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Key Points Noninvasive brain stimulation (NIBS) is a promising approach to enhance recovery after stroke, but its beneficial effect is limited and the technique is not yet ready for broad clinical use We suggest that the disappointments in NIBS trials are related to over-reliance on the interhemispheric competition and vicariation models of recovery, which are oversimplified and do not apply to all patients with stroke The concept of 'structural reserve' integrates the effects that interhemispheric inhibition and vicariation exert on the unlesioned residual network We propose a unified 'bimodal balance–recovery model' that takes into account this individual residual network The model could be used to tailor treatment for individual patients and increase the efficacy of NIBS in stroke rehabilitation Noninvasive brain stimulation (NIBS) is a promising approach for facilitating recovery of motor function after stroke, but trials assessing its efficacy have provided contradictory results. Di Pino and colleagues propose a unified 'bimodal balance–recovery model' for stroke recovery that takes into account the individual residual structural reserve and could aid tailoring of treatment for individual patients, thereby increasing the efficacy of NIBS in stroke rehabilitation. Noninvasive brain stimulation (NIBS) techniques can be used to monitor and modulate the excitability of intracortical neuronal circuits. Long periods of cortical stimulation can produce lasting effects on brain function, paving the way for therapeutic applications of NIBS in chronic neurological disease. The potential of NIBS in stroke rehabilitation has been of particular interest, because stroke is the main cause of permanent disability in industrial nations, and treatment outcomes often fail to meet the expectations of patients. Despite promising reports from many clinical trials on NIBS for stroke recovery, the number of studies reporting a null effect remains a concern. One possible explanation is that the interhemispheric competition model—which posits that suppressing the excitability of the hemisphere not affected by stroke will enhance recovery by reducing interhemispheric inhibition of the stroke hemisphere, and forms the rationale for many studies—is oversimplified or even incorrect. Here, we critically review the proposed mechanisms of synaptic and functional reorganization after stroke, and suggest a bimodal balance–recovery model that links interhemispheric balancing and functional recovery to the structural reserve spared by the lesion. The proposed model could enable NIBS to be tailored to the needs of individual patients.

There is great interest about the therapeutic potentialities of transcutaneous vagus nerve stimulation (tVNS) applied to neuropsychiatric disorders. However, the mechanisms of action of tVNS and its impact on cortical excitability are unclear. To this regard, transcranial magnetic stimulation (TMS) can be useful because it is able of evaluating non-invasively excitatory and inhibitory circuitry of the human cortex. Aim of the present study is to investigate the effects of tVNS on cerebral cortex excitability in healthy volunteers by means of TMS. Ten healthy subjects participated in this randomized placebo-controlled double-blind study. Real tVNS was administered at left external acoustic meatus, while sham stimulation was performed at left ear lobe, both of them for 60 min. We evaluated motor thresholds, motor evoked potential amplitude, recruitment curves, and short-interval intracortical inhibition (SICI) in right and left motor cortex. Such parameters were evaluated before and 60 min after the exposure to tVNS, for both the real and the sham stimulation. Cardiovascular parameters were monitored during the stimulation. A generalized linear model for repeated measures was implemented to assess the effect of time and stimulation type on cardiovascular and neurophysiological variables. SICI, a double-pulse TMS paradigm informative of GABA-A activity, was significantly increased in right motor cortex after real tVNS. Other neurophysiological parameters, as well as cardiovascular variables, remained unchanged. Our findings confirm that tVNS is a safe and effective way to stimulate vagus nerve and provide innovative data about the possible mechanisms of action that supports the potential therapeutic application of this technique.

