Frontal increase of beta modulation during the practice of a motor task is enhanced by visuomotor learning.

Movement is accompanied by beta power changes over frontal and sensorimotor regions: a decrease during movement (event-related desynchronization, ERD), followed by an increase (event-related synchronization, ERS) after the movement end. We previously found that enhancements of beta modulation (from ERD to ERS) during a reaching test (mov) occur over frontal and left sensorimotor regions after practice in a visuo-motor adaptation task (ROT) but not after visual learning practice. Thus, these enhancements may reflect local cumulative effects of motor learning. Here we verified whether they are triggered by the learning component inherent in ROT or simply by motor practice in a reaching task without such learning (MOT). We found that beta modulation during mov increased over frontal and left areas after three-hour practice of either ROT or MOT. However, the frontal increase was greater after ROT, while the increase over the left area was similar after the two tasks. These findings confirm that motor practice leaves local traces in beta power during a subsequent motor test. As they occur after motor tasks with and without learning, these traces likely express the cost of processes necessary for both usage and engagement of long-term potentiation mechanisms necessary for the learning required by ROT.

Covid-19 and Parkinson's disease: an overview.

In March 2020, WHO declared Covid-19 outbreak pandemic. There has been increasing evidence that frail, old, multi-pathological patients are at greater risk of developing severe Covid-19 infection than younger, healthy ones. Covid-19's impact on Parkinson's Disease (PD) patients could be analysed through both the influence on PD patients' health and their risk of developing severe Covid-19, and the consequences of lockdown and restrictive measures on mental and cognitive health on both patients and caregivers. Moreover, there are critical issues to be considered about patients' care and management through an unprecedented time like this. One important issue to consider is physiotherapy, as most patients cannot keep exercising because of restrictive measures which has profoundly impacted on their health. Lastly, the relationship between PD and Sars-Cov2 may be even more complicated than it seems as some studies have hypothesized a possible Covid-19-induced parkinsonism. Hereby, we review the state of the art about the relationship between Covid-19 and Parkinson's Disease, focusing on each of these five points.

Low-intensity repetitive paired associative stimulation targeting the motor hand area at theta frequency causes a lasting reduction in corticospinal excitability.

OBJECTIVE: Sub-motor threshold 5 Hz repetitive paired associative stimulation (5 Hz-rPAS25ms) produces a long-lasting increase in corticospinal excitability. Assuming a spike-timing dependent plasticity-like (STDP-like) mechanism, we hypothesized that 5 Hz-rPAS at a shorter inter-stimulus interval (ISI) of 15 ms (5 Hz-rPAS15ms) would exert a lasting inhibitory effect on corticospinal excitability. METHODS: 20 healthy volunteers received two minutes of 5 Hz-rPAS15ms. Transcranial magnetic stimulation (TMS) was applied over the motor hotspot of the right abductor pollicis brevis muscle at 90% active motor threshold. Sub-motor threshold peripheral electrical stimulation was given to the left median nerve 15 ms before each TMS pulse. We assessed changes in mean amplitude of the unconditioned motor evoked potential (MEP), short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition (LAI), and cortical silent period (CSP) before and for 60 minutes after 5-Hz rPAS15ms. RESULTS: Subthreshold 5-Hz rPAS15ms produced a 20-40% decrease in mean MEP amplitude along with an attenuation in SAI, lasting at least 60 minutes. A follow-up experiment revealed that MEP facilitation was spatially restricted to the target muscle. CONCLUSIONS: Subthreshold 5-Hz rPAS15ms effectively suppresses corticospinal excitability. Together with the facilitatory effects of subthreshold 5-Hz rPAS25ms (Quartarone et al., J Physiol 2006;575:657-670), the results show that sub-motor threshold 5-Hz rPAS induces STDP-like bidirectional plasticity in the motor cortex. SIGNIFICANCE: The results of the present study provide a new short-time paradigm of long term depression (LTD) induction in human sensory-motor cortex.

Spatial Integration of Somatosensory Inputs during Sensory-Motor Plasticity Phenomena Is Normal in Focal Hand Dystonia.

