'Online therapy' to reduce caregiver's distress and to stimulate post-severe acquired brain injury motor and cognitive recovery: A Sicilian hospital experience in the COVID era.

INTRODUCTION: Severe acquired brain injury(SABI) often results in the deterioration of physical, cognitive and emotional functions in the patient and a significant caregiver's distress syndrome, which is now amplified by the social isolation, depression and financial difficulties related to the COVID-19 pandemic. The use of web-based online-therapy has been shown to be useful to overcome caregiver's distress syndrome and further stimulate cognitive-motor recovery of SABI-patients. Our study aimed to investigate whether a systematic online Skype-therapy(OLST) may be of support in favoring global cognitive and sensory-motor recovery in SABI-patients and reducing caregiver distress. METHODS: Twenty-five SABI-subjects in inpatient regimen were provided with intensive OLST with the caregiver for 12 weeks in addition to standard neurorehabilitation. Each subject and caregiver was evaluated before and after the treatment by administering an ad hoc battery. Furthermore, 18 of 27 patients were provided with EEG recording in resting state. RESULTS: We found a significant reduction in caregiver's anxiety (p<0.0001) and burden(p<0.0001). Patients showed significant improvement in trunk control (p<0.0001), functional independence (p = 0.005), functional (p = 0.01) and global communication (p = 0.004), cognitive functioning (p = 0.001), and behavioral responsiveness (p = 0.0004). The training yielded a significant connectivity change within the fronto-centro-parietal areas in the delta frequency band (p<0.0001) and the centro-parieto-occipital areas in the alpha range (p = 0.004). DISCUSSION: OLST may be a useful and complementary treatment to optimize global cognitive and functional recovery in SABI-subjects and reduce caregivers' concerns in the Covid-era. OLST can foster cognitive-motor recovery potentially by favoring the plasticity-dependent functional recovery. Therefore, OLST could be proposed as a tool allowing social conversations also in the hospital setting.

The Role of Innovation Technology in the Rehabilitation of Patients Affected by Huntington's Disease: A Scoping Review.

Huntington's disease is an autosomal dominant neurodegenerative disease caused by the repetition of cytosine, adenine, and guanine trinucleotides on the short arm of chromosome 4p16.3 within the Huntingtin gene. In this study, we aim to examine and map the existing evidence on the use of innovations in the rehabilitation of Huntington's disease. A scoping review was conducted on innovative rehabilitative treatments performed on patients with Huntington's disease. A search was performed on PubMed, Embase, Web of Science, and Cochrane databases to screen references of included studies and review articles for additional citations. Of an initial 1117 articles, only 20 met the search criteria. These findings showed that available evidence is still limited and that studies generally had small sample sizes and a high risk of bias. Regarding cognitive rehabilitation, it has emerged that VR- and PC-based methods as well as NIBS techniques are feasible and may have promising effects in individuals with Huntington's disease. On the other hand, scarce evidence was found for cognitive and motor training that might have a slight impact on overall cognitive function in individuals with Huntington's disease. Data show that further investigation is needed to explore the effects of innovative rehabilitation tools on cognition, especially considering that cognitive and psychiatric symptoms can precede the onset of motor symptoms by many years.

Applications of transcranial magnetic stimulation in migraine: evidence from a scoping review.

Transcranial magnetic stimulation (TMS), a non-invasive brain stimulation method, is trying to emerge as a migraine management strategy for both attack treatment and prevention. This scoping review presents 16 among single-pulse (to manage episodic and chronic migraine) and repetitive TMS randomized clinical trials (to manage chronic migraine). The works we reviewed suggest that TMS may be adopted as add-on therapy in those patients who are refractory to pharmacological therapy only with special arrangements for individualized treatment strategies or research. There are still limited clinical research programs and metaanalysis to promote routinely TMS employment, as TMS has been shown either to have no significant effects for any outcome or to be effective for migraine. These diverging conclusions depend on several biasing factors, including the lack of reliable, large, sham-controlled clinical trials, the dyshomogeneity in study designs (including the area of stimulation, the frequency of stimulation, the number of pulses, pulse intensity, and the number of sessions), patient selection criteria (migraine w/o aura, episodic and chronic migraine; TMS contraindication), and the lack of outcomes homogeneity and long-term real-world efficacy data. Therefore, in the future, it will be important to conduct larger randomized trials to confirm TMS usefulness in migraine management (acute attack and prophylactic treatment), identify those patients who may benefit from TMS, maybe independently of pharmacological treatments (i.e., using TMS as an alternative and not only as an add-on treatment). Otherwise, TMS will play a role in treating migraine only with special arrangements for individualized management strategies or research.

