Intracortical and interhemispheric excitability changes in arm amputees: A TMS study.

OBJECTIVE: To evaluate cortical circuits and excitability of the motor cortex in the hemisphere contralateral to the affected (AH) and to the unaffected arm (UH), in upper limb amputees. METHODS: Motor evoked potentials (MEP) were recorded in 17 subjects who had upper limb amputation: 11 trans-radial (TR) and 6 trans-humeral (TH). Motor thresholds (MT), short interval intracortical inhibition (SICI), and interhemispheric inhibition (IHI) in the available arm muscles of the stump were evaluated. RESULTS: There was no significant difference in MT between hemispheres. SICI was preserved in TR but not in TH group. Additionally, in the TR group, the MEP amplitudes in AH were higher than in UH. A significant IHI was observed in the whole sample but not in each hemisphere or patient group. CONCLUSIONS: In our population of TR amputees, we found increased corticospinal excitability in the AH with preserved intracortical inhibition. This finding was not observed in the TH population. SIGNIFICANCE: Understanding the changes in intracortical excitability in amputees may enhance knowledge of the functional reorganization of the brain in the post-amputation phase, bringing useful information for prosthetic rehabilitation.

Integration of proprioception in upper limb prostheses through non-invasive strategies: a review.

Proprioception plays a key role in moving our body dexterously and effortlessly. Nevertheless, the majority of investigations evaluating the benefits of providing supplemental feedback to prosthetics users focus on delivering touch restitution. These studies evaluate the influence of touch sensation in an attempt to improve the controllability of current robotic devices. Contrarily, investigations evaluating the capabilities of proprioceptive supplemental feedback have yet to be comprehensively analyzed to the same extent, marking a major gap in knowledge within the current research climate. The non-invasive strategies employed so far to restitute proprioception are reviewed in this work. In the absence of a clearly superior strategy, approaches employing vibrotactile, electrotactile and skin-stretch stimulation achieved better and more consistent results, considering both kinesthetic and grip force information, compared with other strategies or any incidental feedback. Although emulating the richness of the physiological sensory return through artificial feedback is the primary hurdle, measuring its effects to eventually support the integration of cumbersome and energy intensive hardware into commercial prosthetic devices could represent an even greater challenge. Thus, we analyze the strengths and limitations of previous studies and discuss the possible benefits of coupling objective measures, like neurophysiological parameters, as well as measures of prosthesis embodiment and cognitive load with behavioral measures of performance. Such insights aim to provide additional and collateral outcomes to be considered in the experimental design of future investigations of proprioception restitution that could, in the end, allow researchers to gain a more detailed understanding of possibly similar behavioral results and, thus, support one strategy over another.

A smart devices based secondary prevention program for cerebrovascular disease patients.

Background: Commercially available health devices are gaining momentum and represent a great opportunity for monitoring patients for prolonged periods. This study aimed at testing the feasibility of a smart device-based secondary prevention program in a cohort of patients with cryptogenic stroke. Methods: In this proof-of-principle study, patients with non-disabling ischemic stroke and transient ischemic attacks (TIA) in the subacute phase were provided with a smartwatch and smart devices to monitor several parameters - i.e., oxygen saturation, blood pressure, steps a day, heart rate and heart rate variability - for a 4-week period (watch group). This group was compared with a standard-of-care group. Our primary endpoint was the compliance with the use of smart devices that was evaluated as the number of measures performed during the observation period. Results: In total, 161 patients were recruited, 87 in the WATCH group and 74 in the control group. In the WATCH group, more than 90% of patients recorded the ECG at least once a day. In total, 5,335 ECGs were recorded during the study. The median blood pressure value was 132/78 mmHg and the median oxygen saturation value was 97%. From a clinical standpoint, although not statistically significant, nine atrial fibrillation episodes (10.3%) in the WATCH group vs. 3 (4%) in the control group were detected. Conclusion: Our study suggests that prevention programs for cerebrovascular disease may benefit from the implementation of new technologies.