The potential impact of disease-modifying therapies (DMTs) for multiple sclerosis (MS) on COVID-19 vaccination is poorly understood. According to recent observations, the humoral immune response could be impaired in patients treated with ocrelizumab or fingolimod. Our study evaluated the immunogenicity and safety of mRNA COVID-19 vaccines in a convenience sample of 140 MS patients treated with different DMTs, undergoing vaccination between April and June 2021. Humoral immune response was tested 1 month after the second dose, using a chemiluminescent microparticle immunoassay to detect IgG against SARS-CoV-2 nucleoprotein. We explored the potential correlation between the IgG titer and DMTs. All patients in treatment with first-line DMTs, natalizumab, cladribine, and alemtuzumab, developed a measurable humoral response. In patients treated with ocrelizumab and fingolimod, the IgG level was significantly lower, but only some patients (22.2% for fingolimod and 66% for ocrelizumab) failed to develop a measurable humoral response. In the ocrelizumab group, the IgG level was positively correlated with the time from last infusion. No SARS-CoV-2 infections were reported after vaccination. The most reported side effects were pain at the injection site (57.1%) and fatigue (37.9%). No patient experienced severe side effects requiring hospitalization. Our study confirms that COVID-19 vaccination is safe and well-tolerated in MS patients and should be recommended to all patients regardless of their current DMTs. Since fingolimod and ocrelizumab could reduce the humoral immune response, in patients treated with these drugs, detecting SARS-CoV-2 antibodies could be helpful to monitor the immune response after vaccination.

Over the past decades, among all the non-invasive brain stimulation (NIBS) techniques, those aiming for neuromodulatory protocols have gained special attention. The traditional neurophysiological outcome to estimate the neuromodulatory effect is the motor evoked potential (MEP), the impact of NIBS techniques is commonly estimated as the change in MEP amplitude. This approach has several limitations: first, the use of MEP limits the evaluation of stimulation to the motor cortex excluding all the other brain areas. Second, MEP is an indirect measure of brain activity and is influenced by several factors. To overcome these limitations several studies have used new outcomes to measure brain changes after neuromodulation techniques with the concurrent use of transcranial magnetic stimulation (TMS) and electroencephalogram (EEG). In the present review, we examine studies that use TMS-EEG before and after a single session of neuromodulatory TMS. Then, we focused our literature research on the description of the different metrics derived from TMS-EEG to measure the effect of neuromodulation.

The last decades have witnessed huge efforts devoted to deciphering the pathological mechanisms underlying Alzheimer’s Disease (AD) and to testing new drugs, with the recent FDA approval of two anti-amyloid monoclonal antibodies for AD treatment. Beyond these drug-based experimentations, a number of pre-clinical and clinical trials are exploring the benefits of alternative treatments, such as non-invasive stimulation techniques on AD neuropathology and symptoms. Among the different non-invasive brain stimulation approaches, transcranial alternating current stimulation (tACS) is gaining particular attention due to its ability to externally control gamma oscillations. Here, we outline the current knowledge concerning the clinical efficacy, safety, ease-of-use and cost-effectiveness of tACS on early and advanced AD, applied specifically at 40 Hz frequency, and also summarise pre-clinical results on validated models of AD and ongoing patient-centred trials.

The semantic variant of primary progressive aphasia (svPPA), known also as “semantic dementia (SD),” is a neurodegenerative disorder that pertains to the frontotemporal lobar degeneration clinical syndromes. There is currently no approved pharmacological therapy for all frontotemporal dementia variants. Transcranial direct current stimulation (tDCS) is a promising non-invasive brain stimulation technique capable of modulating cortical excitability through a sub-threshold shift in neuronal resting potential. This technique has previously been applied as adjunct treatment in Alzheimer’s disease, while data for frontotemporal dementia are controversial. In this scoped review, we summarize and critically appraise the currently available evidence regarding the use of tDCS for improving performance in naming and/or matching tasks in patients with svPPA. Clinical trials addressing this topic were identified through MEDLINE (accessed by PubMed) and Web of Science, as of November 2022, week 3. Clinical trials have been unable to show a significant benefit of tDCS in enhancing semantic performance in svPPA patients. The heterogeneity of the studies available in the literature might be a possible explanation. Nevertheless, the results of these studies are promising and may offer valuable insights into methodological differences and overlaps, raising interest among researchers in identifying new non-pharmacological strategies for treating svPPA patients. Further studies are therefore warranted to investigate the potential therapeutic role of tDCS in svPPA.