Toward Improving Functional Recovery in AIDS-associated Progressive Multifocal Leukoencephalopathy: A Single Case Pilot Study on a Novel Neuromodulation Approach.

Patients with progressive multifocal leukoencephalopathy (PML) in the context of human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS) show a partial improvement following rehabilitation; however, this improvement is rapidly lost if the patient is not provided with intensive rehabilitation. A 42-year-old patient affected by HIV-AIDS had a clinical worsening within a few months following PML onset, despite being treated with antiretroviral drugs and conventional rehabilitation. He developed severe paraparesis and significant dependency in the activities of daily life. A first cycle of intensive rehabilitation provided the patient with some significant functional outcomes, although he experienced a worsening of the clinical condition after two months of rest, before admission to our rehabilitation unit. We thus sought to evaluate the effects of intensive robot-aided gait training (RAGT) coupled with transcranial direct current stimulation (tDCS). The patient significantly improved when provided with intensive RAGT coupled with tDCS (as per 10-meter Walk Test [10MWT] and 6-minute Walk Test [6MWT]), and the improvement was maintained at three-month follow-up. As this advanced approach was feasible, safe, and potentially effective, this case suggests that patients with PML-HIV require prolonged multidisciplinary rehabilitation treatment. We can speculate that individuals with PML should also be treated with innovative technology to improve their functional outcomes and therefore quality of life.

When Two Is Better Than One: A Pilot Study on Transcranial Magnetic Stimulation Plus Muscle Vibration in Treating Chronic Pelvic Pain in Women.

Chronic pelvic pain syndrome (CPPS) affects about 4-16% of adult women, and about one-third of them require medical assistance due to severe symptoms. Repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) has been shown to manage pain in refractory CPPS. Focal muscle vibration (FMV) has also been reported to relieve pelvic pain. The objective of this study was to assess the feasibility and effect of rTMS coupled with FMV to reduce pain in seven adult women with refractory CPPS. This pilot, open-labeled, prospective trial examined treatment by 5 Hz rTMS over SMA and 150 Hz FMV over the perineum, suprapubic, and sacrococcygeal areas, with one daily session for five consecutive days for three weeks. We assessed tolerance and subjective pain changes (as per visual analog scale, VAS) until one month post-treatment, with a primary endpoint at day 7. No patients experienced serious adverse effects or a significant increase in pain. Six out of seven patients experienced a VAS improvement of at least 10% at T7; three of these individuals experienced a VAS improvement of more than 30%. Overall, we found a significant VAS reduction of 15 points (95% CI 8.4-21.6) at T7 (t = 6.3, p = 0.001; ES = 2.3 (1.1-3.9)). Three of the women who demonstrated a significant VAS reduction at T7 retained such VAS improvement at T30. VAS decreased by six points (95% CI 1.3-10.7) at T30 (t = 3.1, p = 0.02; ES = 1.5 (0.2-2.6)). This coupled approach seems promising for pain management in adult women with refractory CPPS and paves the way for future randomized controlled trials.

Finding the Way to Improve Motor Recovery of Patients with Spinal Cord Lesions: A Case-Control Pilot Study on a Novel Neuromodulation Approach.