Background: Surround inhibition is a system that sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, this mechanism probably contributes to the selection of voluntary movements, and it seems to be lost in dystonia. Objectives. To explore if sensory information is abnormally processed and integrated in focal hand dystonia (FHD) and if surround inhibition phenomena are operating during sensory-motor plasticity and somatosensory integration in normal humans and in patients with FHD. Methods. We looked at the MEP facilitation obtained after 5 Hz repetitive paired associative stimulation of median (PAS M), ulnar (PAS U), and median + ulnar nerve (PAS MU) stimulation in 8 normal subjects and 8 FHD. We evaluated the ratio MU/(M + U) ∗ 100 and the spatial and temporal somatosensory integration recording the somatosensory evoked potentials (SEPs) evoked by a dual nerve input. Results: FHD had two main abnormalities: first, the amount of facilitation was larger than normal subjects; second, the spatial specificity was lost. The MU/(M + U) ∗ 100 ratio was similar in healthy subjects and in FHD patients, and the somatosensory integration was normal in this subset of patients. Conclusions. The inhibitory integration of somatosensory inputs and the somatosensory inhibition are normal in patients with focal dystonia as well as lateral surrounding inhibition phenomena during sensory-motor plasticity in FHD.

Visuospatial exploration and art therapy intervention in patients with Parkinson's disease: an exploratory therapeutic protocol.

Though abnormalities of visuospatial function occur in Parkinson's disease, the impact of such deficits on functional independence and psychological wellbeing has been historically under- recognized, and effective treatments for this impairment are unknown. These symptoms can be encountered at any stage of the disease, affecting many activities of daily living, and negatively influencing mood, self-efficacy, independence, and overall quality of life. Furthermore, visuospatial dysfunction has been recently linked to gait impairment and falls, symptoms that are known to be poor prognostic factors. Here, we aim to present an original modality of neurorehabilitation designed to address visuospatial dysfunction and related symptoms in Parkinson's disease, known as "Art Therapy". Art creation relies on sophisticated neurologic mechanisms including shape recognition, motion perception, sensory-motor integration, abstraction, and eye-hand coordination. Furthermore, art therapy may enable subjects with disability to understand their emotions and express them through artistic creation and creative thinking, thus promoting self-awareness, relaxation, confidence and self-efficacy. The potential impact of this intervention on visuospatial dysfunction will be assessed by means of combined clinical, behavioral, gait kinematic, neuroimaging and eye tracking analyses. Potential favorable outcomes may drive further trials validating this novel paradigm of neurorehabilitation.

Neural correlates of fatigue in multiple sclerosis: a combined neurophysiological and neuroimaging approach (R1).

The present study is aimed at further exploring structural and functional correlates of fatigue in Relapsing- Remitting Multiple Sclerosis (RRMS) patients by using a combined approach by means of transcranial magnetic stimulation (TMS) and a Diffusion Tensor Imaging (DTI). The physiopathology of fatigue in MS is still poorly understood, although a variety of pathogenic mechanisms has been proposed. Our working hypothesis is that diffuse microstructural white matter damage may subtend the cortico-subcortical functional disconnection described in patients with MS and fatigue. We enrolled 30 RRMS patients (mean age 39±13; age range 24-63 years) with mild neurological impairment Expanded Disability Status Scale <3.5, divided into two groups on the basis of their fatigue severity scale (FSS) scoring (cutoff ≥ 4). All the patients underwent a neurological evaluation, a brain MRI acquisition (including DTI study) and a neurophysiological assessment by means of TMS in a pre-movement facilitation paradigm. Our data showed a significant mean diffusivity (MD) increase (p=0.036) in left thalamo-frontal reconstructions in the MS patients with fatigue compared to those classified as non-fatigued. Moreover, significant correlations were observed between FSS scale and MD as well as planar coefficient (CP) values extracted from frontal-thalamic connections bilaterally. Instead, the pre-movement facilitation showed a significant difference between the groups with particular regard to the Reaction Time- MEP50ms amplitude (p=0.03). Our work confirms that fatigue is associated with a disruption of brain networks involved in motor preparation processes, depending on several frontal-thalamic pathways. Such findings can have an important role when dealing with fatigue management in MS patients and could be eventually used as prognostic marker of MS course.

