increased torpedoes [15], but other studies suggest that these observations are similar to controls when matched for age [16]. The latter study did, however, find an increased frequency of cerebellar gliosis. (In a different subgroup of patients, Lewy bodies have been seen in the locus coeruleus, but these patients do not look any different clinically to those with cerebellar pathology [15].) An early PET study showed possible abnormality of the inferior olivary nucleus [17], but this has not been confirmed by subsequent neuroimaging studies, and a recent pathology investigation found no abnormality [18]. The cerebellar abnormality might be an abnormality of GABA. Pathology has shown a decrease in GABA-A and GABA-B receptors in the dentate nucleus [19] (but not for GABA-B receptors in cerebellar cortex [20]). A slightly different pathological pattern was found in another study where reduced parvalbumin staining (a marker for a subclass of GABAergic neurons) was found in the locus coeruleus and pons, but not in the cerebellum [21]. Flumazenil PET studies have shown increased binding in the cerebellum indicating increased affinity to the GABA-A receptor, which on the face of it, seems opposite to the pathological finding [22,23]. CSF GABA is diminished, and a tremor looking like essential tremor is seen in mice with a knock-out of the alpha-1 component of the GABA-A receptor. There are also reports of strokes in the cerebellum that eradicated essential tremor on the same side [24]. Considerable attention has been paid to the rodent harmaline model of essential tremor. Harmaline causes tremor that mimics the human condition and this has served as an accurate model to predict the efficacy of drug treatment. Harmaline increases
M. Hallett / Parkinsonism and Related Disorders 20S1 (2014) S118–S122
Fig. 3. Effect of single pulse TMS on essential tremor. Each trace is an average of 25 recordings of rectified EMG from the extensor carpi radialis muscle aligned on the TMS pulse at various intensities. After the motor evoked potential (MEP), there is a silent period (SP) (at least at higher intensities), followed by synchronization of the tremor. Figure from [25] with permission.
the oscillations in the inferior olivary nucleus, and this might occur from one of two mechanisms (or both). The olivary neurons are spontaneously rhythmic, the rhythmicity supported by a low threshold calcium channel. The olivary neuron dendrites come together in clusters called glomeruli where they communicate with each other via gap junctions. In harmaline-induced tremor, the cells are more rhythmic and they communicate more strongly. Perhaps importantly, the gap junction communication is down-modulated by GABA, so a deficiency of GABA would increase synchronicity. The inferior olivary–cerebellar network has been long suspected as being the relevant generator, but the evidence is not strong. The network closely linked to the generation of tremor is certainly the cerebello–thalamo–cortical network. A study with blood flow PET showed hyperactivity of the cerebellum at rest, and then further increase of the cerebellum and abnormal increase of the red nucleus region as well [26]. The VIM nucleus of the cerebellum contains bursting cells strongly linked to tremor bursts, and these cells burst only when the tremor is present [27]. Lesions or DBS of the VIM generally eradicates the tremor. Single pulse transcranial magnetic stimulation (TMS), but not transcranial electrical stimulation (TES) of the primary motor cortex reset essential tremor, implicating the importance of intracortical networks in the primary motor cortex (Fig. 3) [25]. A critical difference of essential tremor and Parkinsonian classic tremor is the setting in which it occurs, action and rest, respectively. It might be that in essential tremor the motor controller involving the cerebellum is dysfunctional. The presence of some ataxia is compatible with that idea. Moreover, there is evidence for a delay in motor control processing. Specifically, the second agonist burst in the ballistic movement pattern is delayed (Fig. 4) [28]. The delay could set up oscillations in the cerebello–thalamo– cortical loop. Interestingly, and perhaps evidence against this idea, the ataxic component might be separable to some extent from the tremor component in these patients. Ataxic gait, similar to tremor, can improve with DBS, but with supra-therapeutic stimulation there is return of ataxia despite continued improvement of tremor [29].
