Consensus Paper: Neurophysiological Assessments of Ataxias in Daily Practice.

The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials.

Non-invasive cerebellar stimulation--a consensus paper.

The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies.

Consensus paper: management of degenerative cerebellar disorders.

Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation.

Concurrent action observation modulates practice-induced motor memory formation.

Motor practice is associated with the formation of elementary motor memories. Here we tested in human subjects the hypothesis that observation of a motor training associated with physical practice will modulate the encoding process of a motor memory relative to physical practice alone. Voluntary thumb motions were practiced (i) alone in a direction opposite to the baseline direction of transcranial magnetic stimulation (TMS)-evoked movements (physical practice, PP) and in combination with observation of synchronous movements that were either (ii) directionally congruent (same direction, PP + AOc) or (iii) non-congruent (opposite direction, PP + AOnc) to the practiced ones. We evaluated the following measures of motor memory formation: percentage of TMS-evoked thumb movements falling in the direction of practiced motions, acceleration of TMS-evoked movements along the principal movement axis and corticomuscular excitability of training muscles as indexed by motor-evoked potential amplitudes. Both PP and PP + AOc, but not PP + AOnc, significantly increased the percentage of TMS-evoked movements falling in the practiced direction, changed the compound acceleration vector into the trained direction and enhanced the motor-evoked potential amplitudes in the training agonist muscle. The percentage of TMS-evoked movements falling in the practiced direction increased significantly more after PP + AOc than after PP. Across all measures of motor memory formation, PP + AOc was most efficacious, followed by PP and PP + AOnc. Action observation modulates practice effects on formation of a motor memory. Strengthening of the process of motor memory encoding depends on the directional congruency of the observed model.

Prevalence of sleep disturbance in closed head injury patients in a rehabilitation unit.

UNLABELLED: Traumatic brain injury (TBI) is a leading cause of disability in young people in the United States. Disorders of arousal and attention are common in closed head injury (CHI). Daytime drowsiness impairs participation in rehabilitation, whereas nighttime wakefulness leads to falls and behavioral disturbances. Sleep disturbances in TBI reported in the literature have included excessive daytime somnolence, sleep phase cycle disturbance, narcolepsy, and sleep apnea. Although well known to the clinician treating these patients, the extent and prevalence of disrupted sleep in patients in an acute inpatient rehabilitation unit has not been described. OBJECTIVE: To determine the prevalence of sleep wake cycle disturbance (SWCD) in patients with CHI in a TBI rehabilitation unit. DESIGN: Prospective observational. SETTING: Inpatient specialized brain injury rehabilitation unit. Patients. Thirty-one consecutive admissions to a brain injury rehabilitation unit with the diagnosis of CHI. RESULTS: Twenty-one patients (68%) had aberrations of nighttime sleep. There was no significant difference in Glasgow Coma Score on admission to trauma nor was there any significant difference in age between the affected and unaffected groups. Patients with SWCD had longer stays in both the trauma center (P < .003) and the rehabilitation center (P < .03). CONCLUSIONS: There is a high prevalence of SWCD in CHI patients admitted to a brain injury rehabilitation unit. Patients with SWCD have longer stays in both acute and rehabilitation settings and may be a marker for more severe injury.

Temporal dynamics of cerebellar and motor cortex physiological processes during motor skill learning.

Learning motor tasks involves distinct physiological processes in the cerebellum (CB) and primary motor cortex (M1). Previous studies have shown that motor learning results in at least two important neurophysiological changes: modulation of cerebellar output mediated in-part by long-term depression of parallel fiber-Purkinje cell synapse and induction of long-term plasticity (LTP) in M1, leading to transient occlusion of additional LTP-like plasticity. However, little is known about the temporal dynamics of these two physiological mechanisms during motor skill learning. Here we use non-invasive brain stimulation to explore CB and M1 mechanisms during early and late motor skill learning in humans. We predicted that early skill acquisition would be proportional to cerebellar excitability (CBI) changes, whereas later stages of learning will result in M1 LTP-like plasticity modifications. We found that early, and not late into skill training, CBI changed. Whereas, occlusion of LTP-like plasticity over M1 occurred only during late, but not early training. These findings indicate a distinct temporal dissociation in the physiological role of the CB and M1 when learning a novel skill. Understanding the role and temporal dynamics of different brain regions during motor learning is critical to device optimal interventions to augment learning.

A technical guide to tDCS, and related non-invasive brain stimulation tools.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.

Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation.

We studied the effects of low-frequency transcranial magnetic stimulation (TMS) on motor cortex excitability in humans. TMS at 0.1 Hz for 1 hour did not change cortical excitability. Stimulation at 0.9 Hz for 15 minutes (810 pulses), similar to the parameters used to induce long-term depression (LTD) in cortical slice preparations and in vivo animal studies, led to a mean decrease in motor evoked potential (MEP) amplitude of 19.5%. The decrease in cortical excitability lasted for at least 15 minutes after the end of the 0.9 Hz stimulation. The mechanism underlying this decrease in excitability may be similar to LTD. TMS-induced reduction of cortical excitability has potential clinical applications in diseases such as epilepsy and myoclonus. Spread of excitation, which may be a warning sign for seizures, occurred in one subject and was not accompanied by increased MEP amplitude, suggesting that spread of excitation and amplitude changes are different phenomena and also indicating the need for adequate monitoring even with stimulations at low frequencies.

Motor cortex excitability in patients with cerebellar degeneration.