The associative brain at work: Evidence from paired associative stimulation studies in humans.

The original protocol of Paired Associative Stimulation (PAS) in humans implies repetitive cortical and peripheral nerve stimuli, delivered at specific inter-stimulus intervals, able to elicit non-invasively long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity in the human motor cortex. PAS has been designed to drive cortical LTP/LTD according to the Hebbian rule of associative plasticity. Over the last two decades, a growing number of researchers have increasingly used the PAS technique to assess cortical associative plasticity in healthy humans and in patients with movement disorders and other neuropsychiatric diseases. The present review covers the physiology, pharmacology, pathology and motor effects of PAS. Further sections of the review focus on new protocols of "modified PAS" and possible future application of PAS in neuromorphic circuits designed for brain-computer interface.

Inter-hemispheric Claustral Connections in Human Brain: A Constrained Spherical Deconvolution-Based Study.

PURPOSE: Complex claustral connection network was widely demonstrated both in humans and animals. Moreover, several studies have suggested that claustral connections directly involve also the contralateral hemisphere. Detection of contralateral cortico-claustral and inter-claustral connections was reported mainly in animals and only partially in humans. The main purpose of this study was to provide more robust tractography-driven support of the existence of inter-hemispheric claustral connections in humans, by means of a dedicated optimized tractographic protocol. METHODS: Fifteen healthy subjects were examined by means of an advanced magnetic resonance imaging-based probabilistic constrained spherical deconvolution tractographic protocol. Moreover, quantitative diffusion parameters were extracted by each reconstructed pathway. RESULTS: In this study, further imaging-based support on the possible existence in humans of contralateral cortico-claustral and inter-claustral connections was provided. These connections were found to involve almost all the superior portion of each claustrum, showing a topographical organization. Moreover, the detection of inter-claustral connections passing through the anterior commissure was reported, for the first time, in humans. CONCLUSIONS: The possible existence of inter-claustral and cortico-claustral contralateral pathways might provide the morphological basis for the complex functional phenomena observed in previous studies. Furthermore, these connections might have several important clinical implications, since they might explain how the inter-hemispheric coordination governed by the claustrum, as well as the functional recovery subsequent to damages involving one claustrum, takes place.

Cortical excitability in patients with resistance to thyroid hormone compared to patients with hypothyroidism and euthyroid controls: a transcranial magnetic stimulation study.

Resistance to thyroid hormone (RTH) describes a rare syndrome in which serum levels of thyroid hormones are elevated but serum levels of thyroid stimulating hormone (TSH) are unsuppressed. The importance of thyroid hormones for the normal function of the adult brain is corroborated by the frequent association of thyroid dysfunctions with neurological and psychiatric symptoms. In this study we investigated whether adult thyroid hormone resistance affects cortical excitability and modulates inhibitory and excitatory intracortical circuitries by using transcranial magnetic stimulation. Cortical excitability was probed with transcranial magnetic stimulation in 4 patients with thyroid hormone resistance, 10 patients affected by overt hypothyroidism (OH) and 10 age-matched healthy controls. We tested motor thresholds, motor evoked potential recruitment curve, cortical silent period (CSP), short interval intracortical inhibition (SICI) and intracortical facilitation. In both OH and RTH patients, the inhibitory cortical circuits were affected compared with euthyroid controls, but in opposite ways. In OH patients, CSP was prolonged and SICI was decreased. On the contrary, in RTH patients CSP was shortened and SICI was increased. Thyroid hormones may influence cortical excitability and cortical inhibitory circuits.

Obsessive-compulsive disorder: a "sensory-motor" problem?

