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Parkinson's disease tremor: pathophysiology
Parkinsonism and Related Disorders 18S1 (2012) S85–S86
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Parkinson’s disease tremor: pathophysiology Mark Hallett* Human Motor Control Section, NINDS, NIH, Bethesda, MD, USA
article info
summary
Keywords: Tremor Basal ganglia Thalamus Cerebellum
There are a number of tremors that may affect patients with Parkinson’s disease, but the classic is tremor-at-rest. The tremor is also seen during postural action after a short pause, and is often called re-emergent tremor although it appears that the physiology is the same. As a manifestation of Parkinson’s disease, it is separate from bradykinesia and rigidity as the magnitude of tremor is not related to dopamine deficiency nor does it respond readily to dopamine treatment. Cellular activity in the different basal ganglia nuclei can be coherent with tremor, but cellular activity in the VIM nucleus of the thalamus, a cerebellar relay nucleus, is more coherent than cellular activity in basal ganglia. It is also notable that different body parts may have similar tremor frequencies, but are generally not exactly the same and are not phase locked. This suggests that each body part has a separate tremor generator. The ability to stay separate may be due to the somatotopic segregation of basal ganglia loops. Analysis of cellular behavior in the thalamus shows that the thalamus is not the generator of tremor. New data suggest that the basal ganglia trigger a cerebellar circuit to produce the tremor. © 2011 Elsevier Ltd. All rights reserved.
Of the classic triad of Parkinson’s disease symptoms, tremor is to some extent the most confusing. First of all, there are really several types of tremor [1]. The classic is the tremor-at-rest, but while the tremor is seen at rest, it can also be seen in action in later stage disease often with a short pause in the transition from rest to posture. This has been called re-emergent tremor, but giving it another name is perhaps misleading since re-emergent tremor certainly seems to be clinically the same as tremor-at-rest. It might actually be better to drop the “at-rest” and just call this “classic tremor”, which is what will be done here. There are also other tremors seen in patients. Some have a distinct postural tremor clearly different from reemergent tremor based either on the frequency which is often faster than tremor-at-rest or the lack of tremor at rest. Another postural tremor can be essential tremor, and there is an increased incidence of Parkinson’s disease in patients with essential tremor. There also can be dystonic tremor, and this might even look similar to classic tremor. In this regard, it has been suggested that the SWEDD (scans without evidence of dopamine deficiency) patients have dystonic tremor [2]. Additionally, a patient can have an exaggerated physiological tremor. This review will deal only with classic tremor. Another confusing feature is that tremor really is a separate symptom from bradykinesia and rigidity. Clinically it is separate. The tremor can even be worse on the side opposite the more severe bradykinesia, which can be called wrong-sided tremor. Pathologically it is separate since the magnitude of tremor is not related to * Correspondence: Mark Hallett, M.D., Chief, Human Motor Control Section, NINDS, NIH, Bldg. 10, Rm. 7D37, 10 Center Dr. MSC 1428, 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 © 2011 Elsevier Ltd. All rights reserved.
the amount of dopamine deficiency in the substantia nigra as determined pathologically. One report suggested a correlation to the degeneration of another dopamine nucleus, the retrorubral area [3]. Additionally, while tremor might respond to dopamine treatment, it also might not respond and some patients even worsen. A number of studies with SPECT scanning for dopamine transporter show less binding in tremor-dominant compared with akinetic-rigid patients and that tremor does not correlate with nigrostriatal dopamine depletion (for example [4,5]). Neurotransmitters other than dopamine may be relevant. It is well known, for example, that anticholinergic agents may be particularly effective in some patients. Positron emission tomography (PET) imaging showed a possible relationship of classic tremor to serotonergic deficiency [6], but serotonergic drugs do not help so the relevance of this finding is not clear. There is abundant evidence that the cerebellum is involved in classic tremor. Anatomical evidence comes from a voxel-based morphometry (VBM) study showed loss of cerebellar gray matter in the right quadrangular lobe and declive of the cerebellum in patients with rest tremor compared to those without [7]. There is more extensive physiological evidence. Using FDG PET, a network of brain areas that correlated with the amount of tremor was determined to be thalamus, pons, and premotor cortical regions [8]. Another study showed a negative correlation of tremor and the putamen and cerebellar vermis [9]. A magnetoencephalographic (MEG) analysis showed a cerebello-diencephalic-cortical network related to tremor-at-rest [10]. Recordings of neuronal activity or local field potentials from basal ganglia structures and thalamus show rhythmic activity related to tremor-at-rest. Coupling is strongest with recordings from the
S86
M. Hallett / Parkinsonism and Related Disorders 18S1 (2012) S85–S86
Fig. 1. Diagram illustrating the idea of how the basal ganglia loop can trigger the tremor and the cerebellar loop can more directly drive the tremor. The diagram indicates that the final output for the tremor comes (at least in part) from the motor cortex, and there is feedback from the tremor to the central nervous system, including to the cerebellum. Where the two loops interact is still not completely clear. There might be more than one point of connection, but two possibilities are the thalamus and motor cortex itself. This concept is described in detail in Helmich et al. 2011 [14].
