High-frequency transcranial alternating current stimulation matching individual frequency of somatosensory evoked high-frequency oscillations can modulate the somatosensory system through thalamocortical pathway.

tACS (transcranial alternating current stimulation) is a technique for modulating brain activity through electrical current. Its effects depend on cortical entrainment, which is most effective when transcranial alternating current stimulation matches the brain's natural rhythm. High-frequency oscillations produced by external stimuli are useful for studying the somatosensory pathway. Our study aims to explore transcranial alternating current stimulation's impact on the somatosensory system when synchronized with individual high-frequency oscillation frequencies. We conducted a randomized, sham-controlled study with 14 healthy participants. The study had three phases: Individualized transcranial alternating current stimulation (matching the individual's high-frequency oscillation rhythm), Standard transcranial alternating current stimulation (600 Hz), and sham stimulation. We measured early and late HFO components after median nerve electrical stimulation at three time points: before (T0), immediately after (T1), and 10 min after transcranial alternating current stimulation (T2). Compared to Sham and Standard stimulation Individualized transcranial alternating current stimulation significantly enhanced high-frequency oscillations, especially the early component, immediately after stimulation and for at least 15 min. No other effects were observed for other high-frequency oscillation measures. In summary, our study provides initial evidence that transcranial alternating current stimulation synchronized with an individual's high-frequency oscillation frequency can precisely and time-specifically modulate thalamocortical activity. These insights may pave the way for innovative, personalized neuromodulation methods for the somatosensory system.

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.

Feasibility and efficacy of an at-home, smart-device aided mindfulness program in people with Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic disease with a high prevalence of neuropsychiatric symptoms. Mindfulness is a practice that encourages individuals to cultivate a present-focused, acceptance-based approach for managing psychological distress. Its positive effect on MS has been demonstrated, but learning such technique is expensive and time-consuming. In this study, we investigated the feasibility and efficacy of an 8-week, at-home, smart-device aided mindfulness program in a cohort of MS patients. Specifically, we explored the role of a brain-sensing headband providing real-time auditory feedback as supportive tool for meditation exercises. METHODS: The study included two visits, one at baseline and another after the mindfulness program. We measured adherence to the proposed mindfulness treatment and its effect on questionnaires investigating different psychological domains, cognition, fatigue, quality of life and quantitative EEG parameters. All participants received a smart biofeedback device to be used during the therapeutic program consisting of daily meditative exercises. RESULTS: Twenty-nine patients were recruited for the present study. Among them, 27 (93%) completed the entire program and 17 (63%) completed more than 80% of the scheduled sessions. We observed a statistically significant reduction of the Ruminative Response Scale score and a significant increase of the Digit Span Backward. Regarding neurophysiological data, we found a significant reduction of the whole-scalp beta and parieto-occipital theta power post intervention. CONCLUSION: Our results show that an at-home, smart-device aided mindfulness program is feasible for people with MS. The efficacy in terms of reappraisals of stress, cognitive and emotional coping responses is also supported by our neurophysiological data. Further studies are warranted to better explore the role of such approaches in managing the psychological impact of MS diagnosis.

May Dual Transcranial Direct Current Stimulation Enhance the Efficacy of Robot-Assisted Therapy for Promoting Upper Limb Recovery in Chronic Stroke?

OBJECTIVE: To assess whether dual transcranial direct current stimulation (tDCS) may enhance the efficacy of exoskeleton robotic training on upper limb motor functions in patients with chronic stroke. METHODS: A prospective, bi-center, double-blind, randomized clinical trial study was performed. Patients with moderate-to-severe stroke (according to The National Institute of Health Stroke Scale) were randomly assigned to receive dual or sham tDCS immediately before robotic therapy (10 sessions, 2 weeks). The primary outcome was the Fugl-Meyer for Upper Extremity, assessed before, after, and at the 12-week follow-up. Neurophysiological evaluation of corticospinal projections to upper limb muscles was performed by recording motor evoked potentials (MEPs). ClinicalTrials.gov-NCT03026712. RESULTS: Two hundred and sixty individuals were tested for eligibility, of which 80 were enrolled and agreed to participate. Excluding 14 dropouts, 66 patients were randomly assigned into the 2 groups. Results showed that chronic patients were stable before treatment and significantly improved after that. The records within subject improvements were not significantly different between the 2 groups. However, a post-hoc analysis subdividing patients in 2 subgroups based on the presence or absence of MEPs at the baseline showed a significantly higher effect of real tDCS in patients without MEPs when compared to patients with MEPs (F = 4.6, P = .007). CONCLUSION: The adjunction of dual tDCS to robotic arm training did not further enhance recovery in the treated sample of patients with chronic stroke. However, a significant improvement in the subgroup of patients with a severe corticospinal dysfunction (as suggested by the absence of MEPs) suggests that they could benefit from such a treatment combination.