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous condition. Although its pathophysiology is not completely understood, neurophysiologic and neuroimaging data have disclosed functional abnormalities in the networks linking frontal cortex, supplementary motor and premotor areas, striatum, globus pallidus, and thalamus (CSPT circuits). By means of transcranial magnetic stimulation (TMS) it is possible to test inhibitory and excitatory circuits within motor cortex. Previous studies on OCD patients under medication have demonstrated altered cortical inhibitory circuits as tested by TMS. On the other hand there is growing evidence suggesting an alteration of sensory-motor integration. Therefore, the aim of the present study was to evaluate sensory-motor integration (SAI and LAI), intracortical inhibition, and facilitation in drug-naïve OCD patients, using TMS. In our sample, we have demonstrated a significant SAI reduction in OCD patients when compared to a cohort of healthy individuals. SAI abnormalities may be related to a dysfunction of CSPT circuits which are involved in sensory-motor integration processes. Thus, it can be speculated that hypofunctioning of such system might impair the ability of OCD patients to suppress internally triggered intrusive and repetitive movements and thoughts. In conclusion, our data suggest that OCD may be considered as a sensory motor disorder where a dysfunction of sensory-motor integration may play an important role in the release of motor compulsions.

A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee.

Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction. This includes but is not limited to patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders, disorders affecting the spinal cord, facial and other cranial nerves. These guidelines cover practical aspects of TMS in a clinical setting. We first discuss the technical and physiological aspects of TMS that are relevant for the diagnostic use of TMS. We then lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS. This is followed by a detailed description of how to examine corticomotor conduction to the hand, leg, trunk and facial muscles in patients. Additional sections cover safety issues, the triple stimulation technique, and neuropediatric aspects of TMS.

Abnormal tactile temporal discrimination in psychogenic dystonia.

OBJECTIVE: Neurophysiologic studies demonstrated that patients with primary torsion dystonia (PTD) and with psychogenic dystonia (Psy-D) share similar abnormalities in the motor system. In this study, we evaluated somatosensory function in Psy-D by testing temporal discrimination threshold (TDT), and compared the results with those obtained in patients with PTD. METHODS: TDT of tactile stimuli was assessed in 10 patients with Psy-D, 10 patients with PTD, and 16 control subjects. The 2 groups of patients were matched for age, gender, disease duration, and distribution of dystonia. Tactile stimuli consisted of pairs of non-noxious electrical shocks delivered to the right or left hand at interstimulus interval increasing from 0 to 400 msec, in 10-msec steps. TDT was defined as the value at which subjects recognized the 2 stimuli as asynchronous. RESULTS: TDT was higher in Psy-D and PTD compared to control subjects, for both the right and the left hand. In a subgroup of patients with unilateral dystonia (Psy-D = 4, PTD = 5), TDT did not differ between the affected and the unaffected side in both groups of patients. Disease duration was not correlated to the increased TDT value. CONCLUSIONS: Our study suggests an impaired processing of somatosensory inputs in both Psy-D and PTD. These abnormalities might represent a neurophysiological trait predisposing to develop a dystonic posture triggered by psychiatric and psychological factors.

Recovery of motor performance deterioration induced by a demanding finger motor task does not follow cortical excitability dynamics.

The performance of a demanding exercise can result in motor performance deterioration and depression of primary motor cortex excitability. In the present work we defined a motor task that requires measurable skilled performance to unveil motor performance changes during the execution of a demanding task and to investigate the dynamics of motor performance and cortical excitability changes in absence of overt peripheral fatigue. Twenty-one normal subjects, divided into three groups were asked to perform a sequence of finger opposition movements (SEQ) paced at 2 Hz for 5 min, quantitatively evaluated by means of a sensor-engineered glove able to perform a spatio-temporal analysis of motor performance. Maximal voluntary contraction (MVC) was evaluated before and after the motor task in group 1 while motor evoked potentials (MEP) were evaluated before and after the motor task in group 2 and 3. Group 1 and 2 performed the 5 min-SEQ while group 3 was asked to perform the 5 min-SEQ twice to assess the dynamics of motor performance and cortical excitability. As a result, we found that the execution of 5 min-SEQ induced motor performance deterioration associated with no change in MVC but a decrease in cortical excitability. We further found that the dynamics of cortical excitability and motor performance were different. In fact, a short rest period (i.e., period necessary to collect MEP) between the execution of two 5 min-SEQs was able to recover the motor performance but not the cortical excitability. Finally, no change in spinal excitability was observed. These findings suggest that although primary motor cortex seems to be mainly involved in motor performance deterioration during the execution of a demanding finger motor task, the recovery of motor performance does not follow cortical excitability dynamics.