Robot-assisted rehabilitation (RAR) and non-invasive brain stimulation (NIBS) are interventions that, both individually and combined, can significantly enhance motor performance after spinal cord injury (SCI). We sought to determine whether repetitive transcranial magnetic stimulation (rTMS) combined with active transvertebral direct current stimulation (tvDCS) (namely, NIBS) in association with RAR (RAR + NIBS) improves lower extremity motor function more than RAR alone in subjects with motor incomplete SCI (iSCI). Fifteen adults with iSCI received one daily session of RAR+NIBS in the early afternoon, six sessions weekly, for eight consecutive weeks. Outcome measures included the 6 min walk test (6MWT), the 10 m walk test (10MWT), the timed up and go (TUG) to test mobility and balance, the Walking Index for Spinal Cord Injury (WISCI II), the Functional Independence Measure-Locomotion (FIM-L), the manual muscle testing for lower extremity motor score (LEMS), the modified Ashworth scale for lower limbs (MAS), and the visual analog scale (VAS) for pain. The data of these subjects were compared with those of 20 individuals matched for clinical and demographic features who previously received the same amount or RAR without NIBS (RAR - NIBS). All patients completed the trial, and none reported any side effects either during or following the training. The 10MWT improved in both groups, but the increase was significantly greater following RAR + NIBS than RAR - NIBS. The same occurred for the FIM-L, LEMS, and WISCI II. No significant differences were appreciable concerning the 6MWT and TUG. Conversely, RAR - NIBS outperformed RAR + NIBS regarding the MAS and VAS. Pairing tvDCS with rTMS during RAR can improve lower extremity motor function more than RAR alone can do. Future research with a larger sample size is recommended to determine longer-term effects on motor function and activities of daily living.

Toward improving functional recovery in spinal cord injury using robotics: a pilot study focusing on ankle rehabilitation.

BACKGROUND: Conventional physical therapy interventions are strongly recommended to improve ambulation potential and upright mobility in persons with incomplete spinal cord injury (iSCI). Ankle rehabilitation plays a significant role, as it aims to stem drop foot consequences. RESEARCH QUESTION: This pilot study aimed to assess the neurophysiological underpinnings of robot-aided ankle rehabilitation (using a platform robot) compared to conventional physiotherapy and its efficacy in improving gait performance and balance in persons with iSCI. METHODS: Ten individuals with subacute/chronic iSCI (six males and four females, 39 ± 13 years, time since injury 8 ± 4 months, ASIA impairment scale grade C-D) were provided with one-month intensive training for robot-aided ankle rehabilitation (24 sessions, 1 h daily, six times a week). Clinical (10-Meter Walk Test (10MWT), 6-Minute Walk Test (6MWT), and Timed Up and Go test (TUG)), and electrophysiological aftereffects (surface-EMG from tibialis anterior and medial gastrocnemius muscles to estimate muscle activation patterns; and corticomuscular coherence-CMC-to assess functional synchronization between sensorimotor cortex and muscles, i.e. the functional integrity of corticospinal output) were assessed at baseline (PRE) and after the trial completion (POST). The experimental group (EG) data were compared with those coming from a retrospective control group (CG; n = 10) matched for clinical-demographic characteristics, who previously underwent conventional ankle rehabilitation. RESULTS: the EG achieved a greater improvement in balance and gait as compared to the CG (TUG EG from 70 ± 18 to 45 ± 15 s, p = 0.002; CG from 68 ± 21 to 48 ± 18 s, p = 0.01; group-comparison p = 0.001; 10MWT EG from 0.43 ± 0.11 to 0.51 ± 0.09 m/s, p = 0.006; CG from 0.4 ± 0.13 to 0.45 ± 0.12, p = 0.01; group-comparison p = 0.006; 6 MWT EG from 231 ± 13 to 274 ± 15 m, p < 0.001; CG from 236 ± 13 to 262 ± 15 m, p = 0.003; group-comparison p = 0.01). Furthermore, the EG showed a retraining of muscle activation (an increase within proper movements, with a reduction of co-contractions) and CMC (beta frequency increase within proper movements, i.e. in a framework of preserved motor coordination). The improvements in CMC, gait, balance, and muscle activation were not correlated with each other. CONCLUSIONS: Robot-aided ankle rehabilitation improved gait performance by selectively ameliorating CMC, muscle activation patterns, and, lastly, gait balance and speed. Despite CMC, gait, balance, and muscle activation were not correlated, this pilot study suggests that robot-aided ankle rehabilitation may favor a better communication between above-SCI and below-SCI structures. This communication improvement may depend on a more synchronized corticospinal output (as per CMC increase) and a better responsiveness of below-SCI motorneurons to corticospinal output (as per specific and ankle movement focused muscle activation increases at the surface EMG), thus favoring greater recruitment of spinal motor units and, ultimately, improving muscle activation pattern and strength. SIGNIFICANCE: Adopting robot-aided ankle rehabilitation protocols for persons with iSCI in the subacute/chronic phase may allow achieving a clinically significant improvement in gait performance.