Focal vibrations enhance somatosensory facilitation in healthy subjects: A pilot study on Equistasi® and high-frequency oscillations.

Background: Equistasi® is a vibrotactile device composed of nanotechnology fibers that converts temperature change into mechanical energy by self-producing a focal vibration. It is used in non-pharmacological rehabilitation in patients with movement disorders and multiple sclerosis sequelae. Nonetheless, the mechanism underlying such an improvement in motor functions is still poorly understood. Objectives: We designed a small uncontrolled pilot trial to explore the effect of Equistasi® on the somatosensory pathway through the analysis of high-frequency oscillations (HFOs). Methods: For all the included subjects, we recorded somatosensory-evoked potentials (SEPs) at the baseline (T0) and at 60 min after the application of Equistasi® (T1) on the seventh cervical vertebra level and at the forearm over each flexor carpi radialis, bilaterally. Then, we extracted the HFOs from the N20 signal and compared the HFO duration and area under the curve pre- and post-Equistasi® application. Results: In a head-to-head comparison of T0 to T1 data, there was a statistically significant reduction in the total HFO area (p < 0.01), which was prominent for the late component (p = 0.025). No statistical differences have been found between T0 and T1 HFO duration (p > 0.05). We further evaluated the N20 amplitude from the onset to the N20 peak to avoid possible interpretational bias. No statistical differences have been found between T0 and T1 (p = 0.437). Conclusion: Our clinical hypothesis, supported by preliminary data, is that vibrotactile afference delivered by the device could work by interfering with the somatosensory processing, rather than by peripheral effects.

High-frequency oscillations-based precise temporal resolution of short latency afferent inhibition in the human brain.

OBJECTIVE: Sensorimotor integration is a crucial process for adaptive behaviour and can be explored non-invasively with a conditioned transcranial magnetic stimulation (TMS) paradigm - i.e. short-latency afferent inhibition (SAI). To gain insight into the sensorimotor integration phenomenon, we used two different approaches to combine peripheral and cortical stimulation in the SAI paradigm, measuring not only the latency of low frequency somatosensory evoked potentials (SEPs) but also the peaks of high frequency oscillations (HFOs) underlying SEPs. METHODS: The interstimulus intervals (ISIs) between the electrical stimulation of the median nerve and the motor cortex magnetic stimulation were determined relative to the latency of the earliest SEPs cortical potential (N20) or the HFOs peaks. In particular, the first and last negative and positive peaks of HFOs were extracted through a custom-made MATLAB script. RESULTS: Thirty-three healthy subjects participated in this study. We found out that muscle responses after TMS were suppressed when ISIs were comprised between -1 to +3 ms relative to the N20 peak and at all ISIs relative to HFOs peaks, except for the first negative peak. CONCLUSIONS: Coupling peripheral and cortical stimulation at early interstimulus intervals - before the SEPs N20 peak - may modulate muscle response. SIGNIFICANCE: Our findings confirm that afferent inhibition is produced both through a direct (thalamus-motor cortex) and indirect (thalamus-somatosensory-motor cortex) pathway.

Sensorimotor integration within the primary motor cortex by selective nerve fascicle stimulation.