The efficacy of standard rehabilitative therapy for improving upper limb functions after stroke is limited; thus, alternative strategies are needed. Vagus nerve stimulation (VNS) paired with rehabilitation is a promising approach, but the invasiveness of this technique limits its clinical application. Recently, a noninvasive method to stimulate vagus nerve has been developed. The aim of the present study was to explore whether noninvasive VNS combined with robotic rehabilitation can enhance upper limb functionality in chronic stroke. Safety and efficacy of this combination have been assessed within a proof-of-principle, double-blind, semirandomized, sham-controlled trial. Fourteen patients with either ischemic or haemorrhagic chronic stroke were randomized to robot-assisted therapy associated with real or sham VNS, delivered for 10 working days. Efficacy was evaluated by change in upper extremity Fugl–Meyer score. After intervention, there were no adverse events and Fugl–Meyer scores were significantly better in the real group compared to the sham group. Our pilot study confirms that VNS is feasible in stroke patients and can produce a slight clinical improvement in association to robotic rehabilitation. Compared to traditional stimulation, noninvasive VNS seems to be safer and more tolerable. Further studies are needed to confirm the efficacy of this innovative approach.

BackgroundSARS-CoV-2 infection has been associated with various neurological manifestations. Since patients affected by SARS-CoV-2 infection present coagulation and immune system dysregulation, ischemic or haemorragic stroke is not uncommon, irrespective of respiratory distress. However, the occurrence of focal neurological deficits together with other symptoms like headache, cortical blindness, seizure and altered mental status should prompt the diagnosis of Posterior Reversible Encephalopathy Syndrome (PRES). Antithrombotic treatment, the alteration of endothelial function, and coagulopathy due to COVID-19 and PRES leading to the breakdown of blood–brain barrier may then contribute to the occurrence of a brain haemorrhage.MethodsWe describe the case of a COVID-19 patient who developed bilateral occipital lobe haemorrhages suggestive of haemorrhagic PRES. We then reviewed the available literature about haemorrhagic evolution of PRES in COVID-19.ResultsWe describe the clinical and radiological features of five COVID-19 patients who developed haemorrhagic PRES.ConclusionsCoagulopathy and endothelial dysfunction resulting from the massive release of cytokines during the host immune response may be key factors in the pathogenesis of COVID-19-related PRES. Antithrombotic therapy and the leakage of the blood–brain barrier can subsequently increase the risk of haemorrhagic transformation of the lesioned brain tissue. A prompt diagnosis of PRES is mandatory, since the timely interruption/reversal of antithrombotic therapy may be a key determinant for a good prognosis.

Multiple Sclerosis (MS) has long been recognized as a multifactorial disease, associated with both genetic and enviromental factors. Its link to inflammatory processes has led to significant advances in understanding the immunological and neurobiological mechanisms underlying the disease. The presumed autoimmune etiology is currently guiding the development of therapeutic protocols in this direction. The intestinal bacteria population, known as Gut Microbiota (GM), plays a well-documented role in autoimmune and inflammatory diseases. Gut microbiota dysbiosis is associated in patients affected by MS. Fecal Microbiota Transplantation (FMT) is emerging as a potential strategy to restore eubiosis and modulate systemic inflammation. We treated a 42-year-old woman with severe MS disability by FMT via colonoscopic infusion followed by a 3-month treatment of daily oral capsules, containing frozen microbiota, in order to resolve gastrointestinal symptoms. Clinical follow-up was conducted at 30, 60, and 90 days. Microbiota profiling (16S rRNA sequencing) and intestinal permeability testing were performed at several time points before and post infusion. Post-FMT, gastrointestinal symptoms improved significantly, as well as in limb spasticity, trunk stability, and fine motor skills. Microbiota analysis revealed a marked reduction in the abundance of Akkermansia muciniphila (22.5% vs 6.6%). At phylum level, Actinomycetota remained elevated (22%), while Bacteroidota consistently showed low abundance (14%). The most favorable microbiota profile was observed at 90 days, which coincided with the peak of clinical improvement. Intestinal permeability also improved over time, despite the patient’s microbiota profile remaining distinct from the donor. This is the first report about combined FMT in MS. The procedure was safe, well tolerated, and associated with both gastrointestinal and neurological improvements. These findings support further exploration of FMT as a therapeutic adjunct in MS through controlled clinical trials.