Improving motor and cognitive recovery following severe traumatic brain injury using advanced emotional audio-video stimulation: Lessons from a case report.

RATIONALE: It is estimated that about 6 million people suffer from severe traumatic brain injury (TBI) each year (73 cases per 100,000 people). TBI may affect emotional, sensory-motor, cognitive, and psychological functions with a consequent worsening of both patient and his/her caregiver's quality of life. In recent years, technological innovations allowed the development of new, advanced sensory stimulation systems, such as Neurowave, to further stimulate residual cognitive abilities and, at the same time, evaluate residual cognition. PATIENT CONCERN: An 69-year-old Italian man entered our neurorehabilitation unit with a diagnosis of minimally conscious state following severe TBI. He breathed spontaneously via tracheostomy and was fed via percutaneous gastrostomy. At the neurological examination, the patient showed severe tetraparesis as he showed fluctuating alertness and responsiveness to external stimuli and opened the eyes without stimulation. DIAGNOSIS: Patient was affected by subarachnoid hemorrhage and frontotemporal bilateral hematoma, which were surgically treated with decompressive craniotomy and subsequent cranioplasty about 6 months before. INTERVENTIONS: The patient underwent a neuropsychological and clinical evaluation before (T0) and after a conventional rehabilitation cycle (T1), and after a Neurowave emotional stimulation-supported rehabilitative cycle (T2). OUTCOMES: Following conventional rehabilitation (T1), the patient achieved a partial improvement in behavioral responsiveness; there was also a mild improvement in the caregiver's distress. Conversely, Neurowave emotional stimulation session determined (at T2) a significant improvement of the patient's behavioral responsiveness, cognition, and in the caregiver's distress. The P300 recording in response to the NES showed a significant change of P300 magnitude and latency. DISCUSSION: Our data suggest that emotional-integrated sensory stimulation using adequate visual stimuli represents a beneficial, complementary rehabilitative treatment for patients in minimally conscious state following a severe TBI. This may occur because stimuli with emotional salience can provide a reliable motivational resource to stimulate motor and cognitive recovery following severe TBI.

A narrative review on non-invasive stimulation of the cerebellum in neurological diseases.

IMPORTANCE: The cerebellum plays an important role in motor, cognitive, and affective functions owing to its dense interconnections with basal ganglia and cerebral cortex. This review aimed at summarizing the non-invasive cerebellar stimulation (NICS) approaches used to modulate cerebellar output and treat cerebellar dysfunction in the motor domain. OBSERVATION: The utility of NICS in the treatment of cerebellar and non-cerebellar neurological diseases (including Parkinson's disease, dementia, cerebellar ataxia, and stroke) is discussed. NICS induces meaningful clinical effects from repeated sessions alone in both cerebellar and non-cerebellar diseases. However, there are no conclusive data on this issue and several concerns need to be still addressed before NICS could be considered a valuable, standard therapeutic tool. CONCLUSIONS AND RELEVANCE: Even though some challenges must be overcome to adopt NICS in a wider clinical setting, this tool might become a useful strategy to help patients with lesions in the cerebellum and cerebral areas that are connected with the cerebellum whether one could enhance cerebellar activity with the intention of facilitating the cerebellum and the entire, related network, rather than attempting to facilitate a partially damaged cortical region or inhibiting the homologs' contralateral area. The different outcome of each approach would depend on the residual functional reserve of the cerebellum, which is confirmed as a critical element to be probed preliminary in order to define the best patient-tailored NICS.

Improvement of brain functional connectivity in autism spectrum disorder: an exploratory study on the potential use of virtual reality.