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Fig. 4. Ballistic (rapid) wrist flexion movements of 15 degrees and 60 degrees in a normal subject and a patient with essential tremor. In the normal subject, the movement is initiated with a triphasic pattern of agonist (finger flexors), antagonist (finger extensors) and agonist activity sequentially. In the patient, there is the triphasic pattern with a delayed second agonist burst and then continued alternating activity similar to a damped tremor. Figure modified from [28] with permission.
4. Conclusion The reviewed data give rise to some possible hypotheses for tremor generation. It appears that the direct generator of both classic tremor and essential tremor is the cerebello–thalamo– cortical network. The difference appears to be in how this network is activated to oscillate. In classic tremor, the setting is stability of a body part where an abnormal beta rhythm synchronizes the basal ganglia and in a mechanism still to be elucidated triggers the cerebellar network. In essential tremor, the abnormality appears to be in the cerebellar network itself, and dysfunction of the motor controller for generating an action sets off the oscillation. Clearly much more data are needed to verify these hypotheses. Acknowledgements This work was supported by the NINDS Intramural Program. Conflict of interests The author has no conflict of interest to declare. References [1] Hallett M. Parkinson’s disease tremor: pathophysiology. Parkinsonism Relat Disord 2012;18(Suppl 1):S85–6. [2] Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? Brain 2012;135(Pt–11):3206–26. [3] Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol 2011;69(2): 269–81. [4] Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ. Tremor in Parkinson’s disease and serotonergic dysfunction: an 11 C-WAY 100635 PET study. Neurology 2003;60(4):601–5. [5] Loane C, Wu K, Bain P, Brooks DJ, Piccini P, Politis M. Serotonergic loss in motor circuitries correlates with severity of action-postural tremor in PD. Neurology 2013;80(20):1850–5.
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[6] Mure H, Hirano S, Tang CC, Isaias IU, Antonini A, Ma Y, et al. Parkinson’s disease tremor-related metabolic network: characterization, progression, and treatment effects. Neuroimage 2011;54(2):1244–53. [7] Timmermann L, Gross J, Dirks M, Volkmann J, Freund HJ, Schnitzler A. The cerebral oscillatory network of parkinsonian resting tremor. Brain 2003;126(Pt 1):199–212. [8] Guo S, Zhuang P, Hallett M, Zheng Z, Zhang Y, Li J, et al. Subthalamic deep brain stimulation for Parkinson’s disease: correlation between locations of oscillatory activity and optimal site of stimulation. Parkinsonism Relat Disord 2013;19(1): 109–14. [9] Zirh TA, Lenz FA, Reich SG, Dougherty PM. Patterns of bursting occurring in thalamic cells during parkinsonian tremor. Neuroscience 1998;83(1):107–21. [10] Magnin M, Morel A, Jeanmonod D. Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients. Neuroscience 2000;96(3):549–64. [11] Bergman H, Feingold A, Nini A, Raz A, Slovin H, Abeles M, et al. Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates. Trends Neurosci 1998;21(1):32–8. [12] Joundi RA, Brittain JS, Green AL, Aziz TZ, Brown P, Jenkinson N. Persistent suppression of subthalamic beta-band activity during rhythmic finger tapping in Parkinson’s disease. Clin Neurophysiol 2013;124(3):565–73. [13] Pagan FL, Butman JA, Dambrosia JM, Hallett M. Evaluation of essential tremor with multi-voxel magnetic resonance spectroscopy. Neurology 2003;60(8): 1344–7. [14] Bagepally BS, Bhatt MD, Chandran V, Saini J, Bharath RD, Vasudev MK, et al. Decrease in cerebral and cerebellar gray matter in essential tremor: a voxelbased morphometric analysis under 3T MRI. J Neuroimaging 2012;22(3): 275–8. [15] Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post-mortem enquiry. Lancet Neurol 2010;9(6):613–22. [16] Shill HA, Adler CH, Sabbagh MN, Connor DJ, Caviness JN, Hentz JG, et al. Pathologic findings in prospectively ascertained essential tremor subjects. Neurology 2008;70(16 Pt 2):1452–5. [17] Hallett M, Dubinsky RM. Glucose metabolism in the brain of patients with essential tremor. J Neurol Sci 1993;114:45–8. [18] Louis ED, Babij R, Cortes E, Vonsattel JP, Faust PL. The inferior olivary nucleus:
