Paired associative stimulation to enhance motor outcome in spinal cord injury: a systematic review of first evidence.

INTRODUCTION: Spinal cord injuries (SCI) often result in motor impairment and lifelong disability. METHODS: This systematic review, conducted in agreement with PRISMA guidelines, aimed to evaluate the effects of cortico-spinal paired associative stimulation (PAS) on motor outcomes in individuals with SCI. PubMed, Scopus/EMBASE, Pedro, and Cochrane databases were consulted from inception to 2023/01/12. RESULTS: In 1021 articles, 10 studies involving 84 patients meet the inclusion criteria, 7 case series/study, and 3 clinical trials. Despite light differences, the included studies performed a cortico-peripheral PAS using a single transcranial magnetic stimulation and high frequency electrical peripheral nerve stimulation for a consistent number of sessions (>20). All included studies reported improvement in motor outcomes recorded via clinical and/or neurophysiological assessment. CONCLUSION: Available evidence showed an increase in motor outcomes after PAS stimulation. Indeed, both clinical and neurophysiological outcomes suggest the effectiveness of a high number of PAS sessions in chronic individuals with SCI. Due to a limited number of studies and an unsatisfactory study design, well-designed RCTs are needed to confirm the potentiality of these approaches and clarify the adequate dose-response of PAS in the SCI population. REGISTRATION ID: The protocol was registered on the PROSPERO database (CRD42023485703).

Transcranial direct current stimulation combined with speech therapy in Fragile X syndrome patients: a pilot study.

Background: Fragile X syndrome (FXS) is the leading cause of genetic intellectual disability. Among the neurobehavioral dysfunctions in FXS individuals, language development and literacy are compromised. Recent evidence hypothesized that the disruption of excitatory glutamatergic and GABAergic inhibitory neurotransmission balance might be responsible for impairment in cognitive function. In this study, we evaluated for the first time, the safety, tolerability, and efficacy of anodal prefrontal transcranial direct current stimulation (tDCS) combined with standard speech therapy to enhance language function in FXS patients. Methods: In total, 16 adult FXS patients were enrolled. Participants underwent 45 min of anodic tDCS combined with speech therapy for 5 weeks (3 times per week). Language function was evaluated using the Test for Reception of Grammar-Version 2 (TROG-2) and subtests of the Italian Language Examination (Esame del Linguaggio - II, EDL-II). Right and left dorsolateral prefrontal cortex transcranial magnetic stimulation and concurrent electroencephalography (TMS-EEG) recordings were collected at baseline and after the treatment to evaluate cortical reactivity and connectivity changes. Results: After 5 weeks of combined therapy, we observed a significant improvement in the writing (7.5%), reading (20.3%), repetition (13.3%), and TROG-2 (10.2%) tests. Parallelly with clinical change, TMS-EEG results showed a significant difference in TMS-evoked potential amplitude over the left frontal cortex after treatment (-0.73 ± 0.87 µV) compared to baseline (0.18 ± 0.84 µV). Conclusion: Our study provides novel evidence that left anodal prefrontal tDCS combined with standard speech therapy could be effective in enhancing language function in FXS patients, mainly by inducing a rebalance of the dysfunctional prefrontal cortical excitability.

Cortico-cortical stimulation and robot-assisted therapy (CCS and RAT) for upper limb recovery after stroke: study protocol for a randomised controlled trial.

BACKGROUND: Since birth, during the exploration of the environment to interact with objects, we exploit both the motor and sensory components of the upper limb (UL). This ability to integrate sensory and motor information is often compromised following a stroke. However, to date, rehabilitation protocols are focused primarily on recovery of motor function through physical therapies. Therefore, we have planned a clinical trial to investigate the effect on functionality of UL after a sensorimotor transcranial stimulation (real vs sham) in add-on to robot-assisted therapy in the stroke population. METHODS: A randomised double-blind controlled trial design involving 32 patients with a single chronic stroke (onset > 180 days) was planned. Each patient will undergo 15 consecutive sessions (5 days for 3 weeks) of paired associative stimulation (PAS) coupled with UL robot-assisted therapy. PAS stimulation will be administered using a bifocal transcranial magnetic stimulator (TMS) on the posterior-parietal cortex and the primary motor area (real or sham) of the lesioned hemisphere. Clinical, kinematics and neurophysiological changes will be evaluated at the end of protocol and at 1-month follow-up and compared with baseline. The Fugl-Meyer assessment scale will be the primary outcome. Secondly, kinematic variables will be recorded during the box-and-block test and reaching tasks using video analysis and inertial sensors. Single pulse TMS and electroencephalography will be used to investigate the changes in local cortical reactivity and in the interconnected areas. DISCUSSION: The presented trial shall evaluate with a multimodal approach the effects of sensorimotor network stimulation applied before a robot-assisted therapy training on functional recovery of the upper extremity after stroke. The combination of neuromodulation and robot-assisted therapy can promote an increase of cortical plasticity of sensorimotor areas followed by a clinical benefit in the motor function of the upper limb. TRIAL REGISTRATION: ClinicalTrials.gov NCT05478434. Registered on 28 Jul 2022.