Patients with Autism Spectrum Disorder (ASD) need to be provided with behavioral, psychological, educational, or skill-building interventions as early as possible. Cognitive Behavior Therapy has proven useful to manage such problems. There is also growing evidence on the usefulness of Virtual Reality Therapy (VRT) in treating various functional deficits in ASD. This exploratory study is aimed at assessing the changes in cognitive functions in children with ASD, and the putative subtending neurophysiological mechanisms, following the provision of rehab training using an innovative VRT system. Twenty patients with ASD, aged 6-15 years, were provided with 24 sessions of VRT by using the pediatric module of the BTS NIRVANA System. Neuropsychological and EEG evaluations were carried out before and at the end of the training. After VRT, all patients showed a significant improvement in their cognitive-behavioral problems concerning attention processes, visuospatial cognition, and anxiety. These findings were paralleled by an evident reshape of frontoparietal connectivity in the alpha and theta frequency range. Our study suggests that VRT could be a useful and promising tool to improve ASD neurorehabilitation outcomes. This improvement is likely to occur through changes in frontoparietal network connectivity following VRT.

Robotic Rehabilitation in Spinal Cord Injury: A Pilot Study on End-Effectors and Neurophysiological Outcomes.

Robot-aided gait training (RAGT) has been implemented to provide patients with spinal cord injury (SCI) with a physiological limb activation during gait, cognitive engagement, and an appropriate stimulation of peripheral receptors, which are essential to entrain neuroplasticity mechanisms supporting functional recovery. We aimed at assessing whether RAGT by means of an end-effector device equipped with body weight support could improve functional ambulation in patients with subacute, motor incomplete SCI. In this pilot study, 15 patients were provided with six RAGT sessions per week for eight consecutive weeks. The outcome measures were muscle strength, ambulation, going upstairs, and disease burden. Furthermore, we estimated the activation patterns of lower limb muscles during RAGT by means of surface electromyography and the resting state networks' functional connectivity (RSN-FC) before and after RAGT. Patients achieved a clinically significant improvement in the clinical outcome measures substantially up to six months post-treatment. These data were paralleled by an improvement in the stair-climbing cycle and a potentiating of frequency-specific and area-specific RSN-FC patterns. Therefore, RAGT, by means of an end-effector device equipped with body weight support, is promising in improving gait in patients with subacute, motor incomplete SCI, and it could produce additive benefit for the neuromuscular reeducation to gait in SCI when combined with conventional physiotherapy.

Breaking the ice to improve motor outcomes in patients with chronic stroke: a retrospective clinical study on neuromodulation plus robotics.

BACKGROUND: Stroke is one of the main causes of impairment affecting daily activities and quality of life. There is a growing effort to potentiate the recovery of functional gait and to enable stroke patients to walk independently. AIM: To estimate the effects of dual-site transcranial direct current stimulation (dstDCS) on gait recovery in chronic stroke patients provided with robot-aided gait training (RAGT). METHODS: Thirty-seven patients were included in this retrospective clinical study. Nine patients were provided with dstDCS during the first 10 min of RAGT by using Lokomat®Pro (on-RAGT), 15 patients immediately after RAGT (post-RAGT), and 13 patients immediately before RAGT (pre-RAGT). RESULTS: Each group improved over time concerning disability burden and lower limb strength. on-RAGT and post-RAGT experienced better improvement in balance (p < 0.001) and, moderately, gait endurance (p = 0.04) as compared to pre-RAGT. Furthermore, all treatments decreased the facilitation of the unaffected hemisphere (p < 0.001) and the inhibition of the affected hemisphere (p < 0.001). The duration of such aftereffects was found to be greater for post-RAGT. DISCUSSION AND CONCLUSION: This is the first trial with dstDCS coupled with RAGT in chronic stroke patients with gait impairment. When timely coupled with RAGT, dstDCS may be considered an effective tool for the recovery of lower limb function in patients with first unilateral stroke in the chronic phase. Moreover, our data suggest the ductility of dstDCS concerning RAGT timing, thus making this intervention suitable in a neurorehabilitation setting and well adaptable to patients' needs.

A Case of Psychogenic Myoclonus Responding to a Novel Transcranial Magnetic Stimulation Approach: Rationale, Feasibility, and Possible Neurophysiological Basis.

