Non-invasive Brain Stimulation Protocols Research Articles

Efficacy and acceptability of noninvasive brain stimulation for treating posttraumatic stress disorder symptoms: A network meta-analysis of randomized controlled trials.

Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management. We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason). We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity. This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms. PROSPERO CRD42023391562.

Information-based rhythmic transcranial magnetic stimulation to accelerate learning during auditory working memory training: a proof-of-concept study.

Rhythmic transcranial magnetic stimulation (rhTMS) has been shown to enhance auditory working memory manipulation, specifically by boosting theta oscillatory power in the dorsal auditory pathway during task performance. It remains unclear whether these enhancements (i) persist beyond the period of stimulation, (ii) if they can accelerate learning and (iii) if they would accumulate over several days of stimulation. In the present study, we investigated the lasting behavioral and electrophysiological effects of applying rhTMS over the left intraparietal sulcus (IPS) throughout the course of seven sessions of cognitive training on an auditory working memory task. A limited sample of 14 neurologically healthy participants took part in the training protocol with an auditory working memory task while being stimulated with either theta (5 Hz) rhTMS or sham TMS. Electroencephalography (EEG) was recorded before, throughout five training sessions and after the end of training to assess to effects of rhTMS on behavioral performance and on oscillatory entrainment of the dorsal auditory network. We show that this combined approach enhances theta oscillatory activity within the fronto-parietal network and causes improvements in auditoryworking memory performance. We show that compared to individuals who received sham stimulation, cognitive training can be accelerated when combined with optimized rhTMS, and that task performance benefits can outlast the training period by ∼ 3 days. Furthermore, we show that there is increased theta oscillatory power within the recruited dorsal auditory network during training, and that sustained EEG changes can be observed ∼ 3 days following stimulation. The present study, while underpowered for definitive statistical analyses, serves to improve our understanding of the causal dynamic interactions supporting auditory working memory. Our results constitute an important proof of concept for the potential translational impact of non-invasive brain stimulation protocols and provide preliminary data for developing optimized rhTMS and training protocols that could be implemented in clinical populations.

Comparative efficacy of different noninvasive brain stimulation protocols on upper-extremity motor function and activities of daily living after stroke: a systematic review and network meta-analysis.

The objectives of the study were to systematically evaluate the rehabilitation effect of noninvasive brain stimulation (NIBS) on upper extremity motor function and activities of daily living in stroke patients and to prioritize various stimulation protocols for reliable evidence-based medical recommendations in patients with upper extremity motor dysfunction after stroke. Web of Science, PubMed, Embase, Cochrane Library, CNKI, Wanfang, VIP, and CBM were searched to collect all randomized controlled trials (RCTs) of NIBS to improve upper extremity motor function in stroke patients. The retrieval time was from the establishment of all databases to May 2023. According to the Cochrane system evaluation manual, the quality of the included studies was evaluated, and the data were extracted. Statistical analysis was carried out by using RevMan 5.3, R 4.3.0, and Stata 17.0 software. Finally, 94 RCTs were included, with a total of 5546 patients. Meta-analysis showed that NIBS improved the Fugl-Meyer assessment (FMA) score (mean difference (MD) = 6.51, 95% CI 6.20 ~ 6.82, P < 0.05), MBI score (MD = 7.69, 95% CI 6.57 ~ 8.81, P < 0.05), ARAT score (MD = 5.06, 95% CI 3.85 ~ 6.27, P < 0.05), and motor evoked potential (MEP) amplitude. The modified Ashworth scale score (MD = - 0.37, 95% CI - 0.60 to - 0.14, P < 0.05), National Institutes of Health Stroke Scale score (MD = - 2.17, 95% CI - 3.32 to - 1.11, P < 0.05), incubation period of MEP (MD = - 0.72, 95% CI - 1.06 to - 0.38, P < 0.05), and central motor conduction time (MD = - 0.90, 95% CI - 1.29 to - 0.50, P < 0.05) were decreased in stroke patients. Network meta-analysis showed that the order of interventions in improving FMA scores from high to low was anodal-transcranial direct current stimulation (tDCS) (surface under the cumulative ranking curve (SUCRA) = 83.7%) > cathodal-tDCS (SUCRA = 80.2%) > high-frequency (HF)-repetitive transcranial magnetic stimulation (rTMS) (SUCRA = 68.5%) > low-frequency (LF)-rTMS (SUCRA = 66.5%) > continuous theta burst stimulation (cTBS) (SUCRA = 54.2%) > bilateral-tDCS (SUCRA = 45.2%) > intermittent theta burst stimulation (iTBS) (SUCRA = 34.1%) > sham-NIBS (SUCRA = 16.0%) > CR (SUCRA = 1.6%). In terms of improving MBI scores, the order from high to low was anodal-tDCS (SUCRA = 88.7%) > cathodal-tDCS (SUCRA = 85.4%) > HF-rTMS (SUCRA = 63.4%) > bilateral-tDCS (SUCRA = 56.0%) > LF-rTMS (SUCRA = 54.2%) > iTBS (SUCRA = 32.4%) > sham-NIBS (SUCRA = 13.8%) > CR (SUCRA = 6.1%). NIBS can effectively improve upper extremity motor function and activities of daily living after stroke. Among the various NIBS protocols, anodal-tDCS demonstrated the most significant intervention effect, followed by cathodal-tDCS and HF-rTMS.