Associative cortico-cortical plasticity may affect ipsilateral finger opposition movements.

We have recently demonstrated that cortico-cortical paired associative stimulation (cc-PAS) can modulate interhemispheric inhibition (IHI) in the human brain. Here we further explored the after effects of cc-PAS on fine hand movements. Ten healthy right-handed volunteers received 90 paired transcranial stimuli to the right and left primary motor hand area (M1(HAND)) at an interstimulus interval (ISI) of 8 ms. We studied the after effects of cc-PAS on the performance of repetitive finger opposition movements of different complexity on both hands using a sensor-engineered glove. A quantitative evaluation of the following parameters was performed: Touch Duration (TD), Inter Tapping Interval (ITI) and Number of Errors (NE). We confirmed previous data by showing that left-to-right and right-to-left cc-PAS attenuated IHI. The new finding is that both left-to-right and right-to-left cc-PAS were able to influence the performance of a simple finger opposition movement changing the duration of TD and ITI. Interestingly the effect on the two hands was opposite in direction. These results provide further insight that cc-PAS can induce associative plasticity in connections between the targeted cortical areas influencing motor hand performances. These results may be relevant for future rehabilitative applications.

Impairment of sensory-motor integration in patients affected by RLS.

Much evidence suggests that restless legs syndrome (RLS) is a disorder characterized by an unsuppressed response to sensory urges due to abnormalities in inhibitory pathways that specifically link sensory input and motor output. Therefore, in the present study, we tested sensory-motor integration in patients with RLS, measured by short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI). SAI and LAI were determined using transcranial magnetic stimulation before and after 1 month of dopaminergic treatment in RLS patients. Ten naïve patients with idiopathic RLS and ten healthy age-matched controls were recruited. Patients with secondary causes for RLS (e.g. renal failure, anaemia, low iron and ferritin) were excluded, as well as those with other sleep disorders. Untreated RLS patients demonstrated deficient SAI in the human motor cortex, which proved revertible toward normal values after dopaminergic treatment. We demonstrated an alteration of sensory-motor integration, which is normalized by dopaminergic treatment, in patients affected by RLS. It is likely that the reduction of SAI might contribute significantly to the release of the involuntary movements and might account for the sensory urge typical of this condition.

Abnormal sensorimotor plasticity in organic but not in psychogenic dystonia.

Dystonia is characterized by two main pathophysiological abnormalities: 'reduced' excitability of inhibitory systems at many levels of the sensorimotor system, and 'increased' plasticity of neural connections in sensorimotor circuits at a brainstem and spinal level. A surprising finding in two recent papers has been the fact that abnormalities of inhibition similar to those in organic dystonia are also seen in patients who have psychogenic dystonia. To try to determine the critical feature that might separate organic and psychogenic conditions, we investigated cortical plasticity in a group of 10 patients with psychogenic dystonia and compared the results with those obtained in a matched group of 10 patients with organic dystonia and 10 healthy individuals. We confirmed the presence of abnormal motor cortical inhibition (short-interval intracortical inhibition) in both organic and psychogenic groups. However, we found that plasticity (paired associative stimulation) was abnormally high only in the organic group, while there was no difference between the plasticity measured in psychogenic patients and healthy controls. We conclude that abnormal plasticity is a hallmark of organic dystonia; furthermore it is not a consequence of reduced inhibition since the latter is seen in psychogenic patients who have normal plasticity.

Paired associative stimulation of left and right human motor cortex shapes interhemispheric motor inhibition based on a Hebbian mechanism.