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a postmortem study of essential tremor cases versus controls. Mov Disord 2013; 28(6):779–86. Paris-Robidas S, Brochu E, Sintes M, Emond V, Bousquet M, Vandal M, et al. Defective dentate nucleus GABA receptors in essential tremor. Brain 2012;135(Pt 1):105–16. Luo C, Rajput AH, Robinson CA, Rajput A. Gamma-aminobutyric acid (GABA)-B receptor 1 in cerebellar cortex of essential tremor. J Clin Neurosci 2012;19(6): 920–1. Shill HA, Adler CH, Beach TG, Lue LF, Caviness JN, Sabbagh MN, et al. Brain biochemistry in autopsied patients with essential tremor. Mov Disord 2012; 27(1):113–7. Boecker H, Weindl A, Brooks DJ, Ceballos-Baumann AO, Liedtke C, Miederer M, et al. GABAergic dysfunction in essential tremor: an 11 C-flumazenil PET study. J Nucl Med 2010;51(7):1030–5. Gironell A, Figueiras FP, Pagonabarraga J, Herance JR, Pascual-Sedano B, Trampal C, et al. GABA and serotonin molecular neuroimaging in essential tremor: a clinical correlation study. Parkinsonism Relat Disord 2012;18(7): 876–80. Dupuis MJ, Evrard FL, Jacquerye PG, Picard GR, Lermen OG. Disappearance of essential tremor after stroke. Mov Disord 2010;25(16):2884–7. Pascual-Leone A, Valls-Sole J, Toro C, Wassermann EM, Hallett M. Resetting of essential tremor and postural tremor in Parkinson’s disease with transcranial magnetic stimulation. Muscle Nerve 1994;17(7):800–7. Wills AJ, Jenkins IH, Thompson PD, Findley LJ, Brooks DJ. Red nuclear and cerebellar but no olivary activation associated with essential tremor: a positron emission tomographic study. Ann Neurol 1994;36:636–42. Hua SE, Lenz FA. Posture-related oscillations in human cerebellar thalamus in essential tremor are enabled by voluntary motor circuits. J Neurophysiol 2005;93(1):117–27. Britton TC, Thompson PD, Day BL, Rothwell JC, Findley LJ, Marsden CD. Rapid wrist movements in patients with essential tremor. The critical role of the second agonist burst. Brain 1994;117(Pt 1):39–47. Fasano A, Herzog J, Raethjen J, Rose FE, Muthuraman M, Volkmann J, et al. Gait ataxia in essential tremor is differentially modulated by thalamic stimulation. Brain 2010;133(Pt 12):3635–48.
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Tremor: Pathophysiology Mark Hallett * Human Motor Control Section, NINDS, NIH, Bethesda, MD, USA
article info
summary
Keywords: Tremor Parkinson’s disease Essential tremor Basal ganglia Cerebellum Inferior olive Ataxia Beta activity Brain networks Oscillators
The precise way that tremors emerge is not well known, but there is some good information and hypotheses. This review will focus on the classic (“rest”) tremor of Parkinson disease and essential tremor. Both have their genesis in central oscillators, which appear to be malfunctioning networks. With classic Parkinson tremor, there appears to be dysfunction of the basal ganglia network and the cerebello– thalamo–cortical network. There is evidence that the basal ganglia network triggers the onset of tremor and the cerebellar network is responsible for the amplitude. Since it is a tremor of stability, the beta activity of the basal ganglia may be the trigger. With essential tremor, the cerebello–thalamo–cortical network itself is dysfunctional and perhaps the inferior olive–cerebellar network as well. This is a tremor of action, and the associated ataxia suggests that delays in motor control processing may set up the oscillation.
