Marked reduction of cerebellar deficits in upper limbs following transcranial cerebello-cerebral DC stimulation: tremor reduction and re-programming of the timing of antagonist commands

Cerebellar ataxias represent a very heterogeneous group of disabling disorders for which we lack effective symptomatic therapies in most cases. There is currently an intense interest in the use of non-invasive transcranial DC stimulation (tDCS) to modulate the activity of the cerebellum in ataxic disorders. We performed a detailed laboratory assessment of the effects of transcranial cerebello-cerebral DC stimulation (tCCDCS, including a sham procedure) on upper limb tremor and dysmetria in 2 patients presenting a dominant spinocerebellar ataxia (SCA) type 2, one of the most common SCAs encountered during practice. Both patients had a very similar triplet expansion size in the ATXN2 gene (respectively, 39 and 40 triplets). tCCDCS reduced both postural tremor and action tremor, as confirmed by spectral analysis. Quadratical PSD (power spectral density) of postural tremor dropped to 38.63 and 41.42% of baseline values in patient 1 and 2, respectively. The integral of the subband 4–20 Hz dropped to 46.9 and 62.3% of baseline values, respectively. Remarkably, tCCDCS canceled hypermetria and reduced dramatically the onset latency of the antagonist EMG activity associated with fast goal-directed movements toward 3 aimed targets (0.2, 0.3, and 0.4 rad). Following tCCDCS, the latency dropped from 108–98 to 63–57 ms in patient 1, and from 74–87 to 41–46 ms in patient 2 (mean control values ± SD: 36 ± 8 to 45 ± 11 ms), corresponding to a major drop of z scores for the 2 patients from 7.12 ± 0.69 to 1.28 ± 1.27 (sham procedure: 6.79 ± 0.71). This is the first demonstration that tCCDCS improves upper limb tremor and hypermetria in SCA type 2. In particular, this is the first report of a favorable effect on the onset latency of the antagonist EMG activity, a neurophysiological marker of the defect in programming of timing of motor commands. Our results indicate that tCCDCS should be considered in the symptomatic management of upper limb motor deficits in cerebellar ataxias. Future studies addressing a tDCS-based neuromodulation to improve motor control of upper limbs are required (a) in a large group of cerebellar disorders, and (b) in different subgroups of ataxic patients. The anatomical location of the cerebellum below the skull is particularly well suited for such studies.

[1]  Hemicerebellectomy blocks the enhancement of cortical motor output associated with repetitive somatosensory stimulation in the rat. , 2005, The Journal of physiology.

[2]  M. Manto,et al.  Trains of Epidural DC Stimulation of the Cerebellum Tune Corticomotor Excitability , 2013, Neural plasticity.

[3]  Marta Parazzini,et al.  Modelling the electric field and the current density generated by cerebellar transcranial DC stimulation in humans , 2014, Clinical Neurophysiology.

[4]  U. Ziemann,et al.  Non-invasive Cerebellar Stimulation—a Consensus Paper , 2022 .

[5]  J. Hore,et al.  Cerebellar dysmetria at the elbow, wrist, and fingers. , 1991, Journal of neurophysiology.

[6]  J. Weber,et al.  Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23–24.1 , 1993, Nature Genetics.

[7]  F. Fregni,et al.  After-effects of consecutive sessions of transcranial direct current stimulation (tDCS) in a rat model of chronic inflammation , 2012, Experimental Brain Research.

[8]  P. Celnik,et al.  Modulation of Cerebellar Excitability by Polarity-Specific Noninvasive Direct Current Stimulation , 2009, The Journal of Neuroscience.

[9]  Masashi Hamada,et al.  Cerebellar modulation of human associative plasticity , 2012, The Journal of physiology.

[10]  P. Celnik,et al.  Dissociating the roles of the cerebellum and motor cortex during adaptive learning: the motor cortex retains what the cerebellum learns. , 2011, Cerebral cortex.

[11]  J. Hore,et al.  Movement and electromyographic disorders associated with cerebellar dysmetria. , 1986, Journal of neurophysiology.

[12]  Erin V. L. Vasudevan,et al.  Modulating locomotor adaptation with cerebellar stimulation. , 2012, Journal of neurophysiology.

[13]  J. Hore,et al.  Changes in motor cortex neural discharge associated with the development of cerebellar limb ataxia. , 1988, Journal of neurophysiology.

[14]  Giuliana Grimaldi,et al.  Tremor: From Pathogenesis to Treatment , 2008, Synthesis Lectures on Biomedical Engineering.

[15]  J. Brotchi,et al.  The Cerebellum Modulates Rodent Cortical Motor Output after Repetitive Somatosensory Stimulation , 2005, Neurosurgery.

[16]  G. Holmes THE SYMPTOMS OF ACUTE CEREBELLAR INJURIES DUE TO GUNSHOT INJURIES , 1917 .

[17]  V. Braitenberg Is the cerebellar cortex a biological clock in the millisecond range? , 1967, Progress in brain research.

[18]  Giuliana Grimaldi,et al.  A New Myohaptic Instrument to Assess Wrist Motion Dynamically , 2010, Sensors.

[19]  J. Delgado-García,et al.  Transcranial direct-current stimulation modulates synaptic mechanisms involved in associative learning in behaving rabbits , 2012, Proceedings of the National Academy of Sciences.