Disease-Modifying Drugs and Breastfeeding in Multiple Sclerosis: A Narrative Literature Review.

Pregnancy-related issues in women with multiple sclerosis (MS) have been receiving increasing attention, with particular interest for the use of disease-modifying therapies (DMTs) before conception, during pregnancy, and postpartum, including breastfeeding. The risk of relapse is higher in the early postpartum period, especially in cases of significant disease activity prior to pregnancy, and thus treatment resumption and/or switching strategies might be necessary. Moreover, breastfeeding provides unmatched health benefits for babies and mothers, and is recommended as the best source of nutrition for infants. Furthermore, a protective role of breastfeeding on MS disease course has not been fully demonstrated and it remains debatable. At the same time, a source of concern is the potential transfer of DMTs into breastmilk and the resulting infant exposure. The use of most DMTs is unlicensed during breastfeeding mainly due to the limited data available on the excretion in human milk and on the effects on infants' exposure. Consequently, women have to face the difficult challenge of choosing between breastfeeding and DMT resumption. The present narrative review summarizes and discusses the available evidence on the safety of DMTs during breastfeeding and the relative approved labels. At the time of diagnosis of MS, specific counseling should be offered to women of childbearing age, making them aware of the possible therapeutic options and their impact on pregnancy and breastfeeding. Women can be encouraged to breastfeed, if clinically feasible, following a review of their medications and clinical status, with a personalized approach.

Focused Ultrasound (FUS) for Chronic Pain Management: Approved and Potential Applications.

Chronic pain is one of the leading causes of disability and disease burden worldwide, accounting for a prevalence between 6.9% and 10% in the general population. Pharmacotherapy alone results ineffective in about 70-60% of patients in terms of a satisfactory degree of pain relief. Focused ultrasound is a promising tool for chronic pain management, being approved for thalamotomy in chronic neuropathic pain and for bone metastases-related pain treatment. FUS is a noninvasive technique for neuromodulation and for tissue ablation that can be applied to several tissues. Transcranial FUS (tFUS) can lead to opposite biological effects, depending on stimulation parameters: from reversible neural activity facilitation or suppression (low-intensity, low-frequency ultrasound, LILFUS) to irreversible tissue ablation (high-intensity focused ultrasounds, HIFU). HIFU is approved for thalamotomy in neuropathic pain at the central nervous system level and for the treatment of facet joint osteoarthritis at the peripheral level. Potential applications include HIFU at the spinal cord level for selected cases of refractory chronic neuropathic pain, knee osteoarthritis, sacroiliac joint disease, intervertebral disc nucleolysis, phantom limb, and ablation of peripheral nerves. FUS at nonablative dosage, LILFUS, has potential reversible and tissue-selective effects. FUS applications at nonablative doses currently are at a research stage. The main potential applications include targeted drug and gene delivery through the Blood-Brain Barrier, assessment of pain thresholds and study of pain, and reversible peripheral nerve conduction block. The aim of the present review is to describe the approved and potential applications of the focused ultrasound technology in the field of chronic pain management.

Celiac Disease Diagnosed in an Older Adult Patient with a Complex Neuropsychiatric Involvement: A Case Report and Review of the Literature.

We present a case of celiac disease (CD) diagnosis in a 75-year-old woman with a long-term history of chronic delusional jealousy and a complex neurological involvement. The case describes a very unusual clinical picture, provides some clinical clues, and highlights the importance of being aware of CD extraintestinal manifestations in order to get a timely diagnosis.

The Potential Role of Neurophysiology in the Management of Multiple Sclerosis-Related Fatigue.

