EDITORIAL
Focal Hand Dystonia: Using Brain Stimulation to Probe Network Interactions and Brain Plasticity Michael Vesia, PhD and Robert Chen, MBBChir, MSc, FRCPC* Division of Neurology, Department of Medicine, University of Toronto and Division of Brain Imaging & Behaviour Systems - Neuroscience, Toronto Western Research Institute, Toronto, Canada
Focal hand dystonias such as writer’s cramp and musician’s cramp are intriguing disorders, and their pathophysiology remains incompletely understood. Both the motor and sensory systems are abnormal in dystonia. In the motor system, dystonia is characterized by loss of inhibition at multiple levels in the central nervous system.1 In the motor cortex, both inhibitory cortical circuits and surround inhibition are reduced in dystonia.2-4 There is also involvement of the sensory system. Patients with focal hand dystonia exhibit abnormal somatotopy with overlapping digit representations in primary somatosensory cortex,5-7 together with diminished temporal8 and spatial tactile acuity.9 Recent studies indicate that altered integration of somatosensory information into the motor plan within the sensorimotor circuit is a key pathophysiological feature of dystonia.10,11 Patients with focal hand dystonia have disturbances of perceptual body representations12 and reduced connectivity between parietal and premotor regions that control writing.13 It is generally considered that abnormalities in the basal ganglia and the cerebellum lead to changes in the primary motor and sensory cortices in dystonia.14 Excessive plasticity and abnormal regulation of plasticity are considered major pathophysiological features of dystonia. Several studies showed that dystonia is associated with exaggerated long-term potentiation (LTP)-like cortical plasticity.15,16 consistent with the hypothesis that dystonia is a disorder of synaptic “scaling.”17 Exaggerated LTP-like plasticity may lead to an excessive tendency to form associations between sensory inputs and motor outputs (abnormal potentiation) and failure to weaken already existing associations (deficient depotentiation).18 Deficient homeostatic
------------------------------------------------------------
*Correspondence to: Dr. Robert Chen, McLaughlin Pavilion, 7th Floor, Room 411, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8, E-mail: [email protected]
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 21 May 2014; Revised: 3 June 2014; Accepted: 16 June 2014 Published online 17 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25971
control of plasticity might trigger maladaptive reorganization and produce dystonic symptoms.18 Recent advances in noninvasive brain stimulation (NIBS) techniques provide a powerful tool to understand the complex interactions both within various circuits of the primary motor cortex (M1)19 and between different connected sensory-motor areas,20,21 and to induce brain plasticity22 in humans. Transcranial magnetic stimulation (TMS) is a widely used technique that allows noninvasive examination of different inhibitory and excitatory circuits at the systems level in the human brain, and has the potential to be used as a diagnostic and prognostic tool.23 Interactions between two nodes of a neural circuit in the human sensory-motor system can be studied using two coils in a paired-pulse TMS protocol.20,21 In this conditioning-test paradigm, a conditioning stimulus is delivered to a non-motor area to examine its effects on a subsequent test stimulus to motor cortex. This approach provides information on the excitability of cortical projections to M1 with millisecond resolution, and how inputs from other areas to M1 are modulated by different task-demands, disease, or injury. In addition, several TMS protocols can be used to induce and measure cortical plasticity and they have potential therapeutic utilities in movement disorders.22 Paired associative stimulation (PAS),24 modeled after LTP induction protocols in animal studies, induces LTPlike plasticity by repeated pairing of electrical stimulus to the median nerve with TMS to M1, with the median nerve stimulation preceding TMS by approximately 25 ms such that the two inputs are timed to arrive at the M1 at roughly the same time. It acts through sensory-motor communications and intracortical circuits of M1, and produces heterosynaptic (involves two different synapses), spike-timing– dependent plasticity. In the current issue of Movement Disorders, two studies25,26 used these relatively new NIBS methods to examine the pathophysiology of focal hand dystonia. Pirio Richardson et al.25 used paired-pulse TMS to examine the interactions between dorsal premotor cortex (PMd) and ipsilateral M1 in patients with writer’s
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V E S I A
A N D
C H E N