VIM (ventralis intermedius) nucleus of the thalamus, which is a cerebellar relay nucleus. VIM thalamotomy or VIM deep brain stimulation (DBS) markedly improves tremor-at-rest; indeed, it seems to improve tremors of all types. Recording of cell burst patterns in the VIM suggest that most cells are followers and not spontaneous bursters [11]. This suggests that the tremor does not originate in the VIM, and that the tremor either originates elsewhere, or that the tremor emerges as an abnormal network property. There is some physiological evidence for involvement of the cerebellum in postural, but not rest tremor although the tremors were not well clinically described in the paper [12]. The investigators found that motor cortical stimulation with transcranial magnetic stimulation reset the tremor rhythm for both rest and postural tremor. In contrast, cerebellar transcranial magnetic stimulation reset postural but not rest tremor. In regard to the postural tremor, this result contrasted with the lack of resetting in essential tremor reported by the same group [13]. The investigators concluded that the rest and postural tremors are mediated by different neural networks and that only the postural tremor utilizes the cerebellothalamocortical network. However, the conclusion should be accepted only very cautiously since it is not clear that the stimulation was strong enough. A recent paper has suggested a model for classic tremor that has two parts, a trigger for the tremor from the basal ganglia and a tremor driving force from the cerebellothalamocortical network [14]. There are several novel observations in this paper. First, using SPECT scanning, is that tremor in Parkinson patients correlates with dopamine depletion in the pallidum rather than in the striatum. This is a degeneration in Parkinson’s disease separate from the well known nigrostriatal dopamine lesion. Second, using functional MRI, the basal ganglia (pallidum and putamen) are active at the onset of tremor, but the cerebellar circuit has activity correlating with the magnitude of on-going tremor. Thus, there has to be basal ganglia pathology to have tremor, but the tremor is more directly produced by the cerebellar pathways (Fig. 1). A question, not immediately answered, is where these two circuits come together. The two circuits have been thought to be completely separate, but recent data are beginning to show some points of contact [15]. The authors suggest that the motor cortex is the site of contact since it is part of both circuits in their functional imaging. Understanding of the classic tremor in Parkinson’s disease is clearly increasing. We can see how the symptom can be separate
from bradykinesia and rigidity, and why improvement can be produced by affecting either basal ganglia or cerebellar circuits. Conflict of interests The author has no conflicts of interest to declare. References 1. Hallett M, Deuschl G. Are we making progress in the understanding of tremor in Parkinson’s disease? Ann Neurol 2010 Dec;68(6):780–1. 2. Schneider SA, Edwards MJ, Mir P, Cordivari C, Hooker J, Dickson J, et al. Patients with adult-onset dystonic tremor resembling parkinsonian tremor have scans without evidence of dopaminergic deficit (SWEDDs). Mov Disord 2007 Nov 15; 22(15):2210–5. 3. Hirsch EC, Mouatt A, Faucheux B, Bonnet AM, Javoy-Agid F, Graybiel AM, et al. Dopamine, tremor, and Parkinson’s disease. Lancet 1992 Jul 11;340(8811): 125–6. 