1. Introduction Given how common tremor is, it is surprising how little we really understand about its pathophysiology. There are many different types of tremor and the pathophysiologies will certainly differ. This review will begin with a broad theoretical background and then emphasize the most common types of tremor. The motor system attempts to control the position of body parts either at rest, in posture or during certain tasks. The control problem is difficult with many degrees of freedom of each body part and a complex central nervous system controller. The general description of a controller is that there is a motor command for a certain position, a system to implement the command, and feedback to indicate how well the command is being carried out. Feedback is used to modulate the command if the body part does not have the exact desired position. However, feedback takes time and the interaction of the original command and the feedback information might be complicated. This process may well become unstable; such instabilities are often oscillatory and this would generate tremor. Any body part is a physical object with mechanical properties. Two of those properties are its weight and its stiffness. If the object gets some mechanical energy, it will tend to oscillate with a frequency proportional to the square root of the ratio of the stiffness divided by the weight. This defines the resonant frequency of an object. With more weight, for example, the frequency will * Correspondence: Mark Hallett, MD, Chief, Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 7D37, 10 Center Drive, Bethesda, MD 20892–1428, USA. Tel.: +1 301 496 9526; fax: +1 301 480 2286. E-mail address: [email protected] (M. Hallett). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
© 2013 Elsevier Ltd. All rights reserved.
be slower. Thus, any body part will have some tremor depending on its characteristics and the amount of energy. One source of energy in humans comes from cardiac motion. If a body part is unsupported it will oscillate at its resonant frequency. This is the origin of an important component of physiological tremor, the natural low amplitude tremor of all body parts. Physiological tremor can be recognized by its characteristic that it will change frequency depending on weight and stiffness. In the laboratory, weighting a limb will lead to a lower frequency. Each body part is connected to the central nervous system. Muscles get the motor command and feedback returns from a variety of sensory receptors. Some of these sensory afferents feedback immediately on the alpha-motoneurons in the spinal cord, producing short loops. The shortest loop comes from the monosynaptic connection of the Ia spindle afferent on the alpha motoneuron, which is responsible for the tendon reflex and much of the H reflex. There are other short loops as well all within the spinal segment, but there are also longer loops, some to brainstem and others to the cerebellum or all the way back to the motor cortex. Hence there are multiple feedback loops all with different timing, critical for optimal control, but providing considerable opportunity for instability. When the excitability of the short latency spinal feedback loops is enhanced, it can couple with the natural resonance of a body part and produce exaggerated physiological tremor. In this circumstance, the tremor frequency will still change with weighting, but the reflexes will participate as demonstrated by EMG bursting in phase with the tremor. In this situation, the peripheral oscillation is the tremor generator and is augmented by the increased spinal excitability. Another mechanism is responsible for most pathological tremors and that is a central nervous system generator. Central nervous
M. Hallett / Parkinsonism and Related Disorders 20S1 (2014) S118–S122
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system generators can be of two types. One would be an unstable loop circuit within the central nervous system, similar to the peripheral loop described earlier. Another would be a nucleus with spontaneous rhythmicity, the spontaneity arising from ion channels in the membrane of the neurons that lead to repetitive depolarizations, generally following hyperpolarizations. A relevant channel in this regard is a low threshold calcium channel. Such nuclei can participate in recurrent circuits in the brain, so there might be abnormal local rhythmicity that drives an otherwise normal circuit. 