cramp in three different conditions: rest, isometric muscle contraction, and a pen-holding task. They found that in patients with focal hand dystonia the PMd exerts a greater inhibitory influence on ipsilateral M1 in all three conditions compared with controls. These findings suggest that abnormal premotor–motor interactions play a role in the pathophysiology of focal dystonia, as a primary abnormality or as compensation. In a separate study, Sadnicka et al.26 examined the potential of anodal cerebellar transcranial direct current stimulation as a therapeutic tool to reduce exaggerated cortical plasticity in writing dystonia. Ten patients with writing dystonia completed a two-part study in which sham or anodal cerebellar stimulation was given simultaneously with PAS. They found that dystonic symptoms were unchanged by cerebellar stimulation, but the patients exhibited much variability in the size and direction of their plasticity responses. Arguably, the most exciting aspect of these studies is the new perspective they may provide us in understanding the pathophysiological mechanisms of focal hand dystonia. This can lead to significant advances in creating basic knowledge that can be tailored to meet individual patient needs by harnessing brain plasticity to minimize dysfunction and disability. Although these two papers25,26 collectively represent an important step forward in understanding the mechanisms and identifying therapeutic targets for effective management of focal hand dystonia, caution should be exercised when drawing conclusions. A potential caveat relates to the limited stimulation parameters tested in the PMd-M1 circuit by Pirio Richardson et al.25 Various inhibitory and excitatory circuits can be differentiated depending on the stimulus intensities, the interstimulus interval between the conditioning and test stimuli, and task demands.27 Testing with different parameters may reveal different abnormal neural populations within the PMd-M1 pathway, and, in turn, better characterize the pathophysiology of focal hand dystonia. A related limitation is the inability to determine whether this is a primary abnormality related to dystonia or attributable to compensation. Irrespective of this, given the abnormalities in somatosensory processing and sensorimotor integration in focal hand dystonia,28 other nodes within the sensorimotor network such as the primary somatosensory cortex and the parietal cortex should be examined in future studies to better characterize the network dynamics resulting from a possible systemwide compensatory mechanism. Similarly, further studies to explore this complex integration of neuronal circuits with NIBS techniques will help elucidate a more holistic understanding of the pathophysiological mechanisms of focal hand dystonia. This may provide additional insight to guide the optimal placement of brain stimulation targets for treatment.
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Another issue with TMS protocols is the inter-subject variability. In both studies, the authors found considerable inter-subject variation in PMd-M1 interactions (see Figure 2 in Pirio-Richardson et al.25) and the plasticity induced by PAS.26 In fact, Sadnicka et al.26 did not find exaggerated PAS plasticity in focal hand dystonia reported by previous studies.15,16,29 This variability can be caused by many factors that influence cortical plasticity and excitability, including genetic factors (i.e., brain-derived neurotrophic factor polymorphism),30 muscle activity,31,32 time of the day,33 and medications. To counter this, Sadnicka and colleagues26 separated the patients into two groups: “responders” who showed facilitation after PAS and “nonresponders.” In “responders” with an LTP-like response to PAS, anodal cerebellar stimulation decreased this excessive abnormal plasticity response. This is a noteworthy approach, although the within-subject reproducibility of the PAS response has not been established. A previous study has found that the cortical circuit activated as indexed by the latency of motor evoked potential critically affects the response of the individual to plasticity induction by NIBS.34 This raises the possibility that in the future individual cortical physiology may be used to select the therapy with the highest likelihood of response. In summary, both studies25,26 provide us with not only a further understanding of the neural changes associated with focal hand dystonia but also a new perspective for modulating specific abnormal sensorimotor circuits as an adjunct to behavioral training. A better understanding of the interactions between neural circuits and mechanisms governing the underlying network plasticity in individual patients may prove to be an effective strategy to select treatment based on individual pathophysiological mechanisms, leading us to the era of personalized medicine for motor and sensorimotor disorders.
References 1.
Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD. The pathophysiology of primary dystonia. Brain 1998;121:1195-1212.
2.