The integration of sensory inputs in the motor cortex is crucial for dexterous movement. We recently demonstrated that a closed-loop control based on the feedback provided through intraneural multichannel electrodes implanted in the median and ulnar nerves of a participant with upper limb amputation improved manipulation skills and increased prosthesis embodiment. Here we assessed, in the same participant, whether and how selective intraneural sensory stimulation also elicits a measurable cortical activation and affects sensorimotor cortical circuits. After estimating the activation of the primary somatosensory cortex evoked by intraneural stimulation, sensorimotor integration was investigated by testing the inhibition of primary motor cortex (M1) output to transcranial magnetic stimulation, after both intraneural and perineural stimulation. Selective sensory intraneural stimulation evoked a low-amplitude, 16 ms-latency, parietal response in the same area of the earliest component evoked by whole-nerve stimulation, compatible with fast-conducting afferent fibre activation. For the first time, we show that the same intraneural stimulation was also capable of decreasing M1 output, at the same time range of the short-latency afferent inhibition effect of whole-nerve superficial stimulation. The inhibition generated by the stimulation of channels activating only sensory fibres was stronger than that due to intraneural or perineural stimulation of channels activating mixed fibres. We demonstrate in a human subject that the cortical sensorimotor integration inhibiting M1 output previously described after the experimental whole-nerve stimulation is present also with a more ecological selective sensory fibre stimulation. KEY POINTS: Cortical integration of sensory inputs is crucial for dexterous movement. Short-latency somatosensory afferent inhibition of motor cortical output is typically produced by peripheral whole-nerve stimulation. We exploited intraneural multichannel electrodes used to provide sensory feedback for prosthesis control to assess whether and how selective intraneural sensory stimulation affects sensorimotor cortical circuits in humans. Activation of the primary somatosensory cortex (S1) was explored by recording scalp somatosensory evoked potentials. Sensorimotor integration was tested by measuring the inhibitory effect of the afferent stimulation on the output of the primary motor cortex (M1) generated by transcranial magnetic stimulation. We demonstrate in humans that selective intraneural sensory stimulation elicits a measurable activation of S1 and that it inhibits the output of M1 at the same time range of whole-nerve superficial stimulation.

The effects of transcutaneous auricular vagal nerve stimulation on pupil size.

OBJECTIVE: Mechanisms of action and optimal stimulation parameters of transcutaneous auricular vagus nerve stimulation (taVNS) are currently unknown. Pupil size has gained attention as a promising biomarker of vagal activation in different studies on animal models. The aim of this study is to investigate the effects of taVNS on pupil diameter in healthy subjects. METHODS: All subjects received taVNS at the left external acoustic meatus and control stimulation at the left earlobe during the same experimental session. Different intensities (0.5 mA; 1.0 mA; 2.0 mA; 3.0 mA) for both conditions were tested. Tonic pupil size was recorded in both eyes at baseline and during each stimulation using an infrared-automated pupillometer in three different illuminance conditions (scotopic, mesopic, photopic). RESULTS: In scotopic illuminance condition, a significant interaction between intensity and condition (real vs control) was found for the left eye. Post-Hoc analysis showed that during real taVNS at 2 mA, pupil size was significantly larger in comparison to baseline and 2 mA control stimulation. CONCLUSIONS: Our study demonstrates that taVNS induces pupil dilation under specific illuminance conditions and at specific stimulation intensity. SIGNIFICANCE: The effects of taVNS are strictly dependent on technical aspects, such as stimulation parameters and experimental set-up.

Classification accuracy of TMS for the diagnosis of mild cognitive impairment.

OBJECTIVE: To evaluate the performance of a Random Forest (RF) classifier on Transcranial Magnetic Stimulation (TMS) measures in patients with Mild Cognitive Impairment (MCI). METHODS: We applied a RF classifier on TMS measures obtained from a multicenter cohort of patients with MCI, including MCI-Alzheimer's Disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), and healthy controls (HC). All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The primary outcome measures were the classification accuracy, precision, recall and F1-score of TMS in differentiating each disorder. RESULTS: 160 participants were included, namely 64 patients diagnosed as MCI-AD, 28 as MCI-FTD, 14 as MCI-DLB, and 47 as healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.72 to 0.86), high precision (0.72-0.90), high recall (0.75-0.98), and high F1-scores (0.78-0.92), in differentiating each neurodegenerative disorder. By computing a new classifier, trained and validated on the current cohort of MCI patients, classification indices showed even higher accuracy (ranging from 0.83 to 0.93), precision (0.87-0.89), recall (0.83-1.00), and F1-scores (0.85-0.94). CONCLUSIONS: TMS may be considered a useful additional screening tool to be used in clinical practice in the prodromal stages of neurodegenerative dementias.

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.

Extremely Low Frequency Magnetic Fields Do Not Affect LTP-Like Plasticity in Healthy Humans.