Fatigue is a very common symptom among people with multiple sclerosis (MS), but its management in clinical practice is limited by the lack of clear evidence about the pathogenic mechanisms, objective tools for diagnosis, and effective pharmacological treatments. In this scenario, neurophysiology could play a decisive role, thanks to its ability to provide objective measures and to explore the peripheral and the central structures of the nervous system. We hereby review and discuss current evidence about the potential role of neurophysiology in the management of MS-related fatigue. In the first part, we describe the use of neurophysiological techniques for exploring the pathogenic mechanisms of fatigue. In the second part, we review the potential application of neurophysiology for monitoring the response to pharmacological therapies. Finally, we show data about the therapeutic implications of neurophysiological techniques based on non-invasive brain stimulation.

Detecting cortical circuits resonant to high-frequency oscillations in the human primary motor cortex: a TMS-tACS study.

Corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) consist of high-frequency bursts (≈667 and ≈333 Hz). However, intracortical circuits producing such corticospinal high-frequency bursts are unknown. We here investigated whether neurons activated by single TMS pulses over M1 are resonant to high-frequency oscillations, using a combined transcranial alternating current stimulation (tACS)-TMS approach. We applied 667, 333 Hz or sham-tACS and, concurrently, we delivered six single-pulse TMS protocols using monophasic or biphasic pulses, different stimulation intensities, muscular states, types and orientations of coils. We recorded motor evoked potentials (MEPs) before, during and after tACS. 333 Hz tACS facilitated MEPs evoked by biphasic TMS through a figure-of-eight coil at active motor threshold (AMT), and by monophasic TMS with anterior-to-posterior-induced current in the brain. 333 Hz tACS also facilitated MEPs evoked by monophasic TMS through a circular coil at AMT, an effect that weakly persisted after the stimulation. 667 Hz tACS had no effects. 333 Hz, but not 667 Hz, tACS may have reinforced the synchronization of specific neurons to high-frequency oscillations enhancing this activity, and facilitating MEPs. Our findings suggest that different bursting modes of corticospinal neurons are produced by separate circuits with different oscillatory properties.

Motor Cortex Inputs at the Optimum Phase of Beta Cortical Oscillations Undergo More Rapid and Less Variable Corticospinal Propagation.

Brain oscillations involve rhythmic fluctuations of neuronal excitability and may play a crucial role in neural communication. The human corticomuscular system is characterized by beta activity and is readily probed by transcranial magnetic stimulation (TMS). TMS inputs arriving at the excitable phase of beta oscillations in the motor cortex are known to lead to muscle responses of greater amplitude. Here we explore two other possible manifestations of rhythmic excitability in the beta band; windows of reduced response variability and shortened latency. We delivered single-pulse TMS to the motor cortex of healthy human volunteers (10 females and 7 males) during electroencephalography recordings made at rest. TMS delivered at a particular phase of the beta oscillation benefited from not only stronger, but also less variable and more rapid transmission, as evidenced by the greater amplitude, lower coefficient of variation, and shorter latency of motor evoked potentials. Thus, inputs aligned to the optimal phase of the beta EEG in the motor cortex enjoy transmission amplitude gain, but may also benefit from less variability and shortened latencies at subsequent synapses. Neuronal phase may therefore impact corticospinal communication.SIGNIFICANCE STATEMENT Brain oscillations involve rhythmic fluctuations of neuronal excitability. Therefore, motor responses to transcranial magnetic stimulation are larger when a cortical input arrives at a particular phase of the beta activity in the motor cortex. Here, we demonstrate that inputs to corticospinal neurons which coincide with windows of higher excitability also benefit from more rapid and less variable corticospinal transmission. This shortening of latency and increased reproducibility may confer additional advantage to inputs at specific phases. Moreover, these benefits are conserved despite appreciable corticospinal conduction delays.

Transcranial Focused Ultrasound (tFUS) and Transcranial Unfocused Ultrasound (tUS) Neuromodulation: From Theoretical Principles to Stimulation Practices.