Hallett M. Neurophysiology of dystonia: the role of inhibition. Neurobiol Dis 2011;42:177-184.
3.
Chen R, Wassermann EM, Canos M, Hallett M. Impaired inhibition in writer’s cramp during voluntary muscle activation. Neurology 1997;49:1054-1059.
4.
Nelson AJ, Hoque T, Gunraj C, Ni Z, Chen R. Impaired interhemispheric inhibition in writer’s cramp. Neurology 2010;75:441-447.
5.
Elbert T, Candia V, Altenmuller E, et al. Alteration of digital representations in somatosensory cortex in focal hand dystonia. Neuroreport 1998;9:3571-3575.
6.
Bara-Jimenez W, Catalan MJ, Hallett M, Gerloff C. Abnormal somatosensory homunculus in dystonia of the hand. Ann Neurol 1998;44:828-831.
7.
Nelson AJ, Blake DT, Chen R. Digit-specific aberrations in the primary somatosensory cortex in writer’s cramp. Ann Neurol 2009; 66:146-154.
8.
Fiorio M, Tinazzi M, Bertolasi L, Aglioti SM. Temporal processing of visuotactile and tactile stimuli in writer’s cramp. Ann Neurol 2003;53:630-635.
F O C A L
H A N D
D Y S T O N I A
9.
Molloy FM, Carr TD, Zeuner KE, Dambrosia JM, Hallett M. Abnormalities of spatial discrimination in focal and generalized dystonia. Brain 2003;126:2175-2182.
23.
Chen R, Cros D, Curra A, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119:504-532.
10.
Delnooz CCS, Helmich RC, Medendorp WP, van de Warrenburg BPC, Toni I. Writer’s cramp: increased dorsal premotor activity during intended writing. Human Brain Mapping 2011;34:613-625.
24.
Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 2000;123:572-584.
11.
Castrop F, Dresel C, Hennenlotter A, Zimmer C, Haslinger B. Basal ganglia-premotor dysfunction during movement imagination in writer’s cramp. Mov Disord 2012;27:1432-1439.
25.
Pirio Richardson S, Beck S, Bliem B, Hallett M. Abnormal dorsal premotor-motor inhibition in writer’s cramp. Mov Disord 2014; doi: 10.1002/mds.25881.
12.
Fiorio M, Weise D, Onal-Hartmann C, Zeller D, Tinazzi M, Classen J. Impairment of the rubber hand illusion in focal hand dystonia. Brain 2011;134:1428-1437.
26.
Sadnicka A, Hamada M, Bhatia K, Rothwell J, Edwards M. Cerebellar stimulation fails to modulate motor cortex plasticity in writing dystonia. Mov Disord 2014; doi: 10.1002/mds.25881.
13.
Delnooz CCS, Helmich RC, Toni I, van de Warrenburg BPC. Reduced parietal connectivity with a premotor writing area in writer’s cramp. Mov Disord 2012;27:1425-1431.
27.
14.
Neychev VK, Gross RE, Lehericy S, Hess EJ, Jinnah HA. The functional neuroanatomy of dystonia. Neurobiol Dis 2011;42:185-201.
B€ aumer T, Schippling S, Kroeger J, et al. Inhibitory and facilitatory connectivity from ventral premotor to primary motor cortex in healthy humans at rest: a bifocal TMS study. Clin Neurophysiol 2009:1-8.
28.
15.
Quartarone A, Bagnato S, Rizzo V, et al. Abnormal associative plasticity of the human motor cortex in writer’s cramp. Brain 2003;126:2586-2596.
Abbruzzese G, Berardelli A. Sensorimotor integration in movement disorders. Mov Disord 2003;18:231-240.
29.
Kojovic M, Caronni A, Bologna M, Rothwell JC, Bhatia KP, Edwards MJ. Botulinum toxin injections reduce associative plasticity in patients with primary dystonia. Mov Disord 2011;26:12821289.
30.
Cheeran B, Talelli P, Mori F, et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Physiol 2008;586:5717-5725.
31.