Challenging inhibitory control with high- and low-calorie food: A behavioural and TMS study.

Most people are often tempted by their impulses to "indulge" in high-calorie food, even if this behaviour is not consistent with their goal to control weight in the long term and might not be healthy. The outcome of this conflict is strongly dependent on inhibitory control. It has already been reported that individuals with weaker inhibitory control consume more high-calorie food, are more often unsuccessful dieters, overweight or obese compared to people with more effective inhibitory control. In the present study, we aimed at investigating inhibitory control in the context of human eating behaviour. A sample of 20 healthy normal-weight adults performed a 50% probability visual affective Go/NoGo task involving food (high- and low-calorie) and non-food images as stimuli. Single-pulse transcranial magnetic stimulation (TMS) was administered over the right primary motor cortex (M1) either 300 ms after image presentation to measure corticospinal excitability during the different stimulus categories or 300 ms after the appearance of a fixation point, as a control stimulation condition. The experimental session consisted of a food target and a non-food target block. Behavioural outcomes showed a natural implicit inclination towards high-calorie food in that participants were faster and more accurate compared to the other categories. This advantage was selectively deleted by TMS, which slowed down reaction times. MEPs did not differ according to the stimulus category, but, as expected, were bigger for Go compared to NoGo trials. Participants judged high-calorie food also as more appetising than low-calorie food images. Overall, our results point to a differential modulation when targeting inhibitory control, in favour of the more palatable food category (high-calorie). Present data suggest that the activity of the motor system is modulated by food nutritional value, being more engaged by appetising food. Future work should explore to what extent these processes are affected in patients with eating disorders and should aim to better characterise the related dynamics of cortical connectivity within the motor network.

Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients.

OBJECTIVE: Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in Alzheimer's disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain areas known to be directly involved in AD pathology. METHODS: We performed TMS-EEG recordings targeting the left dorsolateral prefrontal cortex (l-DLPFC), the left posterior parietal cortex (l-PPC), and the precuneus (PC) in a large sample of patients with mild-to-moderate AD (n = 65) that were compared with a group of age-matched healthy controls (n = 21). RESULTS: We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to some extent, in the frontal lobe, as measured by TMS-evoked potentials. Notably, cortical excitability assessed over the l-PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability was associated with the level of cognitive impairment, as measured with Mini-Mental State Examination, and with corticospinal fluid levels of Aß42 . INTERPRETATION: Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel promising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to stage disease severity and evaluate response to novel therapies. ANN NEUROL 2023;93:371-383.

Simultaneous transcranial electrical and magnetic stimulation boost gamma oscillations in the dorsolateral prefrontal cortex.

Neural oscillations in the gamma frequency band have been identified as a fundament for synaptic plasticity dynamics and their alterations are central in various psychiatric and neurological conditions. Transcranial magnetic stimulation (TMS) and alternating electrical stimulation (tACS) may have a strong therapeutic potential by promoting gamma oscillations expression and plasticity. Here we applied intermittent theta-burst stimulation (iTBS), an established TMS protocol known to induce LTP-like cortical plasticity, simultaneously with transcranial alternating current stimulation (tACS) at either theta (θtACS) or gamma (γtACS) frequency on the dorsolateral prefrontal cortex (DLPFC). We used TMS in combination with electroencephalography (EEG) to evaluate changes in cortical activity on both left/right DLPFC and over the vertex. We found that simultaneous iTBS with γtACS but not with θtACS resulted in an enhancement of spectral gamma power, a trend in shift of individual peak frequency towards faster oscillations and an increase of local connectivity in the gamma band. Furthermore, the response to the neuromodulatory protocol, in terms of gamma oscillations and connectivity, were directly correlated with the initial level of cortical excitability. These results were specific to the DLPFC and confined locally to the site of stimulation, not being detectable in the contralateral DLPFC. We argue that the results described here could promote a new and effective method able to induce long-lasting changes in brain plasticity useful to be clinically applied to several psychiatric and neurological conditions.

Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a non-invasive therapeutic strategy in the battle against Alzheimer's disease. Alzheimer's disease patients primarily show alterations of the default mode network for which the precuneus is a key node. Here, we hypothesized that targeting the precuneus with TMS represents a promising strategy to slow down cognitive and functional decline in Alzheimer's disease patients. We performed a randomized, double-blind, sham-controlled, phase 2, 24-week trial to determine the safety and efficacy of precuneus stimulation in patients with mild-to-moderate Alzheimer's disease. Fifty Alzheimer's disease patients were randomly assigned in a 1:1 ratio to either receive precuneus or sham rTMS (mean age 73.7 years; 52% female). The trial included a 24-week treatment, with a 2-week intensive course in which rTMS (or sham) was applied daily five times per week, followed by a 22-week maintenance phase in which stimulation was applied once weekly. The Clinical Dementia Rating Scale-Sum of Boxes was selected as the primary outcome measure, in which post-treatment scores were compared to baseline. Secondary outcomes included score changes in the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Moreover, single-pulse TMS in combination with EEG was used to assess neurophysiological changes in precuneus cortical excitability and oscillatory activity. Our findings show that patients that received precuneus repetitive magnetic stimulation presented a stable performance of the Clinical Dementia Rating Scale-Sum of Boxes score, whereas patients treated with sham showed a worsening of their score. Compared with the sham stimulation, patients in the precuneus stimulation group also showed also significantly better performances for the secondary outcome measures, including the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental State Examination and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale. Neurophysiological results showed that precuneus cortical excitability remained unchanged after 24 weeks in the precuneus stimulation group, whereas it was significantly reduced in the sham group. Finally, we found an enhancement of local gamma oscillations in the group treated with precuneus stimulation but not in patients treated with sham. We conclude that 24 weeks of precuneus rTMS may slow down cognitive and functional decline in Alzheimer's disease. Repetitive TMS targeting the default mode network could represent a novel therapeutic approach in Alzheimer's disease patients.

Decreased Frontal Gamma Activity in Alzheimer Disease Patients.

OBJECTIVE: In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high-frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild-to-moderate AD patients. METHODS: Sixty mild-to-moderate AD patients and 21 age-matched healthy volunteers (HVs) underwent 3 TMS-EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS-based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution. RESULTS: AD patients showed a significant reduction of frontal gamma activity as compared to age-matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long-term potentiation-like plasticity and a more pronounced cognitive decline at subsequent follow-up evaluation at 24 weeks. INTERPRETATION: Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS-EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 2022;92:464-475.

Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19.

OBJECTIVE: A high proportion of patients experience fatigue and impairment of cognitive functions after coronavirus disease 2019 (COVID-19). Here we applied transcranial magnetic stimulation (TMS) to explore the activity of the main inhibitory intracortical circuits within the primary motor cortex (M1) in a sample of patients complaining of fatigue and presenting executive dysfunction after resolution of COVID-19 with neurological manifestations. METHODS: Twelve patients who recovered from typical COVID-19 pneumonia with neurological complications and complained of profound physical and mental fatigue underwent, 9 to 13 weeks from disease onset, a psychometric evaluation including a self-reported fatigue numeric-rating scale (FRS, Fatigue Rating Scale) and the Frontal Assessment Battery (FAB). Intracortical activity was evaluated by means of well-established TMS protocols including short-interval intracortical inhibition (SICI), reflecting GABAA-mediated inhibition, long-interval intracortical inhibition (LICI), a marker of GABAB receptor activity, and short-latency afferent inhibition (SAI) that indexes central cholinergic transmission. TMS data were compared to those obtained in a control group of ten healthy subjects (HS) matched by age, sex and education level. RESULTS: Post-COVID-19 patients reported marked fatigue according to FRS score (8.1 ± 1.7) and presented pathological scores at the FAB based on Italian normative data (12.2 ± 0.7). TMS revealed marked reduction of SICI, and disruption of LICI as compared to HS. SAI was also slightly diminished. CONCLUSIONS: The present study documents for the first time reduced GABAergic inhibition in the M1 in patients who recovered from COVID-19 with neurological complications and manifested fatigue and dysexecutive syndrome. SIGNIFICANCE: TMS may serve as diagnostic tool in cognitive disturbances and fatigue in post-COVID-19 patients.

Cerebellar Intermittent Theta-Burst Stimulation Combined with Vestibular Rehabilitation Improves Gait and Balance in Patients with Multiple Sclerosis: a Preliminary Double-Blind Randomized Controlled Trial.