OBJECTIVES: To study motor cortex (M1) excitability and the effect of subthreshold transcranial magnetic stimulation (TMS) in patients with cerebellar degeneration and normals performing a reaction time (RT) task. METHODS: Time to wrist flexion after a visual go-signal was measured. TMS was always delivered at 90% of resting motor evoked potential (MEP) threshold. In one experiment, test TMS was delivered at various intervals after the go-signal. In half the trials priming TMS was also given with the go-signal. A second experiment examined the effect on RT of M1 and occipital priming stimulation alone. RESULTS: M1 excitability, measured as the likelihood of producing MEPs in the wrist flexor muscles, increased immediately after the go-signal in the patients and stayed high until movement. In controls, excitability rose gradually. This difference was largely eliminated by priming TMS. RT was longer in the patient group, but improved with priming TMS. Occipital priming produced less effect on RT than M1 stimulation in both controls (P=0.008) and patients (P=0.0004). CONCLUSIONS: M1 excitability prior to movement in an RT task increases abnormally early in cerebellar patients. This may reflect compensation for deficient thalamocortical drive. Subthreshold TMS can partially normalize the prolonged RT and abnormal excitability rise in cerebellar patients.

Syncope and seizure-like activity secondary to acute herpes zoster infection of the trigeminal nerve.

Syncope may occur with glossopharyngeal neuralgia. We describe a patient with acute herpetic infection of the first branch of the trigeminal nerve associated with episodes of shooting pain, cardiac arrest and tonic-clonic movements. Resemblances with the so-called "cardiovascular" form of glossopharyngeal neuralgia, as well as putative mechanisms of the syncope, are discussed.

Period of susceptibility for cross-modal plasticity in the blind.

Cross-modal plasticity in blind subjects contributes to sensory compensation when vision is lost early in life, but it is not known if it does so when visual loss occurs at an older age. We used H2(15)O positron emission tomography to identify cerebral regions activated in association with Braille reading, and repetitive transcranial magnetic stimulation to induce focal transient disruption of function during Braille reading, in 8 subjects who became blind after age 14 years (late-onset blind), after a lengthy period of normal vision. Results were compared with those previously reported obtained from congenitally and early-onset blind subjects. As shown by H2(15)O positron emission tomographic scanning, the occipital cortex was strongly activated in the congenitally blind and early-onset blind groups but not in the late-onset blind group. Occipital repetitive transcranial magnetic stimulation disrupted the Braille reading task in congenitally blind and early-onset blind subjects but not in late-onset blind subjects. These results indicate that the susceptible period for this form of functionally relevant cross-modal plasticity does not extend beyond 14 years.

Cutaneomotor integration in humans is somatotopically organized at various levels of the nervous system and is task dependent.

Integration of tactile afferent signals with motor commands is crucial for the performance of purposeful movements such as during manipulation of an object in the hand. To study the somatotopic organization of sensorimotor integration we applied electrical peripheral conditioning stimuli to a digit located near (homotopic stimulation) or distant from (heterotopic stimulation) relaxed or isometrically contracted intrinsic hand muscles at variable time intervals prior to transcranial magnetic stimulation (TMS). Cutaneous stimulation has previously been shown to modulate the amplitude of the motor evoked potential (MEP) and to shorten the duration of the silent period (SP) evoked by TMS. In relaxed target muscles the time-dependent modulation of TMS-evoked motor responses by homotopic conditioning stimulation differed from modulation by heterotopic stimulation. Similar differences in the modulation pattern evoked by homotopic and heterotopic conditioning stimulation were observed for two distinct target muscles of the hand (abductor digiti minimi, abductor pollicis brevis muscle). Differences in modulation were maximal when the conditioning stimulation was applied 25-30 ms and 150-200 ms prior to TMS. Comparison of the modulation of the amplitudes of MEPs evoked by transcranial electrical stimulation (TES) and the modulation of those evoked by TMS suggests that differences between homotopic and heterotopic stimulation originate subcortically at 25- to 30-ms and, at least partially, cortically at 150- to 200-ms interstimulus intervals. In isometrically contracted intrinsic hand muscles the degree to which the SP was shortened reflected the location and the timing of the conditioning stimulus. Shortening was maximal when the conditioning stimulus was applied nearest to the contracted target muscle and 20 ms prior to the test stimulus. In contrast to the SP duration, the MEP size in voluntarily contracted target muscles was unaffected by the location of the conditioning stimulus. The somatotopic gradient of SP shortening was abolished when the two target muscles were simultaneously activated isometrically. Together, our findings suggest that somatotopy of input-output relationships is implemented at both a spinal and a cortical level in the human central nervous system and may also depend on the motor task involved.

Functional relevance of cross-modal plasticity in blind humans.

Functional imaging studies of people who were blind from an early age have revealed that their primary visual cortex can be activated by Braille reading and other tactile discrimination tasks. Other studies have also shown that visual cortical areas can be activated by somatosensory input in blind subjects but not those with sight. The significance of this cross-modal plasticity is unclear, however, as it is not known whether the visual cortex can process somatosensory information in a functionally relevant way. To address this issue, we used transcranial magnetic stimulation to disrupt the function of different cortical areas in people who were blind from an early age as they identified Braille or embossed Roman letters. Transient stimulation of the occipital (visual) cortex induced errors in both tasks and distorted the tactile perceptions of blind subjects. In contrast, occipital stimulation had no effect on tactile performance in normal-sighted subjects, whereas similar stimulation is known to disrupt their visual performance. We conclude that blindness from an early age can cause the visual cortex to be recruited to a role in somatosensory processing. We propose that this cross-modal plasticity may account in part for the superior tactile perceptual abilities of blind subjects.