Electric-field-based dosing for TMS

Abstract Transcranial magnetic stimulation (TMS) is an invaluable non-invasive brain stimulation (NIBS) technique to modulate cortical activity and behavior, but high within- and between-participant variability limits its efficacy and reliability. Here, we explore the potential of electric field (e-field) based TMS dosing to reduce its variability and discuss current challenges as well as future pathways. In contrast to previous dosing approaches, e-field dosing better matches the stimulation strength across cortical areas, both within and across individuals. Challenges include methodological uncertainties of the e-field simulation, target definitions, and comparability of different stimulation thresholds across cortical areas and NIBS protocols. Despite these challenges, e-field dosing promises to substantially improve NIBS applications in neuroscientific research and personalized medicine.

Assessing the synergistic effectiveness of intermittent theta burst stimulation and the vestibular ocular reflex rehabilitation protocol in the treatment of Mal de Debarquement Syndrome: a randomised controlled trial

IntroductionMal de Debarquement Syndrome (MdDS) is a rare central vestibular disorder characterised by a constant sensation of motion (rocking, swaying, bobbing), which typically arises after motion experiences (e.g. sea, air, and road travel), though can be triggered by non-motion events. The current standard of care is non-specific medications and interventions that only result in mild-to-moderate improvements. The vestibular ocular reflex (VOR) rehabilitation protocol, a specialised form of rehabilitation, has shown promising results in reducing symptoms amongst people with MdDS. Accumulating evidence suggests that it may be possible to augment the effects of VOR rehabilitation via non-invasive brain stimulation protocols, such as theta burst stimulation (TBS).MethodsThe aim of this randomised controlled trial was to evaluate the effectiveness of intermittent TBS (iTBS) over the dorsolateral prefrontal cortex in enhancing the effectiveness of a subsequently delivered VOR rehabilitation protocol in people with MdDS. Participants were allocated randomly to receive either Sham (n = 10) or Active (n = 10) iTBS, followed by the VOR rehabilitation protocol. Subjective outcome measures (symptom ratings and mental health scores) were collected 1 week pre-treatment and for 16 weeks post-treatment. Posturography (objective outcome) was recorded each day of the treatment week.ResultsSignificant improvements in subjective and objective outcomes were reported across both treatment groups over time, but no between-group differences were observed.DiscussionThese findings support the effectiveness of the VOR rehabilitation protocol in reducing MdDS symptoms. Further research into iTBS is required to elucidate whether the treatment has a role in the management of MdDS. TRN: ACTRN12619001519145 (Date registered: 04 November 2019).

Somatosensory evoked potentials amplitude is enhanced after non-invasive brain stimulation in chronic ischemic stroke: Preliminary results from a randomised control trial