2. Classic Parkinson tremor Patients with Parkinson disease can have many tremor types. The most common is often called tremor at rest, but this tremor can reappear in posture after a pause (“re-emergent tremor”). Then it is a type of action tremor. There are also separate types of action tremors that can be seen in Parkinson patients. Hence, this tremor is best referred to as “classic tremor” without the erroneous implication that it is only seen at rest. The tremor can be most annoying, for example, when a patient is holding a newspaper to read. It appears that it might be a tremor that is most prominent in stable states – either rest or an unchanging posture. It tends to go away with kinetic movements, such as going from rest to posture or doing a specific task. There is good evidence that classic tremor is pathophysiologically separate from bradykinesia and rigidity [1]. Clinically, the manifestations are separate, and the response of tremor to dopaminergic agents is less certain than bradykinesia. Putaminal dopamine content, measured with SPECT or PET or even postmortem, does not correlate with tremor. There is a possible dopamine connection, however. One post-mortem study linked dopamine content of the retrorubral area to tremor severity. A more recent study linked dopamine SPECT of the globus pallidus to tremor [2,3]. Hence, if there is a dopamine connection, it is not the traditional nigrostriatal pathway that is relevant. There is evidence from neuroimaging studies that serotonin might be more relevant than dopamine to classic tremor. A PET study with a ligand that binds to the 5-HT1A receptor indicated that there is more tremor with less binding in the raphe [4]. A more recent study, however, re-evaluating this observation in more detail, indicated that the correlation is more with postural tremor than rest tremor [5]. It has been uncertain what to make of these observations, since, at least so far, manipulating serotonin does not seem to be an influential modulator of tremor. The oscillatory network in the brain that correlates with tremor has been identified with several techniques. A pattern has emerged from FDG PET scans. In a large group of patient scans, the correlate to the amount of tremor included activity in the dentate nucleus and rostral parts of the cerebellum, the putamen and the motor cortex [6]. Using magnetoencephalography during tremor, it is possible to look at the link between brain activity and EMG bursting with corticomuscular coherence and corticocortical coherence [7]. Corticomuscular coherence shows the contralateral primary motor cortex (M1) most strongly indicating that M1 is the main driver of the tremor. Corticocortical coherence reveals those structures oscillating with M1 to be the secondary somatosensory cortex, the posterior parietal cortex, the cingulate and supplementary motor areas, the diencephalon and the cerebellum. In another study, fMRI was used and separately correlated brain activity with the onset of tremor periods and the amplitude of tremor during the tremor periods (Fig. 1) [3]. Correlating with onset is activity in the putamen and both divisions of the globus pallidus. Correlating with amplitude is activity in the cerebellum, VIM nucleus of the thalamus and motor and premotor cortex. While these studies are
Fig. 1. Functional MRI of Parkinson classic tremor. The graphs show activation in the motor cortex on top and in the internal division of the globus pallidus on the bottom. In each part, there are lines for the MRI activity, the tremor amplitude and the tremor on or offset. Note the correlation of tremor amplitude and motor cortex activity and the correlation of tremor on/offset with pallidal activity. Figure modified from [3] with permission.
not completely concordant, some features emerge. M1 is likely the major driver and its network with the cerebellum via the thalamus seems to be the principal circuit for tremor amplitude. The fact that the VIM nucleus is such a good surgical target for tremor is consistent. The clever idea of looking particularly at tremor onset activity reveals a role for an abnormal basal ganglia, and suggests that the basal ganglia triggers the cortical–cerebellar circuit to produce the tremor. The model emerges of coupled oscillators of basal ganglia and cerebellar circuits [2,3]. This idea now has strong support from the relatively new anatomical observations showing bidirectional links between basal ganglia and cerebellum. Where in these circuits is the abnormality that produces the tremor? In Parkinson disease there is the basal ganglia abnormality and, of course, that is an important suspect. The possible neurotransmitter abnormalities noted earlier might be a clue in this regard. Recordings from patients undergoing surgery for Parkinson’s disease demonstrate that there are cells in STN and GPi that burst at tremor frequency and can be demonstrated to be in phase with tremor. It is known that different body parts generally oscillate out of phase with each other and this can be appreciated in the cellular recordings as well, as the cells will be in phase with only certain body parts. The tremor frequency cells are intermixed with cells firing at beta frequency, an abnormal activity related to bradykinesia (Fig. 2) [8]. This finding indicates involvement of the basal ganglia, but does not constitute proof of being the initiating factor. The VIM of the thalamus also has cells bursting in tight phase with tremor and since thalamic cells have a low threshold calcium
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Fig. 2. Neuronal firing patterns in the subthalamic nucleus in a patient with Parkinson’s disease. Part A shows three different neurons with both raw data and extracted times of action potentials. Part B shows interspike interval histograms, and Part C the power density for the same three neurons, respectively. Figure from [8] with permission.
