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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Changes in spinal cord excitability in patients affected by ulnar neuropathy.

OBJECTIVE: To evaluate whether ulnar neuropathy could induce changes in spinal cord and motor cortex excitability and therefore predispose to development of focal dystonia. BACKGROUND: A high incidence of ulnar neuropathy has been observed in patients with musician's cramp. Polygraphic electromyograph recordings in patients with entrapment of the ulnar nerve at the elbow have demonstrated long-duration bursts of co-contraction in antagonistic muscles, similar to those observed in focal dystonia. METHODS: All control subjects and 12 patients with ulnar neuropathy underwent an electrophysiologic protocol consisting of polygraphic recordings of a repetitive tapping task of the fourth finger, assessment of reciprocal inhibition in forearm muscles, and investigation of motor cortex excitability after paired transcranial magnetic stimulation. RESULTS: Eleven of 12 patients with ulnar neuropathy showed a loss of alternation and of well-formed bursts in both flexor and extensor muscles. Evaluation of reciprocal inhibition in these patients revealed a reduction in the amount of inhibition in the disynaptic and presynaptic phases. None of the patients presented with a clinically evident dystonia of the upper limb. The study of intracortical excitability after paired shocks did not reveal any difference in the amount of intracortical inhibition and facilitation compared with the control group. CONCLUSIONS: A peripheral nerve injury can induce a rearrangement of reciprocal inhibition circuits at the spinal cord level. These changes might predispose to the development of a focal dystonia. However, it is likely that another, yet unknown, factor is required to alter the intracortical circuits and produce a clinically evident dystonia.

Preliminary clinical observations on a new trigeminal reflex: the trigemino-cervical reflex.

Short latency trigemino-cervical reflexes can be recorded from sternocleidomastoid muscle after stimulation of the infraorbital branch of the trigeminal nerve. We studied the trigemino-cervical reflexes and the conventional blink reflex in three patients with an isolated lesion in the medulla oblongata, eight patients with multiple sclerosis, and two patients with supratentorial ischemic lesion. The trigemino-cervical response was abnormal in the patients with an isolated lesion in the medulla oblongata and in all multiple sclerosis patients, whereas both components of the blink reflex were preserved in the patients with a lesion in the medulla oblongata and in half of the patients with multiple sclerosis. The trigemino-cervical reflex was preserved in patients with supratentorial lesions, whereas the late component of the blink reflex was abnormal. These findings suggest that central pathways generating the trigemino-cervical reflex are confined to the medulla oblongata and that they are independent from those generating the long latency (R2) component of the blink reflex. The trigemino-cervical reflex may help in disclosing and localizing brainstem lesions.

Botulinum toxin in upper limb spasticity: study of reciprocal inhibition between forearm muscles.

To establish whether botulinum A toxin (BTX-A) acts on modifying reciprocal inhibition between forearm muscles in spasticity, 20 patients with post-stroke upper limb spasticity lasting for more than 1 year were studied. Clinical examination, physiotherapeutic evaluation, standardized video-tape assessment and electrophysiological testing (flexor carpi radialis muscle M and H responses with study of reciprocal inhibition) were performed at baseline and 2 weeks, 1, 2, 3, 4 months after BTX-A treatment. BTX-A induced a significant decrease of tone and an improvement of motility and functional status, with a significant decrease of the M wave and the H reflex. The reduction in both inhibitory phases of reciprocal inhibition did not change after BTX-A treatment differently from that reported in upper limb dystonia. These findings indicate that the efficacy of BTX-A in upper limb spasticity is mainly due to peripheral effects.

Different patterns of I-waves summation in ALS patients according to the central conduction time.

OBJECTIVES: To study facilitatory I-waves interaction, using two near threshold stimuli, to test both excitability and conductivity changes related to cortico-motoneuronal involvement in amyotrophic lateral sclerosis (ALS) patients in different stages of the disease. METHODS: Pairs of threshold magnetic stimuli were applied over the motor cortex at inter-stimulus intervals (ISI) ranging from 1-1.5 to 2.5-3 ms and from 4 to 4.5ms. The electromyogram responses were recorded from relaxed first dorsal interosseus (FDI). RESULTS: The data of I-waves summation were distributed according to the central conduction time (CCT) and all 3 peaks of facilitation were considered for statistical analysis. Patients with normal CCT showed a normal I-waves summation for the first peak, whilst patients with abnormal CCT had a significant reduction in facilitation (P<0.02). Six out of 11 patients with normal CCT had facilitation in the first peak, which exceeded 2 SD of normal values. CONCLUSIONS: In conclusion ALS patients showed two different and opposite patterns of I-waves summation which could be related to different stages of the disease.

Short latency trigemino-sternocleidomastoid response in muscles in patients with spasmodic torticollis and blepharospasm.

OBJECTIVES: To further elucidate the pathogenesis of focal dystonias. METHODS: Short latency responses can be recorded in tonically active sternocleidomastoid muscles after stimulation of the infraorbital branch of the trigeminal nerve. Such trigemino-sternocleidomastoid response consists of a bilateral positive/negative wave in the average of unrectified surface EMG, corresponding to a short period of inhibition of motor unit firing. This brain stem reflex was investigated in 10 normal subjects, in 16 patients affected by spasmodic torticollis (ST) and in 10 patients with blepharospasm (BSP). RESULTS: All ST patients presented abnormalities of SCM responses after infraorbital nerve stimulation. The abnormalities were bilateral in all but one of the patients and were independent from previous treatment with botulinum toxin. No BSP patients showed alterations of this reflex. CONCLUSIONS: Abnormalities of brain stem interneurons which are responsible for oligosynaptic exteroceptive suppression reflexes occur specifically in ST. These findings further support the relevance of sensory inputs in the determinism of focal dystonias.

Electrophysiological study of neuromuscular system involvement in mitochondrial cytopathy.

OBJECTIVES: To define the neuromuscular involvement in 'mitochondrial' patients with clinical evidence of a neuromuscular disorder, and to evaluate if the proposed electrophysiological protocol was suitable to reveal a subclinical neuropathy or myopathy in 'mitochondrial' patients with no clinical sign of a neuromuscular disturbance. METHODS: Quantitative concentric needle electromyography (CNEMG), single fiber electromyography (SFEMG) and nerve conduction studies (NCS) were performed in 33 patients with mitochondrial cytopathies. Lastly, we studied 9 clinically unaffected relatives. RESULTS: NCS were abnormal in 18% of patients, with CNEMG and SFEMG in 58% of cases, but there was not a complete overlapping of the positivity of the different techniques. No asymptomatic relatives showed abnormalities of the electrophysiological studies. CONCLUSIONS: Electrophysiological findings did not correlate with any specific biochemical or genetic defect, but were consistent with clinical diagnosis in almost all of the patients with clinical signs of myopathy and/or neuropathy. Increase of both SFEMG jitter and fiber density was significantly tied to a neuropathic process. CNEMG and SFEMG were altered in about 30% of subjects without clinical signs of myopathy or neuropathy and were therefore able to reveal a subclinical involvement of neuromuscular system in some patients who had external ophthalmoplegia or retinitis only.