Managing Dystonia With Noninvasive Brain Stimulation: Therapy Update
Symptoms of dystonia include involuntary muscle contractions, abnormal postures, and nonmotor symptoms.
Symptoms of dystonia, a movement disorder featuring involuntary muscle contractions, abnormal postures, and accompanying nonmotor symptoms, were first thought to originate in the brainstem, as deep brain stimulation (DBS) studies showed that disruptions of normal activity in the basal ganglia thalamic circuit were linked to symptoms of reduced inhibition, altered brain plasticity, and sensory processing disorders.1-6 Multiple recent investigations, however, have pointed to larger-scale network involvement of the cerebellar and cortical regions of the brain.7,8
Cerebellar Mechanisms Related to Motor Function and Learning
As a central location for motor control and learning in the brain, new evidence suggests cerebellar involvement in most types of dystonia. A recent review by Bologna and Berardelli1 observed that “experimental studies on animals have consistently shown that abnormal cerebellar signaling may produce dystonia-like movements.” Numerous subsequent clinical case studies have shown direct links between lesions of the brainstem and cerebellum to dystonia symptoms.9
Investigations in the early 1990s by Ugawa and colleagues10 first identified a response called “cerebellar inhibition (CBI)” through transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) techniques. Assuming that the primary motor cortex, M1, was fixed, it could then be presumed that changes in magnitude of CBI at any given time were caused by excitability in the cerebellum or at some point in the thalamic relay. Neuroimaging studies have indicated lower resting functional connectivity rates among patients with dystonia compared with healthy individuals, which was also suggestive of cerebellar involvement.11
In a 2015 review published in Cerebellum,12 Pablo Celnik, MD, of Johns Hopkins University School of Medicine and Johns Hopkins Hospital in Baltimore, Maryland wrote, “CBI has been used to demonstrate at a physiological level the effects of applying TMS or transcranial direct current stimulation (tDCS) to modulate, up or down, the excitability of cerebellar-M1 connectivity.”
Noninvasive cerebellar stimulation has also shown potential in modulating motor learning. Galea et al13 administered visuomotor adaptation tests with cerebellar M1, V1 (visual cortex), or sham anodal tDCS, and found that tDCS was associated with more rapid learning and a significant reduction in movement errors during the testing.
Using primarily TMS, Ugawa and colleagues were able to map a preconditioning effect to stimulation of the cerebellum that could be used to modify responses to a second pulse to M1.10,13,14
Both paired and single TMS technologies are widely used to explore connectivity measures and plasticity of the cerebello-thalamo-cortical pathways. Bidirectional changes to motor evoked potential amplitude are readily induced by repetitive TMS stimuli, which can be assessed by single-pulse TMS over the contralateral M1, and are believed to be indicative of underlying mechanisms of neuroplasticity.15 Likewise, measures of M1 excitability on various dystonia subtypes have occasionally been evaluated using TMS or continuous theta-burst stimulation.16
An obvious challenge to proper use of such modalities is the broadly heterogeneous pathophysiology of dystonia. “A big part of the argument in the field is whether cerebellar abnormalities are the primary or secondary problems that result in dystonia,” Dr Celnik told Neurology Advisor. “I think at this point no one argues that there are cerebellar changes in relation to dystonia, but one of the questions is whether those changes are an attempt of the central nervous system to compensate for abnormalities in other regions or whether the initial problem is in the cerebellum.”
Where Research Is Going
Investigations into CBI and the use of noninvasive transcranial modalities are continuing. “On one hand, some groups have tested CBI in different neurological conditions to determine whether this measurement is useful to predict, diagnose, or understand the pathophysiology of different neurological diseases,” Dr Celnik said. “On the other hand, some other work, from my group for instance, has focused on understanding whether CBI is somatotropic specific and how it is modulated in the context of movement preparation. In addition, we also have been using CBI to investigate the role of the cerebellum when performing or learning different motor tasks.”
The potential of these noninvasive modalities to manage a variety of cerebellar conditions, including dystonia, is a “game-changer,” according to Dr Celnik. “I would comment that CBI is a sensible tool to understand the role of the cerebellum in different brain disorders. Given then that there are different types of dystonias (eg, generalized, familiar, focal, or task-dependent), it would be of interest to test whether cerebellar abnormalities are present in these different conditions via CBI testing,” Dr Celnik said.
- Bologna M, Berardelli A. Cerebellum: An explanation for dystonia? Cerebellum Ataxias. 2017;4:6.
- Defazio G, Berardelli A, Hallett M. Do primary adult-onset focal dystonias share aetiological factors? Brain. 2007;130:1183-1193.
- Colosimo C, Suppa A, Fabbrini G, Bologna M, Berardelli A. Craniocervical dystonia: clinical and pathophysiological features. Eur J Neurol. 2010;17(Suppl 1):15-21.
- Hallett M. Neurophysiology of dystonia: the role of inhibition. Neurobiol Dis. 2011;42:177-184.
- Quartarone A, Hallett M. Emerging concepts in the physiological basis of dystonia. Mov Disord. 2013;28:958-967.
- Defazio G, Conte A, Gigante AF, Fabbrini G, Berardelli A. Is tremor in dystonia a phenotypic feature of dystonia? Neurology. 2015;84:1053-1059.
- Shakkottai VG, Batla A, Bhatia K, et al. Current opinions and areas of consensus on the role of the cerebellum in dystonia. Cerebellum. 2017;16:577-594.
- Avanzino L, Abbruzzese G. How does the cerebellum contribute to the pathophysiology of dystonia? Basal Ganglia. 2012;2:231-235.
- Kumandaş S, Per H, Gümüş H, et al. Torticollis secondary to posterior fossa and cervical spinal cord tumors: report of five cases and literature review. Neurosurg Rev. 2006;29:333-338.
- Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I. Magnetic stimulation over the cerebellum in humans. Ann Neurol. 1995;37:703-713.
- Bharath RD, Biswal BB, Bhaskar MV, et al. Repetitive transcranial magnetic stimulation induced modulations of resting state motor connectivity in writer's cramp. Eur J Neurol. 2015;22:796-805.
- Celnik P. Understanding and modulating motor learning with cerebellar stimulation. Cerebellum. 2015;14:171-174.
- Galea JM, Vazquez A, Pasricha N, de Xivry JJ, Celnik P. Dissociating the roles of the cerebellum and motor cortex during adaptive learning: the motor cortex retains what the cerebellum learns. Cereb Cortex. 2011;21:1761-1770.
- Ugawa Y, Day BL, Rothwell JC, Thompson PD, Merton PA, Marsden CD. Modulation of motor cortical excitability by electrical stimulation over the cerebellum in man. J Physiol. 1991;441:57-72.
- Oliveri M, Koch G, Torriero S, Caltagirone C. Increased facilitation of the primary motor cortex following 1 Hz repetitive transcranial magnetic stimulation of the contralateral cerebellum in normal humans. Neurosci Lett. 2005;376:188-193.
- Bologna M, Paparella G, Fabbrini A, Leodori G, Rocchi L, Hallett M. Effects of cerebellar theta-burst stimulation on arm and neck movement kinematics in patients with focal dystonia. Clin Neurophysiol. 2016;127:3472-3479.