Repetitive transcranial magnetic stimulation (rTMS) can relieve motor symptoms related to psychogenic movement disorders (PMDs), but the subtending neurophysiological basis is unclear. We report on a 50-year-old woman with a diagnosis of psychogenic myoclonus in the right lower limb, who was treated with a daily session (in the late morning/early afternoon) of 1 Hz rTMS over the left premotor cortex (PMC), five times a week for 6 weeks. Clinical data and EEG at rest were collected before and immediately and 2-month after the rTMS protocol completion. The patient reported a significant reduction of involuntary movement frequency and intensity and the related disability burden up to the follow-up. In parallel, any abnormality in terms of source current density within and connectivity between the frontal and parietal areas was reset. The short follow-up period, the lack of extensive neurophysiological measures, and the lack of control treatment represent the main limitation of the study. However, low-frequency rTMS over PMC seems a safe and promising approach for the management of psychogenic myoclonus owing to the combination of cortical neuromodulation and non-specific mechanisms suggesting cognitive-behavioral effects.

A Case-Controlled Pilot Study on Rhythmic Auditory Stimulation-Assisted Gait Training and Conventional Physiotherapy in Patients With Parkinson's Disease Submitted to Deep Brain Stimulation.

Deep brain stimulation (DBS) is indicated when motor disturbances in patients with idiopathic Parkinson's disease (PD) are refractory to current treatment options and significantly impair quality of life. However, post-DBS rehabilitation is essential, with particular regard to gait. Rhythmic auditory stimulation (RAS)-assisted treadmill gait rehabilitation within conventional physiotherapy program plays a major role in gait recovery. We explored the effects of a monthly RAS-assisted treadmill training within a conventional physiotherapy program on gait performance and gait-related EEG dynamics (while walking on the RAS-aided treadmill) in PD patients with (n = 10) and without DBS (n = 10). Patients with DBS achieved superior results than those without DBS concerning gait velocity, overall motor performance, and the timed velocity and self-confidence in balance, sit-to-stand (and vice versa) and walking, whereas both groups improved in dynamic and static balance, overall cognitive performance, and the fear of falling. The difference in motor outcomes between the two groups was paralleled by a stronger remodulation of gait cycle-related beta oscillations in patients with DBS as compared to those without DBS. Our work suggests that RAS-assisted gait training plus conventional physiotherapy is a useful strategy to improve gait performance in PD patients with and without DBS. Interestingly, patients with DBS may benefit more from this approach owing to a more focused and dynamic re-configuration of sensorimotor network beta oscillations related to gait secondary to the association between RAS-treadmill, conventional physiotherapy, and DBS. Actually, the coupling of these approaches may help restoring a residually altered beta-band response profile despite DBS intervention, thus better tailoring the gait rehabilitation of these PD patients.

Virtual Reality Based Cognitive Rehabilitation in Minimally Conscious State: A Case Report with EEG Findings and Systematic Literature Review.

Chronic disorders of consciousness cause a total or partial and fluctuating unawareness of the surrounding environment. Virtual reality (VR) can be useful as a diagnostic and/or a neurorehabilitation tool, and its effects can be monitored by means of both clinical and electroencephalography (EEG) data recording of brain activity. We reported on the case of a 17-year-old patient with a disorder of consciousness (DoC) who was provided with VR training to improve her cognitive-behavioral outcomes, which were assessed using clinical scales (the Coma Recovery Scale-Revised, the Disability Rating Scale, and the Rancho Los Amigos Levels of Cognitive Functioning), as well as EEG recording, during VR training sessions. At the end of the training, significant improvements in both clinical and neurophysiological outcomes were achieved. Then, we carried out a systematic review of the literature to investigate the role of EEG and VR in the management of patients with DoC. A search on PubMed, Web of Science, Scopus, and Google Scholar databases was performed, using the keywords: "disorders of consciousness" and "virtual reality", or "EEG". The results of the literature review suggest that neurophysiological data in combination with VR could be useful in evaluating the reactions induced by different paradigms in DoC patients, helping in the differential diagnosis. In conclusion, the EEG plus VR approach used with our patient could be promising to define the most appropriate stimulation protocol, so as to promote a better personalization of the rehabilitation program. However, further clinical trials, as well as meta-analysis of the literature, are needed to be affirmative on the role of VR in patients with DoC.

Brain functional connectivity in chronic tic disorders and Gilles de la Tourette syndrome.