Gentner R, Wankerl K, Reinsberger C, Zeller D, Classen J. Depression of human corticospinal excitability induced by magnetic theta-burst stimulation: evidence of rapid polarity-reversing metaplasticity. Cerebral Cortex 2008;18:2046-2053.
32.
Huang YZ, Rothwell JC, Edwards MJ, Chen RS. Effect of physiological activity on an NMDA-dependent form of cortical plasticity in human. Cerebral Cortex 2008;18:563-570.
33.
Sale MV, Ridding MC, Nordstrom MA. Cortisol inhibits neuroplasticity induction in human motor cortex. J Neurosci 2008;28: 8285-8293.
34.
Hamada M, Murase N, Hasan A, Balaratnam M, Rothwell JC. The role of interneuron networks in driving human motor cortical plasticity. Cerebral Cortex 2013;23:1593-1605.
16.
Weise D, Schramm A, Stefan K, et al. The two sides of associative plasticity in writer’s cramp. Brain 2006;129:2709-2721.
17.
Quartarone A, Pisani A. Abnormal plasticity in dystonia: Disruption of synaptic homeostasis. Neurobiol Dis 2011;42:162-170.
18.
Quartarone A, Siebner HR, Rothwell JC. Task-specific hand dystonia: can too much plasticity be bad for you? Trends Neurosci 2006;29:192-199.
19.
Ni Z, M€ uller-Dahlhaus F, Chen R, Ziemann U. Triple-pulse TMS to study interactions between neural circuits in human cortex. Brain Stimul 2011;4:281-293.
20.
Koch G, Rothwell JC. TMS investigations into the task-dependent functional interplay between human posterior parietal and motor cortex. Behav Brain Res 2009;202:147-152.
21.
Vesia M, Davare M. Decoding action intentions in parietofrontal circuits. J Neurosci 2011;31:16491-16493.
22.
Chen R, Udupa K. Measurement and modulation of plasticity of the motor system in humans using transcranial magnetic stimulation. Motor Control 2009;13:442-453.
Movement Disorders, Vol. 29, No. 10, 2014
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Focal Hand Dystonia: Using Brain Stimulation to Probe Network Interactions and Brain Plasticity Michael Vesia, PhD and Robert Chen, MBBChir, MSc, FRCPC* Division of Neurology, Department of Medicine, University of Toronto and Division of Brain Imaging & Behaviour Systems - Neuroscience, Toronto Western Research Institute, Toronto, Canada
Focal hand dystonias such as writer’s cramp and musician’s cramp are intriguing disorders, and their pathophysiology remains incompletely understood. Both the motor and sensory systems are abnormal in dystonia. In the motor system, dystonia is characterized by loss of inhibition at multiple levels in the central nervous system.1 In the motor cortex, both inhibitory cortical circuits and surround inhibition are reduced in dystonia.2-4 There is also involvement of the sensory system. Patients with focal hand dystonia exhibit abnormal somatotopy with overlapping digit representations in primary somatosensory cortex,5-7 together with diminished temporal8 and spatial tactile acuity.9 Recent studies indicate that altered integration of somatosensory information into the motor plan within the sensorimotor circuit is a key pathophysiological feature of dystonia.10,11 Patients with focal hand dystonia have disturbances of perceptual body representations12 and reduced connectivity between parietal and premotor regions that control writing.13 It is generally considered that abnormalities in the basal ganglia and the cerebellum lead to changes in the primary motor and sensory cortices in dystonia.14 Excessive plasticity and abnormal regulation of plasticity are considered major pathophysiological features of dystonia. Several studies showed that dystonia is associated with exaggerated long-term potentiation (LTP)-like cortical plasticity.15,16 consistent with the hypothesis that dystonia is a disorder of synaptic “scaling.”17 Exaggerated LTP-like plasticity may lead to an excessive tendency to form associations between sensory inputs and motor outputs (abnormal potentiation) and failure to weaken already existing associations (deficient depotentiation).18 Deficient homeostatic
------------------------------------------------------------
*Correspondence to: Dr. Robert Chen, McLaughlin Pavilion, 7th Floor, Room 411, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8, E-mail: [email protected]
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 21 May 2014; Revised: 3 June 2014; Accepted: 16 June 2014 Published online 17 July 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25971