Difficulties in gait and balance disorders are among the most common mobility limitations in multiple sclerosis (MS), mainly due to a damage of cerebellar circuits. Moreover, the cerebellum plays a critical role in promoting new motor tasks, which is an essential function for neurorehabilitation. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol able to increase cerebellar activity, on gait and balance in a sample of 20 hospitalized participants with MS, undergoing vestibular rehabilitation (VR), an exercise-based program primarily designed to reduce vertigo and dizziness, gaze instability, and/or imbalance and falls in MS. Patients were assigned to receive either c-iTBS or sham iTBS before being treated with VR during 2 weeks. VR consisted of two types of training: gaze stability and postural stability exercises. The primary outcome measure was the change from baseline in the Tinetti Balance and Gait scale (TBG). The secondary outcome measures were changes from baseline in Berg Balance Scale (BBS), Fatigue Severity Scale (FSS), Two Minute Walking Test (2MWT), and Timed 25-ft walk test (T25FW) scales. MS patients treated with c-iTBS-VR showed a significant improvement in the TBG as compared to patients treated with sham iTBS-VR. Moreover, MS patients in the c-iTBS groups showed better performances in the vestibular-ocular reflex exercises. Combined c-iTBS and VR improves gait and balance abilities more than standard VR treatment in MS patients with a high level of disability.

Effects of Palmitoylethanolamide Combined with Luteoline on Frontal Lobe Functions, High Frequency Oscillations, and GABAergic Transmission in Patients with Frontotemporal Dementia.

BACKGROUND: Frontotemporal dementia (FTD) is a presenile neurodegenerative disease for which there is no effective pharmacological treatment. Recently, a link has been proposed between neuroinflammation and FTD. OBJECTIVE: Here, we aim to investigate the effects of palmitoylethanolamide (PEA) combined with luteoline (PEA-LUT), an endocannabinoid with anti-inflammatory and neuroprotective effects, on behavior, cognition, and cortical activity in a sample of FTD patients. METHODS: Seventeen patients with a diagnosis of probable FTD were enrolled. Cognitive and neurophysiological evaluations were performed at baseline and after 4 weeks of PEA-LUT 700 mg×2/day. Cognitive effects were assessed by Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, Frontal Assessment Battery (FAB), Screening for Aphasia in Neurodegeneration, Activities of Daily Living-Instrumental Activities of Daily Living, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating scale. To investigate in vivo neurophysiological effects of PEA-LUT, we used repetitive and paired-pulse transcranial magnetic stimulation (TMS) protocols assessing LTP-like cortical plasticity, short-interval intracortical inhibition, long-interval intracortical inhibition (LICI), and short-latency afferent inhibition. Moreover, we used TMS combined with EEG to evaluate the effects on frontal lobe cortical oscillatory activity. RESULTS: Treatment with PEA-LUT was associated with an improvement in NPI and FAB scores. Neurophysiological evaluation showed a restoration of LICI, in particular at ISI 100 ms, suggesting a modulation of GABA(B) activity. TMS-EEG showed a remarkable increase of TMS-evoked frontal lobe activity and of high-frequency oscillations in the beta/gamma range. CONCLUSION: PEA-LUT could reduce behavioral disturbances and improve frontal lobe functions in FTD patients through the modulation of cortical oscillatory activity and GABA(B)ergic transmission.

Novel TMS-EEG indexes to investigate interhemispheric dynamics in humans.

OBJECTIVE: To validate two indexes of interhemispheric signal propagation (ISP) and balance (IHB) by combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG). METHODS: We used TMS-EEG to non-invasively stimulate the two hemispheres of 50 healthy volunteers and measured interhemispheric dynamics in terms of ISP and IHB. We repeated our evaluation after three weeks to assess the reliability of our indexes. We also tested whether our TMS-EEG measures were correlated with traditional interhemispheric inhibition (IHI), as measured with motor-evoked potentials (MEPs). RESULTS: Our main results showed that ISP and IHB (1) have a high reproducibility among all the participants tested; (2) have a high test-retest reliability (3) are linearly correlated with IHI, as measured with MEPs. CONCLUSIONS: The main contribution of this study lies in the proposal of new TMS-EEG cortical measures of interhemispheric dynamics and in their validation in terms of intra- and inter-subject reliability. We also provide the first demonstration of the correlation between ISP and IHI. SIGNIFICANCE: Our results are relevant for the investigation of interhemispheric dynamics in clinical populations where MEPs are not reliable.