The pathophysiology of chronic tic disorder (cTD) and Gilles de la Tourette syndrome (GTS) is characterized by the dysfunction of both motor and non - motor cortico - striatal - thalamo - cortical (CSTC) circuitries, which leads to tic release and comorbids. A role of fronto - parietal network (FPN) connectivity breakdown has been postulated for tic pathogenesis, given that the FPN entertain connections with limbic, paralimbic, and CSTC networks. Our study was aimed at characterizing the FPN functional connectivity in cTD and GTS in order to assess the role of its deterioration in tic severity and the degree of comorbids. We recorded scalp EEG during resting state in patients with cTD and GTS. The eLORETA current source densities were analyzed, and the lagged phase synchronization (LPS) was calculated to estimate nonlinear functional connectivity between cortical areas. We found that the FPN functional connectivity in delta band was more detrimental in more severe GTS patients. Also, the sensorimotor functional connectivity in beta2 band was stronger in more severe cTD and GTS patients. FPN functional connectivity deterioration correlated with comorbids presence and severity in patients with GTS. Our data suggest that a FPN disconnection may contribute to the motoric symptomatology and comorbid severity in GTS, whereas sensorimotor disconnection may contribute to tic severity in cTD and GTS. Although preliminary, our study points out a differently disturbed brain connectivity between patients with cTD and GTS. This may serve as diagnostic marker and potentially interesting base to develop pharmacological and noninvasive neuromodulation trials aimed at reducing tic symptomatology.

Peri-Personal Space Tracing by Hand-Blink Reflex Modulation in Patients with Chronic Disorders of Consciousness.

The assessment of awareness in patients with chronic Disorders of Consciousness (DoC), including Unresponsive Wakefulness Syndrome (UWS) and Minimally Conscious State (MCS), is challenging. The level of awareness impairment may depend on the degree of deterioration of the large-scale cortical-thalamo-cortical networks induced by brain injury. Electrophysiological approaches may shed light on awareness presence in patients with DoC by estimating cortical functions related to the cortical-thalamo-cortical networks including, for example, the cortico-subcortical processes generating motor responses to the perturbation of the peri-personal space (PPS). We measured the amplitude, latency, and duration of the hand-blink reflex (HBR) responses by recording electromyography (EMG) signals from both the orbicularis oculi muscles while electrically stimulating the median nerve at the wrist. Such a BR is thought to be mediated by a neural circuit at the brainstem level. Despite its defensive-response nature, HBR can be modulated by the distance between the stimulated hand and the face. This suggests a functional top-down control of HBR as reflected by HBR features changes (latency, amplitude, and magnitude). We therefore estimated HBR responses in a sample of patients with DoC (8 MCS and 12 UWS, compared to 15 healthy controls -HC) while performing a motor task targeting the PPS. This consisted of passive movements in which the hand of the subject was positioned at different distances from the participant's face. We aimed at demonstrating a residual top-down modulation of HBR properties, which could be useful to differentiate patients with DoC and, potentially, demonstrate awareness preservation. We found a decrease in latency, and an increase in duration and magnitude of HBR responses, which were all inversely related to the hand-to-face distance in HC and patients with MCS, but not in individuals with UWS. Our data suggest that only patients with MCS have preserved, residual, top-down modulation of the processes related to the PPS from higher-order cortical areas to sensory-motor integration network. Although the sample size was relatively small, being thus our data preliminary, HBR assessment seems a rapid, easy, and first-level tool to differentiate patients with MCS from those with UWS. We may also hypothesize that such a HBR modulation suggests awareness preservation.

Toward Improving Diagnostic Strategies in Chronic Disorders of Consciousness: An Overview on the (Re-)Emergent Role of Neurophysiology.