ObjectiveTo investigate the effects of transcranial electrical and magnetic non-invasive brain stimulation (NIBS) protocols on somatosensory evoked potential (SEP) in chronic ischemic stroke. Methods33 patients were randomly assigned to one of the four treatment groups of the transcranial direct current stimulation (tDCS) and/or repetitive transcranial magnetic stimulation (rTMS) protocol. SEP parameters were recorded before and after ten days of the treatment session. All the statistical analyses were carried out using SPSS version 19. ResultsIt was found that there is a statistically significant improvement in the N20-P22 mean amplitude after treatment sessions in all groups except the group where tDCS and rTMS groups were sham. On paired t-tests, the difference betweeen post and pre-stimulation SEP amplitudes for the real tDCS and real rTMS coupled group was 1.045 ± 0.732 (p value = 0.005). For sham tDCS+real rTMS group, 1.05 ± 0.96 (P = 0.04); for real tDCS+sham rTMS 0.543 ± 0.332 (P = 0.01) and for double sham stimulation, 0.204 ± 0.648 (P = 0.4) respectively ConclusionIn ischemic stroke patients, either or coupled true transcranial tDCS and rTMS was found to be safe and significantly enhanced the amplitude of cortical somatosensory potentials when combined with standard physiotherapy, in the interim analysis of an ongoing randomised controlled trial. Clinical Trial Registry of IndiaCTRI/2019/11/022009 SignificanceThe results of this research indicates the importance of RCTs in developing robust improved NIBS protocols coupled to physiotherapy to enhance the sensory-motor functional recovery following ischemic stroke.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable

Background and Aims: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. Methods: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. Results and Conclusions: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

High-definition transcranial direct current stimulation for upper extremity rehabilitation in moderate-to-severe ischemic stroke: a pilot study.

Previous studies found that post-stroke motor impairments are associated with damage to the lesioned corticospinal tract (CST) and hyperexcitability of the contralesional cortico-reticulospinal tract (CRST). This proof-of-concept study aims to develop a non-invasive brain stimulation protocol that facilitates the lesioned CST and inhibits the contralesional CRST to improve upper extremity rehabilitation in individuals with moderate-to-severe motor impairments post-stroke. Fourteen individuals (minimum 3 months post ischemic stroke) consented. Physician decision of the participants baseline assessment qualified eight to continue in a randomized, double-blind cross-over pilot trial (ClinicalTrials.gov Identifier: NCT05174949) with: (1) anodal high-definition transcranial direct stimulation (HD-tDCS) over the ipsilesional primary motor cortex (M1), (2) cathodal HD-tDCS over contralesional dorsal premotor cortex (PMd), (3) sham stimulation, with a two-week washout period in-between. Subject-specific MR images and computer simulation were used to guide HD-tDCS and verified by Transcranial Magnetic Stimulation (TMS) induced Motor Evoked Potential (MEP). The motor behavior outcome was evaluated by an Fugl-Meyer Upper Extremity score (primary outcome measure) and the excitability of the ipslesoinal CST and contralesional CRST was determined by the change of MEP latencies and amplitude (secondary outcome measures). The baseline ipsilesional M1 MEP latency and amplitude were correlated with FM-UE. FM-UE scores were improved post HD-tDCS, in comparison to sham stimulation. Both anodal and cathodal HD-tDCS reduced the latency of the ipsilesional M1 MEP. The contralesional PMd MEP disappeared/delayed after HD-tDCS. These results suggest that HD-tDCS could improve the function of the lesioned corticospinal tract and reduce the excitability of the contralesional cortico-reticulospinal tract, thus, improving motor function of the upper extremity in more severely impaired individuals.

Influence of frontal-to-parietal connectivity in pseudoneglect: A cortico-cortical paired associative stimulation study

Pseudoneglect is a set of visuospatial biases that entails a behavioral advantage for stimuli appearing in the left hemifield compared to the right one. Although right hemisphere dominance for visuospatial processing has been invoked to explain this phenomenon, its neurophysiological mechanisms are still debated, and the role of intra- and inter-hemispheric connectivity is yet to be defined. The present study explored the possibility of modulating pseudoneglect in healthy participants through a cortico-cortical paired associative stimulation protocol (ccPAS): a non-invasive brain stimulation protocol that manipulates the interplay between brain regions through the repeated, time-locked coupling of two transcranial magnetic stimulation (TMS) pulses. In the first experiment, healthy participants underwent a frontal-to-parietal (FP) and a parietal-to-frontal (PF) ccPAS. In the FP protocol, the first TMS pulse targeted the right frontal eye field (FEF), and the second pulse the right inferior parietal lobule (IPL), two critical areas for visuospatial and attentional processing. In the PF condition, the order of the pulses was reversed. In both protocols, the inter-stimulus interval (ISI) was 10 ms. Before and after stimulation, pseudoneglect was assessed with a landmark task and a manual line bisection task. A second experiment controlled for ccPAS timing dependency by testing FP-ccPAS with a longer ISI of 100 ms. Results showed that after administering the FP-ccPAS with the ISI of 10 ms, participants’ leftward bias in the landmark task increased significantly, with no effects in the manual line bisection task. The other two protocols tested were ineffective. Our findings showed that ccPAS could be used to modulate pseudoneglect by exploiting frontal-to-parietal connectivity, possibly through increased top-down attentional control. FP-ccPAS could represent a promising tool to investigate connectivity properties within visuospatial and attentional networks in the healthy and as a potential rehabilitation protocol in patients suffering from severe visuospatial pathologies.