channel, there has been a question as to whether these cells could be the pacemaker. The successive interspike intervals in a burst can be interpreted as to whether the neuron is following a tremor generated elsewhere or whether it itself is spontaneously generating the bursts. The findings from two groups are that tremor bursts are generally following and not initiating the tremor [9,10]. In conclusion, it looks like there is a tremor network involving both basal ganglia and cerebellar circuits, but that a specific generator node in the network is not identified. Perhaps the network goes into oscillation as the result of an instability, such as a delay or asynchrony in one part of the network or perhaps excessive synchrony of local groups of neurons. Increased synchrony of neurons related to the beta rhythm is indeed seen in the monkey MPTP model of Parkinson’s disease, and the strong beta rhythm demonstrable in patients with Parkinson’s disease suggests that this is true also in humans [11]. The network oscillates at rest and in stable posture, but does not when a kinetic movement is made. It appears that the motor commands coming through the network disrupt the tremor oscillations, and, indeed, the beta oscillations diminish with voluntary movement [12]. 3. Essential tremor It is traditional to think of essential tremor as a tremor in posture and kinetic action, commonly involving predominantly both arms, with no other neurological deficits. Tremor can involve other body parts such as the head, rarely can be present at rest, and there can be minor amounts of cerebellar ataxia. Essential tremor can also co-exist with dystonia, and, in this circumstance, the question arises as to whether this is an association between two independent disorders or whether this means the tremor is different in type, and should be called dystonic tremor. There are also tremors that look similar to essential tremor, but are task specific, like primary writing tremor. There are enough variations and overlaps that some authorities even question if there really is a pure essential tremor, but I will take the view here that it does exist and can be studied.
Essential tremor often appears to be autosomal dominant, but for some reason mutations have been very difficult to find. There is some evidence for cerebellar involvement in the basic pathophysiology, and this has some face validity given the ataxic features in the patients. Magnetic resonance spectroscopy shows diminished N-acetylaspartate (NAA) [13], and voxelbased morphometry (VBM) shows cerebellar atrophy [14]. Some pathological studies show loss of Purkinje cells and increased torpedoes [15], but other studies suggest that these observations are similar to controls when matched for age [16]. The latter study did, however, find an increased frequency of cerebellar gliosis. (In a different subgroup of patients, Lewy bodies have been seen in the locus coeruleus, but these patients do not look any different clinically to those with cerebellar pathology [15].) An early PET study showed possible abnormality of the inferior olivary nucleus [17], but this has not been confirmed by subsequent neuroimaging studies, and a recent pathology investigation found no abnormality [18]. The cerebellar abnormality might be an abnormality of GABA. Pathology has shown a decrease in GABA-A and GABA-B receptors in the dentate nucleus [19] (but not for GABA-B receptors in cerebellar cortex [20]). A slightly different pathological pattern was found in another study where reduced parvalbumin staining (a marker for a subclass of GABAergic neurons) was found in the locus coeruleus and pons, but not in the cerebellum [21]. Flumazenil PET studies have shown increased binding in the cerebellum indicating increased affinity to the GABA-A receptor, which on the face of it, seems opposite to the pathological finding [22,23]. CSF GABA is diminished, and a tremor looking like essential tremor is seen in mice with a knock-out of the alpha-1 component of the GABA-A receptor. There are also reports of strokes in the cerebellum that eradicated essential tremor on the same side [24]. Considerable attention has been paid to the rodent harmaline model of essential tremor. Harmaline causes tremor that mimics the human condition and this has served as an accurate model to predict the efficacy of drug treatment. Harmaline increases
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Fig. 3. Effect of single pulse TMS on essential tremor. Each trace is an average of 25 recordings of rectified EMG from the extensor carpi radialis muscle aligned on the TMS pulse at various intensities. After the motor evoked potential (MEP), there is a silent period (SP) (at least at higher intensities), followed by synchronization of the tremor. Figure from [25] with permission.