[20]  Alberto Priori,et al.  Transcranial cerebellar direct current stimulation (tcDCS): Motor control, cognition, learning and emotions , 2014, NeuroImage.

[21]  Giuliana Grimaldi,et al.  Neurological Tremor: Sensors, Signal Processing and Emerging Applications , 2010, Sensors.

[22]  Transcranial Direct Current Stimulation (tDCS) of the Cortical Motor Areas in Three Cases of Cerebellar Ataxia , 2014, The Cerebellum.

[23]  M. Ridding,et al.  Transcranial electric and magnetic stimulation: technique and paradigms. , 2013, Handbook of clinical neurology.

[24]  L. Optican,et al.  Irregularity distinguishes limb tremor in cervical dystonia from essential tremor , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[25]  K. Wessel,et al.  Enhancement of inhibitory mechanisms in the motor cortex of patients with cerebellar degeneration: a study with transcranial magnetic brain stimulation. , 1996, Electroencephalography and clinical neurophysiology.

[26]  M. Manto,et al.  Augmented visual feedback counteracts the effects of surface muscular functional electrical stimulation on physiological tremor , 2013, Journal of NeuroEngineering and Rehabilitation.

[27]  Y. Agid,et al.  Pathology of Symptomatic Tremors , 2008, Movement disorders : official journal of the Movement Disorder Society.

[28]  R. Ivry,et al.  The neural representation of time , 2004, Current Opinion in Neurobiology.

[29]  Pilar Latorre,et al.  Ataxia Rating Scales—Psychometric Profiles, Natural History and Their Application in Clinical Trials , 2011, The Cerebellum.

[30]  Sara Marceglia,et al.  Cerebellar Transcranial Direct Current Stimulation Impairs the Practice-dependent Proficiency Increase in Working Memory , 2008, Journal of Cognitive Neuroscience.

[31]  Manto Mario,et al.  Hemicerebellectomy blocks the enhancement of cortical motor output associated with repetitive somatosensory stimulation in the rat , 2005 .

[32]  Stefano Tamburin,et al.  Enhanced intracortical inhibition in cerebellar patients , 2004, Journal of the Neurological Sciences.

[33]  Paul A. Pope,et al.  Task-specific facilitation of cognition by cathodal transcranial direct current stimulation of the cerebellum , 2012, Brain Stimulation.

[34]  Giuliana Grimaldi,et al.  Anodal Transcranial Direct Current Stimulation (tDCS) Decreases the Amplitudes of Long-Latency Stretch Reflexes in Cerebellar Ataxia , 2013, Annals of Biomedical Engineering.

[35]  Domenico Restuccia,et al.  State Estimation, Response Prediction, and Cerebellar Sensory Processing for Behavioral Control , 2009, The Cerebellum.

[36]  Mario Manto,et al.  Cerebellar ataxias , 2009, Current opinion in neurology.

[37]  P. Laguna,et al.  Signal Processing , 2002, Yearbook of Medical Informatics.

[38]  G L Gottlieb,et al.  Muscle activation patterns during two types of voluntary single-joint movement. , 1998, Journal of neurophysiology.

[39]  Bihemispheric tDCS enhances language recovery but does not alter BDNF levels in chronic aphasic patients. , 2014, Restorative neurology and neuroscience.

[40]  Rodrigo Quian Quiroga,et al.  Imaging Brain Function With EEG , 2013, Springer New York.

[41]  V. Kimiskidis,et al.  θ-burst stimulation of the right neocerebellar vermis selectively disrupts the practice-induced acceleration of lexical decisions. , 2011, Behavioral neuroscience.

[42]  Dagmar Nolte,et al.  Subthalamic‐thalamic DBS in a case with spinocerebellar ataxia type 2 and severe tremor—A unusual clinical benefit , 2007, Movement disorders : official journal of the Movement Disorder Society.

[43]  M. Nitsche,et al.  Facilitation of Implicit Motor Learning by Weak Transcranial Direct Current Stimulation of the Primary Motor Cortex in the Human , 2003, Journal of Cognitive Neuroscience.

[44]  J Jacquy,et al.  Recovery of hypermetria after a cerebellar stroke occurs as a multistage process , 1995, Annals of neurology.

[45]  J Dichgans,et al.  Characteristic alterations of long-loop "reflexes" in patients with Friedreich's disease and late atrophy of the cerebellar anterior lobe. , 1984, Journal of neurology, neurosurgery, and psychiatry.

[46]  M. Manto,et al.  Trains of transcranial direct current stimulation antagonize motor cortex hypoexcitability induced by acute hemicerebellectomy. , 2009, Journal of neurosurgery.

[47]  R. Bracewell,et al.  Brain stimulation studies of non-motor cerebellar function: A systematic review , 2013, Neuroscience & Biobehavioral Reviews.

[48]  Walter J. Freeman,et al.  Imaging Brain Function With EEG: Advanced Temporal and Spatial Analysis of Electroencephalographic Signals , 2012 .

[49]  R. Sheppard,et al.  The dielectric properties of the cerebellum, cerebrum and brain stem of mouse brain at radiowave and microwave frequencies. , 1983, Physics in Medicine and Biology.

[50]  M. Manto,et al.  Cerebellar hypermetria is larger when the inertial load is artificially increased , 1994, Annals of neurology.