The differential diagnosis of patients with Disorder of Consciousness (DoC), in particular in the chronic phase, is significantly difficult. Actually, about 40% of patients with unresponsive wakefulness syndrome (UWS) and the minimally conscious state (MCS) are misdiagnosed. Indeed, only advanced paraclinical approaches, including advanced EEG analyses, can allow achieving a more reliable diagnosis, that is, discovering residual traces of awareness in patients with UWS (namely, functional Locked-In Syndrome (fLIS)). These approaches aim at capturing the residual brain network models, at rest or that may be activated in response to relevant stimuli, which may be appropriate for awareness to emerge (despite their insufficiency to generate purposeful motor behaviors). For this, different brain network models have been studied in patients with DoC by using sensory stimuli (i.e., passive tasks), probing response to commands (i.e., active tasks), and during resting-state. Since it can be difficult for patients with DoC to perform even simple active tasks, this scoping review aims at summarizing the current, innovative neurophysiological examination methods in resting state/passive modality to differentiate and prognosticate patients with DoC. We conclude that the electrophysiologically-based diagnostic procedures represent an important resource for diagnosis, prognosis, and, therefore, management of patients with DoC, using advance passive and resting state paradigm analyses for the patients who lie in the "greyzones" between MCS, UWS, and fLIS.

Walking on the Moon: A randomized clinical trial on the role of lower body positive pressure treadmill training in post-stroke gait impairment.

Body weight-supported treadmill training (BWSTT) can be usefully employed to facilitate gait recovery in patients with neurological injuries. Specifically, lower body positive pressure support system (LBPPSS) decreases weight-bearing and ground reaction forces with potentially positive effects on qualitative gait indices. However, which gait features are being shaped by LBPPSS in post-stroke patients is yet poorly predictable. A pilot study on the effects of LBPPSS on qualitative and quantitative gait indices was carried out in patients with hemiparesis due to stroke in the chronic phase. Fifty patients, who suffered from a first, single, ischemic, supra-tentorial stroke that occurred at least 6 months before study inclusion, were enrolled in the study. They were provided with 24 daily sessions of gait training using either the AlterG device or conventional treadmill gait training (TGT). These patients were compared with 25 age-matched healthy controls (HC), who were provided with the same amount of AlterG. Qualitative and quantitative gait features, including Functional Ambulation Categories, gait cycle features, and muscle activation patterns were analyzed before and after the training. It was found that AlterG provided the patients with higher quantitative but not qualitative gait features, as compared to TGT. In particular, AlterG specifically shaped muscle activation phases and gait cycle features in patients, whereas it increased only overall muscle activation in HC. These data suggest that treadmill gait training equipped with LBPPSS specifically targets the gait features that are abnormal in chronic post-stroke patients. It is hypothesizable that the specificity of AlterG effects may depend on a selective reshape of gait rhythmogenesis elaborated by the locomotor spinal circuits receiving a deteriorated corticospinal drive. Even though further studies are warranted to clarify the role of treadmills equipped with LBPPSS in gait training of chronic post-stroke patients, the knowledge of the exact gait pattern during weight-relief is potentially useful to plan patient-tailored locomotor training.

Theta burst stimulation for the treatment of obsessive-compulsive disorder: a pilot study.

A non-negligible part of patients with obsessive-compulsive disorder (OCD) experiences inadequate response to pharmacological and cognitive therapies. Therefore, new approaches are required to overcome this problem. The present pilot study estimates the capacity of theta burst stimulation (TBS) in reducing OCD symptoms, also focusing on the neurophysiological basis of TBS aftereffects. Ten patients with OCD who were unsatisfactorily responsive to the pharmacological and neuropsychological treatment, participated to the present randomized crossover pilot study, in which they were subjected to a real or sham intermittent TBS (iTBS) paradigm over the left dorsolateral prefrontal cortex (L-DLPFC) as add-on treatment. They were randomly assigned to a real or sham iTBS in a 1:1 allocation ratio. Patients received the TBS treatment every morning, 5 days a week for 1 month, and were clinically and electrophysiologically evaluated (EEG phase synchronization and coherence) before, immediately after (T0), and one (T1), three (T3) and six (T6) months after the end of the TBS treatment. Then, each patient was subjected to the alternative treatment (that was not practiced before), and followed up to 6 months. We found that all the patients improved in OCD symptomatology up to T1, while four among them improved up to T3. These patients were those showing a more extensive reshape of frontal areas phase synchronization and frontoparietal coherence compared to the other participants. Our pilot study suggests that iTBS over L-DLPFC may represent a feasible approach to improve OCD symptoms. The efficacy of iTBS seems to depend on the extent of frontal and frontoparietal connectivity modulation.