INTRODUCTION: Several studies explored the biological effects of extremely low-frequency magnetic fields (ELF-MFs) in vitro, reporting the induction of functional changes in neuronal activity. In particular, ELF-MFs can influence synaptic plasticity both in vitro and in animal models but some studies reported an increase in long-term potentiation (LTP) whereas others suggested its reduction. However, no specific study has investigated such effect on humans. AIMS: To evaluate whether ELF-MFs affect the propensity of the human cortex to undergo LTP-like plasticity. METHODS: We designed a randomized, single-blind, sham-controlled, cross-over study on 10 healthy subjects. Cortical plasticity was induced by intermittent theta burst stimulation (iTBS) before and after 45-min ELF-MFs (75 Hz; 1.8 mT) or sham exposure and was estimated by measuring the changes of motor evoked potentials (MEP) amplitude before and after each iTBS. RESULTS: No adverse events were reported. No significant effects of ELF-MFs on cortical plasticity were found. CONCLUSION: Whole-brain exposure to ELF-MFs (75 Hz; 1.8 mT) is safe and does not seem to significantly affect LTP-like plasticity in human motor cortex.

Classification Accuracy of Transcranial Magnetic Stimulation for the Diagnosis of Neurodegenerative Dementias.

OBJECTIVE: Transcranial magnetic stimulation (TMS) has been suggested as a reliable, noninvasive, and inexpensive tool for the diagnosis of neurodegenerative dementias. In this study, we assessed the classification performance of TMS parameters in the differential diagnosis of common neurodegenerative disorders, including Alzheimer disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). METHODS: We performed a multicenter study enrolling patients referred to 4 dementia centers in Italy, in accordance with the Standards for Reporting of Diagnostic Accuracy. All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The investigators who performed the index test were masked to the results of the reference test and all other investigations. We trained and tested a random forest classifier using 5-fold cross-validation. The primary outcome measures were the classification accuracy, precision, recall, and F1 score of TMS in differentiating each neurodegenerative disorder. RESULTS: A total of 694 participants were included, namely 273 patients diagnosed as AD, 67 as DLB, and 207 as FTD, and 147 healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.89 to 0.92), high precision (0.86-0.92), high recall (0.93-0.98), and high F1 scores (0.89-0.95) in differentiating each neurodegenerative disorder. INTERPRETATION: TMS is a noninvasive procedure that reliably and selectively distinguishes AD, DLB, FTD, and HC, representing a useful additional screening tool to be used in clinical practice. Ann Neurol 2020;87:394-404.

Thalamo-cortical dysfunction contributes to fatigability in multiple sclerosis patients: A neurophysiological study.

BACKGROUND: Fatigue and fatigability are common symptoms reported by patients affected by Multiple Sclerosis (MS). The pathogenic mechanisms of such symptoms are currently unknown, but increasing evidence suggests that thalamus could play a key-role. High-frequency oscillations (HFOs) are a neurophysiological measure reflecting the activity of thalamo-cortical network. In particular, the early component is generated from thalamic axons while the late part results from neurons located in somatosensory cortex. OBJECTIVE: To investigate the effect of a fatigue-inducing exercise on HFOs and on strength performances in MS patients and healthy controls (HCs). METHODS: Fifteen patients and fifteen HCs participated in this study. We recorded HFOs from median nerve somatosensory evoked potentials and assessed strength performances, before and after a fatigue-inducing exercise of hand muscles. RESULTS: Compared to HCs, after repeated fatiguing tasks, patients showed a significant reduction of early component of HFOs area and a significant increase of late component of HFOs duration. Strength performance declined both in patients and in HCs but remained lower in patients at all time-points. CONCLUSIONS: HFOs, a neurophysiological marker of thalamo-cortical pathway, are significantly modified by fatiguing tasks in MS patients, in particular the early component that refers to the functionality of thalamic axons.

Spinal cord dysfunction contributes to balance impairment in multiple sclerosis patients.

OBJECTIVES: Balance impairment is very common in multiple sclerosis (MS) but its causes are still unclear. Some studies suggest that balance deficit originates mainly from damage in specific locations of the central nervous system such as cerebellum and spinal cord, that are involved in transmission and integration of sensory inputs and motor outputs. The aim of this study is to investigate the contribution of spinal cord to MS-related imbalance, by combining neurophysiologic and neuroimaging techniques. PATIENTS AND METHODS: Balance performance was correlated with clinical, neurophysiological and MRI findings. The functionality of spinal cord was tested by somatosensory (SEP) and motor (MEP) evoked potentials. MRI was used to identify spinal and cerebellar lesions. Balance performance was assessed by Tinetti Scale (TS). Clinical disability was measured by EDSS. RESULTS: 38 patients were included. Linear regression model revealed significant negative correlations between TS and EDSS scores, between TS and cervical lesions, and between TS and SEP findings. CONCLUSION: Our study, by combining neurophysiologic and neuroimaging techniques, confirms that spinal cord plays an important role for balance control and that its dysfunction, especially in lower limbs somatosensory ascending pathways conveying proprioceptive information, contributes to balance impairment in MS patients.