control of plasticity might trigger maladaptive reorganization and produce dystonic symptoms.18 Recent advances in noninvasive brain stimulation (NIBS) techniques provide a powerful tool to understand the complex interactions both within various circuits of the primary motor cortex (M1)19 and between different connected sensory-motor areas,20,21 and to induce brain plasticity22 in humans. Transcranial magnetic stimulation (TMS) is a widely used technique that allows noninvasive examination of different inhibitory and excitatory circuits at the systems level in the human brain, and has the potential to be used as a diagnostic and prognostic tool.23 Interactions between two nodes of a neural circuit in the human sensory-motor system can be studied using two coils in a paired-pulse TMS protocol.20,21 In this conditioning-test paradigm, a conditioning stimulus is delivered to a non-motor area to examine its effects on a subsequent test stimulus to motor cortex. This approach provides information on the excitability of cortical projections to M1 with millisecond resolution, and how inputs from other areas to M1 are modulated by different task-demands, disease, or injury. In addition, several TMS protocols can be used to induce and measure cortical plasticity and they have potential therapeutic utilities in movement disorders.22 Paired associative stimulation (PAS),24 modeled after LTP induction protocols in animal studies, induces LTPlike plasticity by repeated pairing of electrical stimulus to the median nerve with TMS to M1, with the median nerve stimulation preceding TMS by approximately 25 ms such that the two inputs are timed to arrive at the M1 at roughly the same time. It acts through sensory-motor communications and intracortical circuits of M1, and produces heterosynaptic (involves two different synapses), spike-timing– dependent plasticity. In the current issue of Movement Disorders, two studies25,26 used these relatively new NIBS methods to examine the pathophysiology of focal hand dystonia. Pirio Richardson et al.25 used paired-pulse TMS to examine the interactions between dorsal premotor cortex (PMd) and ipsilateral M1 in patients with writer’s
Movement Disorders, Vol. 29, No. 10, 2014
1227
V E S I A
A N D
C H E N
cramp in three different conditions: rest, isometric muscle contraction, and a pen-holding task. They found that in patients with focal hand dystonia the PMd exerts a greater inhibitory influence on ipsilateral M1 in all three conditions compared with controls. These findings suggest that abnormal premotor–motor interactions play a role in the pathophysiology of focal dystonia, as a primary abnormality or as compensation. In a separate study, Sadnicka et al.26 examined the potential of anodal cerebellar transcranial direct current stimulation as a therapeutic tool to reduce exaggerated cortical plasticity in writing dystonia. Ten patients with writing dystonia completed a two-part study in which sham or anodal cerebellar stimulation was given simultaneously with PAS. They found that dystonic symptoms were unchanged by cerebellar stimulation, but the patients exhibited much variability in the size and direction of their plasticity responses. Arguably, the most exciting aspect of these studies is the new perspective they may provide us in understanding the pathophysiological mechanisms of focal hand dystonia. This can lead to significant advances in creating basic knowledge that can be tailored to meet individual patient needs by harnessing brain plasticity to minimize dysfunction and disability. Although these two papers25,26 collectively represent an important step forward in understanding the mechanisms and identifying therapeutic targets for effective management of focal hand dystonia, caution should be exercised when drawing conclusions. A potential caveat relates to the limited stimulation parameters tested in the PMd-M1 circuit by Pirio Richardson et al.25 Various inhibitory and excitatory circuits can be differentiated depending on the stimulus intensities, the interstimulus interval between the conditioning and test stimuli, and task demands.27 Testing with different parameters may reveal different abnormal neural populations within the PMd-M1 pathway, and, in turn, better characterize the pathophysiology of focal hand dystonia. A related limitation is the inability to determine whether this is a primary abnormality related to dystonia or attributable to compensation. Irrespective of this, given the abnormalities in somatosensory processing and sensorimotor integration in focal hand dystonia,28 other nodes within the sensorimotor network such as the primary somatosensory cortex and the parietal cortex should be examined in future studies to better characterize the network dynamics resulting from a possible systemwide compensatory mechanism. Similarly, further studies to explore this complex integration of neuronal circuits with NIBS techniques will help elucidate a more holistic understanding of the pathophysiological mechanisms of focal hand dystonia. This may provide additional insight to guide the optimal placement of brain stimulation targets for treatment.