4. Rossi C, Frosini D, Volterrani D, De Feo P, Unti E, Nicoletti V, et al. Differences in nigro-striatal impairment in clinical variants of early Parkinson’s disease: evidence from a FP-CIT SPECT study. Eur J Neurol 2010 Apr;17(4):626–30. 5. Spiegel J, Hellwig D, Samnick S, Jost W, Mollers MO, Fassbender K, et al. Striatal FP-CIT uptake differs in the subtypes of early Parkinson’s disease. J Neural Transm 2007 Mar;114(3):331–5. 6. Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ. Tremor in Parkinson’s disease and serotonergic dysfunction: an 11C-WAY 100635 PET study. Neurology 2003 Feb 25;60(4):601–5. 7. Benninger DH, Thees S, Kollias SS, Bassetti CL, Waldvogel D. Morphological differences in Parkinson’s disease with and without rest tremor. J Neurol 2009 Feb;256(2):256–63. 8. Antonini A, Moeller JR, Nakamura T, Spetsieris P, Dhawan V, Eidelberg D. The metabolic anatomy of tremor in Parkinson’s disease. Neurology 1998 Sep;51(3): 803–10. 9. Lozza C, Marie RM, Baron JC. The metabolic substrates of bradykinesia and tremor in uncomplicated Parkinson’s disease. Neuroimage 2002 Oct;17(2): 688–99. 10. Timmermann L, Gross J, Dirks M, Volkmann J, Freund HJ, Schnitzler A. The cerebral oscillatory network of parkinsonian resting tremor. Brain 2003 Jan;126(Pt 1):199–212. 11. Zirh TA, Lenz FA, Reich SG, Dougherty PM. Patterns of bursting occurring in thalamic cells during parkinsonian tremor. Neuroscience 1998;83(1):107–21. 12. Ni Z, Pinto AD, Lang AE, Chen R. Involvement of the cerebellothalamocortical pathway in Parkinson’s disease. Ann Neurol 2010;68(6):816–24. 13. Pinto AD, Lang AE, Chen R. The cerebellothalamocortical pathway in essential tremor. Neurology 2003 Jun 24;60(12):1985–7. 14. Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol 2011 Feb;69(2): 269–81. 15. Bostan AC, Dum RP, Strick PL. The basal ganglia communicate with the cerebellum. Proc Natl Acad Sci U S A 2010 May 4;107(18):8452–6.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Parkinson’s disease tremor: pathophysiology Mark Hallett* Human Motor Control Section, NINDS, NIH, Bethesda, MD, USA
article info
summary
Keywords: Tremor Basal ganglia Thalamus Cerebellum
There are a number of tremors that may affect patients with Parkinson’s disease, but the classic is tremor-at-rest. The tremor is also seen during postural action after a short pause, and is often called re-emergent tremor although it appears that the physiology is the same. As a manifestation of Parkinson’s disease, it is separate from bradykinesia and rigidity as the magnitude of tremor is not related to dopamine deficiency nor does it respond readily to dopamine treatment. Cellular activity in the different basal ganglia nuclei can be coherent with tremor, but cellular activity in the VIM nucleus of the thalamus, a cerebellar relay nucleus, is more coherent than cellular activity in basal ganglia. It is also notable that different body parts may have similar tremor frequencies, but are generally not exactly the same and are not phase locked. This suggests that each body part has a separate tremor generator. The ability to stay separate may be due to the somatotopic segregation of basal ganglia loops. Analysis of cellular behavior in the thalamus shows that the thalamus is not the generator of tremor. New data suggest that the basal ganglia trigger a cerebellar circuit to produce the tremor. © 2011 Elsevier Ltd. All rights reserved.