the oscillations in the inferior olivary nucleus, and this might occur from one of two mechanisms (or both). The olivary neurons are spontaneously rhythmic, the rhythmicity supported by a low threshold calcium channel. The olivary neuron dendrites come together in clusters called glomeruli where they communicate with each other via gap junctions. In harmaline-induced tremor, the cells are more rhythmic and they communicate more strongly. Perhaps importantly, the gap junction communication is down-modulated by GABA, so a deficiency of GABA would increase synchronicity. The inferior olivary–cerebellar network has been long suspected as being the relevant generator, but the evidence is not strong. The network closely linked to the generation of tremor is certainly the cerebello–thalamo–cortical network. A study with blood flow PET showed hyperactivity of the cerebellum at rest, and then further increase of the cerebellum and abnormal increase of the red nucleus region as well [26]. The VIM nucleus of the cerebellum contains bursting cells strongly linked to tremor bursts, and these cells burst only when the tremor is present [27]. Lesions or DBS of the VIM generally eradicates the tremor. Single pulse transcranial magnetic stimulation (TMS), but not transcranial electrical stimulation (TES) of the primary motor cortex reset essential tremor, implicating the importance of intracortical networks in the primary motor cortex (Fig. 3) [25]. A critical difference of essential tremor and Parkinsonian classic tremor is the setting in which it occurs, action and rest, respectively. It might be that in essential tremor the motor controller involving the cerebellum is dysfunctional. The presence of some ataxia is compatible with that idea. Moreover, there is evidence for a delay in motor control processing. Specifically, the second agonist burst in the ballistic movement pattern is delayed (Fig. 4) [28]. The delay could set up oscillations in the cerebello–thalamo– cortical loop. Interestingly, and perhaps evidence against this idea, the ataxic component might be separable to some extent from the tremor component in these patients. Ataxic gait, similar to tremor, can improve with DBS, but with supra-therapeutic stimulation there is return of ataxia despite continued improvement of tremor [29].
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Fig. 4. Ballistic (rapid) wrist flexion movements of 15 degrees and 60 degrees in a normal subject and a patient with essential tremor. In the normal subject, the movement is initiated with a triphasic pattern of agonist (finger flexors), antagonist (finger extensors) and agonist activity sequentially. In the patient, there is the triphasic pattern with a delayed second agonist burst and then continued alternating activity similar to a damped tremor. Figure modified from [28] with permission.
4. Conclusion The reviewed data give rise to some possible hypotheses for tremor generation. It appears that the direct generator of both classic tremor and essential tremor is the cerebello–thalamo– cortical network. The difference appears to be in how this network is activated to oscillate. In classic tremor, the setting is stability of a body part where an abnormal beta rhythm synchronizes the basal ganglia and in a mechanism still to be elucidated triggers the cerebellar network. In essential tremor, the abnormality appears to be in the cerebellar network itself, and dysfunction of the motor controller for generating an action sets off the oscillation. Clearly much more data are needed to verify these hypotheses. Acknowledgements This work was supported by the NINDS Intramural Program. Conflict of interests The author has no conflict of interest to declare. References [1] Hallett M. Parkinson’s disease tremor: pathophysiology. Parkinsonism Relat Disord 2012;18(Suppl 1):S85–6. [2] Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? Brain 2012;135(Pt–11):3206–26. [3] Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol 2011;69(2): 269–81. [4] Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ. Tremor in Parkinson’s disease and serotonergic dysfunction: an 11 C-WAY 100635 PET study. Neurology 2003;60(4):601–5. [5] Loane C, Wu K, Bain P, Brooks DJ, Piccini P, Politis M. Serotonergic loss in motor circuitries correlates with severity of action-postural tremor in PD. Neurology 2013;80(20):1850–5.
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