1228
Movement Disorders, Vol. 29, No. 10, 2014
Another issue with TMS protocols is the inter-subject variability. In both studies, the authors found considerable inter-subject variation in PMd-M1 interactions (see Figure 2 in Pirio-Richardson et al.25) and the plasticity induced by PAS.26 In fact, Sadnicka et al.26 did not find exaggerated PAS plasticity in focal hand dystonia reported by previous studies.15,16,29 This variability can be caused by many factors that influence cortical plasticity and excitability, including genetic factors (i.e., brain-derived neurotrophic factor polymorphism),30 muscle activity,31,32 time of the day,33 and medications. To counter this, Sadnicka and colleagues26 separated the patients into two groups: “responders” who showed facilitation after PAS and “nonresponders.” In “responders” with an LTP-like response to PAS, anodal cerebellar stimulation decreased this excessive abnormal plasticity response. This is a noteworthy approach, although the within-subject reproducibility of the PAS response has not been established. A previous study has found that the cortical circuit activated as indexed by the latency of motor evoked potential critically affects the response of the individual to plasticity induction by NIBS.34 This raises the possibility that in the future individual cortical physiology may be used to select the therapy with the highest likelihood of response. In summary, both studies25,26 provide us with not only a further understanding of the neural changes associated with focal hand dystonia but also a new perspective for modulating specific abnormal sensorimotor circuits as an adjunct to behavioral training. A better understanding of the interactions between neural circuits and mechanisms governing the underlying network plasticity in individual patients may prove to be an effective strategy to select treatment based on individual pathophysiological mechanisms, leading us to the era of personalized medicine for motor and sensorimotor disorders.
References 1.
Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD. The pathophysiology of primary dystonia. Brain 1998;121:1195-1212.
2.
Hallett M. Neurophysiology of dystonia: the role of inhibition. Neurobiol Dis 2011;42:177-184.
3.
Chen R, Wassermann EM, Canos M, Hallett M. Impaired inhibition in writer’s cramp during voluntary muscle activation. Neurology 1997;49:1054-1059.
4.
Nelson AJ, Hoque T, Gunraj C, Ni Z, Chen R. Impaired interhemispheric inhibition in writer’s cramp. Neurology 2010;75:441-447.
5.
Elbert T, Candia V, Altenmuller E, et al. Alteration of digital representations in somatosensory cortex in focal hand dystonia. Neuroreport 1998;9:3571-3575.
6.
Bara-Jimenez W, Catalan MJ, Hallett M, Gerloff C. Abnormal somatosensory homunculus in dystonia of the hand. Ann Neurol 1998;44:828-831.
7.
Nelson AJ, Blake DT, Chen R. Digit-specific aberrations in the primary somatosensory cortex in writer’s cramp. Ann Neurol 2009; 66:146-154.
8.
Fiorio M, Tinazzi M, Bertolasi L, Aglioti SM. Temporal processing of visuotactile and tactile stimuli in writer’s cramp. Ann Neurol 2003;53:630-635.
F O C A L
H A N D
D Y S T O N I A
9.
Molloy FM, Carr TD, Zeuner KE, Dambrosia JM, Hallett M. Abnormalities of spatial discrimination in focal and generalized dystonia. Brain 2003;126:2175-2182.
23.
Chen R, Cros D, Curra A, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119:504-532.
10.
Delnooz CCS, Helmich RC, Medendorp WP, van de Warrenburg BPC, Toni I. Writer’s cramp: increased dorsal premotor activity during intended writing. Human Brain Mapping 2011;34:613-625.
24.
Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 2000;123:572-584.
11.
Castrop F, Dresel C, Hennenlotter A, Zimmer C, Haslinger B. Basal ganglia-premotor dysfunction during movement imagination in writer’s cramp. Mov Disord 2012;27:1432-1439.