Transcranial focused ultrasound is an emerging technique for non-invasive neurostimulation. Compared to magnetic or electric non-invasive brain stimulation, this technique has a higher spatial resolution and can reach deep structures. In addition, both animal and human studies suggest that, potentially, different sites of the central and peripheral nervous system can be targeted by this technique. Depending on stimulation parameters, transcranial focused ultrasound is able to determine a wide spectrum of effects, ranging from suppression or facilitation of neural activity to tissue ablation. The aim is to review the state of the art of the human transcranial focused ultrasound neuromodulation literature, including the theoretical principles which underlie the explanation of the bioeffects on neural tissues, and showing the stimulation techniques and parameters used and their outcomes in terms of clinical, neurophysiological or neuroimaging results and safety.

Transcutaneous Vagus Nerve Stimulation Combined with Robotic Rehabilitation Improves Upper Limb Function after Stroke.

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.

Val66Met BDNF Polymorphism Implies a Different Way to Recover From Stroke Rather Than a Worse Overall Recoverability.

In search for individualized predictors of stroke recovery, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) is attracting great interest, because it has a negative impact on neurotrophin function. Since stroke recovery relies on brain plastic processes, on which BDNF is permissive, the dominant thought is in favor of a worse recovery in Met carriers. Conversely, we suggest that Met carriers do not differ in terms of absolute ability to recover from stroke, but they do differ on the way they recover. In particular, Met carriers rely more on subcortical plasticity, while ValVal patients more on intracortical plastic processes. Indeed, the direct evidence of impaired Met carrier recovery is inconsistent, as a high worldwide diffusion of the polymorphism suggests. The plasticity taking place in cortex, which is the one targeted by noninvasive brain stimulation strategies aimed at enhancing recovery, is less pronounced in Met carrier stroke patients, who have instead spared global recovery potential. Enhanced subcortical plasticity sustains better stroke recovery of Met carrier mice: this may also happen in humans, explaining the weaker interhemispheric cortical excitability imbalance recently described in Met carriers. Thus, BDNF haplotype determines mechanisms and structures involved in stroke recovery. The less pronounced cortical plasticity of Met carrier implies that plastic changes induced by interventional neurophysiological protocols would be better predictors of ValVal chronic outcome and those protocols would be more effective to boost their recovery. Other strategies, more focused on subcortical mechanisms, should be used in Met carriers.

Cortical ischemic lesion burden measured by DIR is related to carotid artery disease severity.

BACKGROUND: Over time, exposure to cerebrovascular risk factors and carotid artery disease may cause multiple asymptomatic brain cortical and subcortical microinfarcts, which are commonly found at brain autopsy. So far, lack of convenient neuroimaging tools limited the investigation of grey matter ischemic damage in vivo. We applied the Double Inversion Recovery (DIR) sequence to explore the impact of carotid artery disease on intracortical ischemic lesion load in vivo, taking into account the impact of demographic characteristics and vascular risk factors. METHODS: DIR was acquired in 62 patients with common cerebrovascular risk factors stratified in three groups according to carotid artery disease severity. Intracortical lesions scored on DIR (DIRlns) were classified by vascular territory, lobe and hemisphere. White matter hyperintensities (WMHs) volume was also quantified on Fluid Attenuated Inversion Recovery sequence (FLAIR). RESULTS: Among demographic characteristics and cerebrovascular risk variables explored, General Linear Model indicated that age and carotid artery disease were significantly associated to DIRlns. After correcting for age, DIRlns load was found to be significantly dependent on carotid artery stenosis severity (F(2, 58) = 5.56, p = 0.006). A linear positive correlation between DIRlns and WMHs was found after correcting for age (p = 0.003). CONCLUSIONS: Carotid disease severity is associated with DIRlns accrual. Microembolism and impaired cerebral hemodynamics may act as physiopathological mechanisms underlying cortical ischemic damage. The role of other factors, such as small vessel disease and the possible interaction with carotid disease, remains to be further explored.