This study was designed to examine whether corticocortical paired associative stimulation (cc-PAS) can modulate interhemispheric inhibition (IHI) in the human brain. Twelve healthy right-handed volunteers received 90 paired transcranial stimuli to the right and left primary motor hand area (M1(HAND)) at an interstimulus interval (ISI) of 8 ms. Left-to-right cc-PAS (first pulse given to left M1(HAND)) attenuated left-to-right IHI for one hour after cc-PAS. Left-to-right cc-PAS also increased corticospinal excitability in the conditioned right M1(HAND). These effects were not seen in an asymptomatic individual with callosal agenesis. Additional experiments showed no changes in left-to-right IHI or corticospinal excitability when left-to-right cc-PAS was given at an ISI of 1 ms or at multiple ISIs in random order. At the behavioral level, left-to-right cc-PAS speeded responses with the left but not right index finger during a simple reaction time task. Right-to-left cc-PAS (first pulse given to right M1(HAND)) reduced right-to-left IHI without increasing corticospinal excitability in left M1(HAND). These results provide a proof of principle that cc-PAS can induce associative plasticity in connections between the targeted cortical areas. The efficacy of cc-PAS to induce lasting changes in excitability depends on the exact timing of the stimulus pairs suggesting an underlying Hebbian mechanism.

Abnormal plasticity of sensorimotor circuits extends beyond the affected body part in focal dystonia.

OBJECTIVE: To test whether abnormal sensorimotor plasticity in focal hand dystonia is a primary abnormality or is merely a consequence of the dystonic posture. METHODS: This study used the paired associative stimulation (PAS) paradigm, an experimental intervention, capable of producing long term potentiation (LTP) like changes in the sensorimotor system in humans. PAS involves transcranial magnetic stimulation combined with median nerve stimulation. 10 patients with cranial and cervical dystonia, who showed no dystonic symptoms in the hand, and nine patients with hemifacial spasm (HFS), a non-dystonic condition, were compared with 10 healthy age matched controls. Motor evoked potential amplitudes and cortical silent period (CSP) duration were measured at baseline before PAS and for up to 60 min (T0, T30 and T60) after PAS in the abductor pollicis brevis and the first dorsal interosseus muscles. RESULTS: Patients with dystonia showed a stronger increase in corticospinal excitability than healthy controls and patients with HFS. In addition, patients with dystonia showed a loss of topographical specificity of PAS induced effects, with a facilitation in both the median and ulnar innervated muscles. While PAS conditioning led to a prolonged CSP in healthy controls and patients with HFS, it had no effect on the duration of the CSP in patients with cranial and cervical dystonia. CONCLUSION: The data suggests that excessive motor cortex plasticity is not restricted to the circuits clinically affected by dystonia but generalises across the entire sensorimotor system, possibly representing an endophenotypic trait of the disease.

The basal ganglia are hyperactive during the discrimination of tactile stimuli in writer's cramp.

Writer's cramp is a focal hand dystonia that specifically affects handwriting. Though writer's cramp has been attributed to a dysfunction of the basal ganglia, the role of the basal ganglia in the pathogenesis of writer's cramp remains to be determined. Seventeen patients with writer's cramp (nine females; age range: 24-71 years) and 17 healthy individuals (six females; age range: 27-68 years) underwent functional MRI (fMRI) while they discriminated the orientation of gratings delivered to the tip of the right index finger. Statistical parametric mapping was used to analyse the fMRI data. The significance level was set at a corrected P-value of 0.05. Relative to healthy controls, patients with writer's cramp showed a widespread bilateral increase in task-related activity in the putamen, caudate nucleus, internal globus pallidus and lateral thalamus. In these areas, hyperactivity was more pronounced in patients who had recently developed writer's cramp. The enhanced response of the basal ganglia to tactile input from the affected hand is compatible with the concept of impaired centre-surround inhibition within the basal ganglia-thalamic circuit and may lead to an excessive activation of sensorimotor cortical areas during skilled movements affected by dystonia. Outside the basal ganglia, dystonic patients showed task-related overactivity in visual cortical areas, left anterior insula and right intraparietal sulcus, but not in the primary or secondary sensory cortex. In addition, task-related activity in the cerebellar nuclei, posterior vermis, right paramedian cerebellar hemisphere and dorsal pons was inversely related with the severity of hand dystonia. Regional activity in these areas may reflect secondary adaptive reorganization at the systems level to compensate for the dysfunction in the basal ganglia-thalamic loop.