25.
Pirio Richardson S, Beck S, Bliem B, Hallett M. Abnormal dorsal premotor-motor inhibition in writer’s cramp. Mov Disord 2014; doi: 10.1002/mds.25881.
12.
Fiorio M, Weise D, Onal-Hartmann C, Zeller D, Tinazzi M, Classen J. Impairment of the rubber hand illusion in focal hand dystonia. Brain 2011;134:1428-1437.
26.
Sadnicka A, Hamada M, Bhatia K, Rothwell J, Edwards M. Cerebellar stimulation fails to modulate motor cortex plasticity in writing dystonia. Mov Disord 2014; doi: 10.1002/mds.25881.
13.
Delnooz CCS, Helmich RC, Toni I, van de Warrenburg BPC. Reduced parietal connectivity with a premotor writing area in writer’s cramp. Mov Disord 2012;27:1425-1431.
27.
14.
Neychev VK, Gross RE, Lehericy S, Hess EJ, Jinnah HA. The functional neuroanatomy of dystonia. Neurobiol Dis 2011;42:185-201.
B€ aumer T, Schippling S, Kroeger J, et al. Inhibitory and facilitatory connectivity from ventral premotor to primary motor cortex in healthy humans at rest: a bifocal TMS study. Clin Neurophysiol 2009:1-8.
28.
15.
Quartarone A, Bagnato S, Rizzo V, et al. Abnormal associative plasticity of the human motor cortex in writer’s cramp. Brain 2003;126:2586-2596.
Abbruzzese G, Berardelli A. Sensorimotor integration in movement disorders. Mov Disord 2003;18:231-240.
29.
Kojovic M, Caronni A, Bologna M, Rothwell JC, Bhatia KP, Edwards MJ. Botulinum toxin injections reduce associative plasticity in patients with primary dystonia. Mov Disord 2011;26:12821289.
30.
Cheeran B, Talelli P, Mori F, et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Physiol 2008;586:5717-5725.
31.
Gentner R, Wankerl K, Reinsberger C, Zeller D, Classen J. Depression of human corticospinal excitability induced by magnetic theta-burst stimulation: evidence of rapid polarity-reversing metaplasticity. Cerebral Cortex 2008;18:2046-2053.
32.
Huang YZ, Rothwell JC, Edwards MJ, Chen RS. Effect of physiological activity on an NMDA-dependent form of cortical plasticity in human. Cerebral Cortex 2008;18:563-570.
33.
Sale MV, Ridding MC, Nordstrom MA. Cortisol inhibits neuroplasticity induction in human motor cortex. J Neurosci 2008;28: 8285-8293.
34.
Hamada M, Murase N, Hasan A, Balaratnam M, Rothwell JC. The role of interneuron networks in driving human motor cortical plasticity. Cerebral Cortex 2013;23:1593-1605.
16.
Weise D, Schramm A, Stefan K, et al. The two sides of associative plasticity in writer’s cramp. Brain 2006;129:2709-2721.
17.
Quartarone A, Pisani A. Abnormal plasticity in dystonia: Disruption of synaptic homeostasis. Neurobiol Dis 2011;42:162-170.
18.
Quartarone A, Siebner HR, Rothwell JC. Task-specific hand dystonia: can too much plasticity be bad for you? Trends Neurosci 2006;29:192-199.
19.
Ni Z, M€ uller-Dahlhaus F, Chen R, Ziemann U. Triple-pulse TMS to study interactions between neural circuits in human cortex. Brain Stimul 2011;4:281-293.
20.
Koch G, Rothwell JC. TMS investigations into the task-dependent functional interplay between human posterior parietal and motor cortex. Behav Brain Res 2009;202:147-152.
21.
Vesia M, Davare M. Decoding action intentions in parietofrontal circuits. J Neurosci 2011;31:16491-16493.
22.
Chen R, Udupa K. Measurement and modulation of plasticity of the motor system in humans using transcranial magnetic stimulation. Motor Control 2009;13:442-453.
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