Of the classic triad of Parkinson’s disease symptoms, tremor is to some extent the most confusing. First of all, there are really several types of tremor [1]. The classic is the tremor-at-rest, but while the tremor is seen at rest, it can also be seen in action in later stage disease often with a short pause in the transition from rest to posture. This has been called re-emergent tremor, but giving it another name is perhaps misleading since re-emergent tremor certainly seems to be clinically the same as tremor-at-rest. It might actually be better to drop the “at-rest” and just call this “classic tremor”, which is what will be done here. There are also other tremors seen in patients. Some have a distinct postural tremor clearly different from reemergent tremor based either on the frequency which is often faster than tremor-at-rest or the lack of tremor at rest. Another postural tremor can be essential tremor, and there is an increased incidence of Parkinson’s disease in patients with essential tremor. There also can be dystonic tremor, and this might even look similar to classic tremor. In this regard, it has been suggested that the SWEDD (scans without evidence of dopamine deficiency) patients have dystonic tremor [2]. Additionally, a patient can have an exaggerated physiological tremor. This review will deal only with classic tremor. Another confusing feature is that tremor really is a separate symptom from bradykinesia and rigidity. Clinically it is separate. The tremor can even be worse on the side opposite the more severe bradykinesia, which can be called wrong-sided tremor. Pathologically it is separate since the magnitude of tremor is not related to * Correspondence: Mark Hallett, M.D., Chief, Human Motor Control Section, NINDS, NIH, Bldg. 10, Rm. 7D37, 10 Center Dr. MSC 1428, 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 © 2011 Elsevier Ltd. All rights reserved.
the amount of dopamine deficiency in the substantia nigra as determined pathologically. One report suggested a correlation to the degeneration of another dopamine nucleus, the retrorubral area [3]. Additionally, while tremor might respond to dopamine treatment, it also might not respond and some patients even worsen. A number of studies with SPECT scanning for dopamine transporter show less binding in tremor-dominant compared with akinetic-rigid patients and that tremor does not correlate with nigrostriatal dopamine depletion (for example [4,5]). Neurotransmitters other than dopamine may be relevant. It is well known, for example, that anticholinergic agents may be particularly effective in some patients. Positron emission tomography (PET) imaging showed a possible relationship of classic tremor to serotonergic deficiency [6], but serotonergic drugs do not help so the relevance of this finding is not clear. There is abundant evidence that the cerebellum is involved in classic tremor. Anatomical evidence comes from a voxel-based morphometry (VBM) study showed loss of cerebellar gray matter in the right quadrangular lobe and declive of the cerebellum in patients with rest tremor compared to those without [7]. There is more extensive physiological evidence. Using FDG PET, a network of brain areas that correlated with the amount of tremor was determined to be thalamus, pons, and premotor cortical regions [8]. Another study showed a negative correlation of tremor and the putamen and cerebellar vermis [9]. A magnetoencephalographic (MEG) analysis showed a cerebello-diencephalic-cortical network related to tremor-at-rest [10]. Recordings of neuronal activity or local field potentials from basal ganglia structures and thalamus show rhythmic activity related to tremor-at-rest. Coupling is strongest with recordings from the
S86
M. Hallett / Parkinsonism and Related Disorders 18S1 (2012) S85–S86
Fig. 1. Diagram illustrating the idea of how the basal ganglia loop can trigger the tremor and the cerebellar loop can more directly drive the tremor. The diagram indicates that the final output for the tremor comes (at least in part) from the motor cortex, and there is feedback from the tremor to the central nervous system, including to the cerebellum. Where the two loops interact is still not completely clear. There might be more than one point of connection, but two possibilities are the thalamus and motor cortex itself. This concept is described in detail in Helmich et al. 2011 [14].