Evidence for associative plasticity in the human visual cortex.

BACKGROUND: Repetitive convergent inputs to a single post-synaptic neuron can induce long-term potentiation (LTP) or depression (LTD) of synaptic activity in a spike timing-dependent manner. OBJECTIVE: Here we set a protocol of visual paired associative stimulation (vPAS) of the primary visual cortex (V1) in humans to induce persistent changes in the excitatory properties of V1 with a spike timing rule. METHODS: We provided convergent inputs to V1 by coupling transcranial magnetic stimulation (TMS) pulses of the occipital cortex with peripheral visual inputs, at four interstimulus intervals of -50/-25/+25/+50 ms relative to the visual evoked potential (VEP) P1 latency. We analysed VEP amplitude and delayed habituation before and up to 10 min after each vPAS protocol. RESULTS: VEP amplitude was reduced after vPAS+25. Delayed VEP habituation was increased after vPAS-25 while it was reduced after vPAS+25. CONCLUSIONS: We provide evidence that associative bidirectional synaptic plasticity is a feature not only of the sensorimotor but also of the human visual system.

Safety and effects on motor cortex excitability of five anodal transcranial direct current stimulation sessions in 24hours.

BACKGROUND AND OBJECTIVE: Application parameters of transcranial direct current stimulation (tDCS) for therapeutic purposes are relatively restricted. The aim of this study was to assess safety and effects on motor cortex excitability of an intensive anodal-tDCS protocol. METHODS: In 26 healthy subjects, five 15-minute anodal-tDCS sessions were delivered, at increasing time intervals, over 24hours. Safety was defined as absence of serious adverse events including brain tissue alterations on magnetic resonance imaging. Effect on motor cortex excitability was evaluated by motor evoked potential (MEP) amplitude, measured eight times. RESULTS: No serious adverse events occurred. Mild adverse events, such as reversible scalp erythema or transient metallic taste, were observed in 27% of subjects. MEP amplitudes did not change in any of the recording periods. When inter-individual variability was taken into account and threshold values defined, 50% of subjects were classified as responders, 15% were inverse responders, and 35% non-responders. In the responders, normalized MEP was increased by 57% 1hour after the first anodal-tDCS and increased by 50% three hours after two stimulations delivered 1hour apart. Intra-individual, inter-sessional consistency of MEP response over four measurements was 61-77%. DISCUSSION: Five anodal-tDCS delivered in 24hours are safe and well tolerated, expanding the safety standard of tDCS. However, only half of subjects respond to anodal-tDCS with a robust and durable MEP augmentation. On the other hand, the response to a single anodal-tDCS predicts fairly well the response to other sessions in the same subject. CONCLUSIONS: These findings should be considered in clinical trials utilizing repeated anodal-tDCS.

Safety and effects on motor cortex excitability of five cathodal transcranial direct current stimulation sessions in 25hours.

OBJECTIVE: To assess the safety and effects on motor cortex excitability of five cathodal-tDCS sessions (charge density 342.9C/m2) delivered over the dominant motor cortex with a return electrode over the ipsilateral shoulder at increasing time intervals in 25hours. METHODS: Safety was operatively defined as absence of serious adverse events related to tDCS including brain tissue alterations documentable by magnetic resonance imaging and spectroscopy. Effects on motor cortex excitability were evaluated by motor evoked potential (MEP) amplitude. RESULTS: Thirty-two healthy subjects were enrolled. No serious adverse events occurred. Magnetic resonance imaging and spectroscopy did not show alterations. Inter-individual MEP variability was assessed by the standard error of mean at baseline and subjects were classified on the basis of the ratio between normalized MEPs after the first stimulation compared to baseline. Fifty-six percent of subjects responded with reduction of MEP amplitude, 25% were non-responders and 19% were inverse responders. In responders, MEP suppression was 32% one hour after the end of first cathodal-tDCS, 21% three hours after the second, no longer present with increasing stimulation intervals and 38% two and half hours after the fifth stimulation. Intra-individual inter-sessional reliability in response was high (88-92%). CONCLUSIONS: Five cathodal-tDCS sessions in 25hours are safe. Inter-individual variability in MEP suppression is considerable but response to one cathodal-tDCS highly predicts the response to other sessions. Duration of MEP suppression is limited to three hours. These findings should be considered in trials utilizing repeated cathodal-tDCS.