VIM (ventralis intermedius) nucleus of the thalamus, which is a cerebellar relay nucleus. VIM thalamotomy or VIM deep brain stimulation (DBS) markedly improves tremor-at-rest; indeed, it seems to improve tremors of all types. Recording of cell burst patterns in the VIM suggest that most cells are followers and not spontaneous bursters [11]. This suggests that the tremor does not originate in the VIM, and that the tremor either originates elsewhere, or that the tremor emerges as an abnormal network property. There is some physiological evidence for involvement of the cerebellum in postural, but not rest tremor although the tremors were not well clinically described in the paper [12]. The investigators found that motor cortical stimulation with transcranial magnetic stimulation reset the tremor rhythm for both rest and postural tremor. In contrast, cerebellar transcranial magnetic stimulation reset postural but not rest tremor. In regard to the postural tremor, this result contrasted with the lack of resetting in essential tremor reported by the same group [13]. The investigators concluded that the rest and postural tremors are mediated by different neural networks and that only the postural tremor utilizes the cerebellothalamocortical network. However, the conclusion should be accepted only very cautiously since it is not clear that the stimulation was strong enough. A recent paper has suggested a model for classic tremor that has two parts, a trigger for the tremor from the basal ganglia and a tremor driving force from the cerebellothalamocortical network [14]. There are several novel observations in this paper. First, using SPECT scanning, is that tremor in Parkinson patients correlates with dopamine depletion in the pallidum rather than in the striatum. This is a degeneration in Parkinson’s disease separate from the well known nigrostriatal dopamine lesion. Second, using functional MRI, the basal ganglia (pallidum and putamen) are active at the onset of tremor, but the cerebellar circuit has activity correlating with the magnitude of on-going tremor. Thus, there has to be basal ganglia pathology to have tremor, but the tremor is more directly produced by the cerebellar pathways (Fig. 1). A question, not immediately answered, is where these two circuits come together. The two circuits have been thought to be completely separate, but recent data are beginning to show some points of contact [15]. The authors suggest that the motor cortex is the site of contact since it is part of both circuits in their functional imaging. Understanding of the classic tremor in Parkinson’s disease is clearly increasing. We can see how the symptom can be separate
from bradykinesia and rigidity, and why improvement can be produced by affecting either basal ganglia or cerebellar circuits. Conflict of interests The author has no conflicts of interest to declare. References 1. Hallett M, Deuschl G. Are we making progress in the understanding of tremor in Parkinson’s disease? Ann Neurol 2010 Dec;68(6):780–1. 2. Schneider SA, Edwards MJ, Mir P, Cordivari C, Hooker J, Dickson J, et al. Patients with adult-onset dystonic tremor resembling parkinsonian tremor have scans without evidence of dopaminergic deficit (SWEDDs). Mov Disord 2007 Nov 15; 22(15):2210–5. 3. Hirsch EC, Mouatt A, Faucheux B, Bonnet AM, Javoy-Agid F, Graybiel AM, et al. Dopamine, tremor, and Parkinson’s disease. Lancet 1992 Jul 11;340(8811): 125–6. 4. Rossi C, Frosini D, Volterrani D, De Feo P, Unti E, Nicoletti V, et al. Differences in nigro-striatal impairment in clinical variants of early Parkinson’s disease: evidence from a FP-CIT SPECT study. Eur J Neurol 2010 Apr;17(4):626–30. 5. Spiegel J, Hellwig D, Samnick S, Jost W, Mollers MO, Fassbender K, et al. Striatal FP-CIT uptake differs in the subtypes of early Parkinson’s disease. J Neural Transm 2007 Mar;114(3):331–5. 6. Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ. Tremor in Parkinson’s disease and serotonergic dysfunction: an 11C-WAY 100635 PET study. Neurology 2003 Feb 25;60(4):601–5. 7. Benninger DH, Thees S, Kollias SS, Bassetti CL, Waldvogel D. Morphological differences in Parkinson’s disease with and without rest tremor. J Neurol 2009 Feb;256(2):256–63. 8. Antonini A, Moeller JR, Nakamura T, Spetsieris P, Dhawan V, Eidelberg D. The metabolic anatomy of tremor in Parkinson’s disease. Neurology 1998 Sep;51(3): 803–10. 9. Lozza C, Marie RM, Baron JC. The metabolic substrates of bradykinesia and tremor in uncomplicated Parkinson’s disease. Neuroimage 2002 Oct;17(2): 688–99. 10. Timmermann L, Gross J, Dirks M, Volkmann J, Freund HJ, Schnitzler A. The cerebral oscillatory network of parkinsonian resting tremor. Brain 2003 Jan;126(Pt 1):199–212. 11. Zirh TA, Lenz FA, Reich SG, Dougherty PM. Patterns of bursting occurring in thalamic cells during parkinsonian tremor. Neuroscience 1998;83(1):107–21. 12. Ni Z, Pinto AD, Lang AE, Chen R. Involvement of the cerebellothalamocortical pathway in Parkinson’s disease. Ann Neurol 2010;68(6):816–24. 13. Pinto AD, Lang AE, Chen R. The cerebellothalamocortical pathway in essential tremor. Neurology 2003 Jun 24;60(12):1985–7. 14. Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol 2011 Feb;69(2): 269–81. 15. Bostan AC, Dum RP, Strick PL. The basal ganglia communicate with the cerebellum. Proc Natl Acad Sci U S A 2010 May 4;107(18):8452–6.