Clinical and Physiological Effects of Single Day Accelerated Theta Burst Transcranial Focused Ultrasound in Parkinson’s Disease (P4-11.008)

<h3>Objective:</h3> To evaluate the tolerability and efficacy of an accelerated schedule of theta burst focused ultrasound stimulation (tbTUS) delivered to the primary motor cortex in Parkinson’s disease (PD) patients assessed by transcranial magnetic stimulation (TMS) and United Parkinson’s Disease Rating Scale (UPDRS)-Part III. <h3>Background:</h3> Low intensity transcranial focused ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation (NIBS) that can penetrate deeper in the brain with more focal stimulation compared to currently used forms of NIBS. TUS delivered in a theta burst pattern (tbTUS) for 80s induces sustained increases in motor cortex excitability lasting at least 30 minutes and is a promising NIBS protocol for treatment of neurological disorders. Accelerated stimulation schedules with several treatments per day can shorten treatment duration and improve accessibility. <h3>Design/Methods:</h3> Three sets of tbTUS were delivered in consecutive order to the right and left primary motor cortices at 30-minute intervals. 10 PD patients attended one visit each for real and sham treatments in random order. Before and after interventions, TMS measures of motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), short-interval intracortical excitation (SICF), and UPDRS-Part III scores were collected. Patients and UPDRS raters were blinded to the stimulation condition. <h3>Results:</h3> Real but not sham tbTUS treatment led to increased MEP amplitude and SICF. While both conditions led to similar changes in UPDRS-III scores, rigidity subscores were reduced only with real treatment. There were no adverse effects. <h3>Conclusions:</h3> The study is ongoing, and more patients are being recruited. Preliminary findings show that accelerated tbTUS is a safe and tolerable treatment schedule for PD patients. Improvements in rigidity suggests that tbTUS could be further studied as a non-invasive treatment for PD. Future research may investigate the optimal time between sonications with a longer treatment duration and a larger number of patients. <b>Disclosure:</b> Yi Rong Ding has nothing to disclose. Dr. Samuel has nothing to disclose. Dr. Grippe has nothing to disclose. Dr. SARICA has nothing to disclose. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Insightec. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Scientific. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Functional Neuromodulation. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merz. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Paladin Labs. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Chen has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Canadian Journal of Neurological Sciences. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Movement Disorders. The institution of Dr. Chen has received research support from Canadian Institutes of Health Research. The institution of Dr. Chen has received research support from NIH. The institution of Dr. Chen has received research support from Natural Science and Engineering Research Council of Canada. Dr. Chen has received research support from Parkinson Foundation. The institution of Dr. Chen has received research support from National Organization for Rare Disease. The institution of Dr. Chen has received research support from Merz.

Noninvasive modulation of human corticostriatal activity

Corticostriatal activity is an appealing target for nonpharmacological treatments of brain disorders. In humans, corticostriatal activity may be modulated with noninvasive brain stimulation (NIBS). However, a NIBS protocol with a sound neuroimaging measure demonstrating a change in corticostriatal activity is currently lacking. Here, we combine transcranial static magnetic field stimulation (tSMS) with resting-state functional MRI (fMRI). We first present and validate the ISAAC analysis, a well-principled framework that disambiguates functional connectivity between regions from local activity within regions. All measures of the framework suggested that the region along the medial cortex displaying greater functional connectivity with the striatum is the supplementary motor area (SMA), where we applied tSMS. We then use a data-driven version of the framework to show that tSMS of the SMA modulates the local activity in the SMA proper, in the adjacent sensorimotor cortex, and in the motor striatum. We finally use a model-driven version of the framework to clarify that the tSMS-induced modulation of striatal activity can be primarily explained by a change in the shared activity between the modulated motor cortical areas and the motor striatum. These results suggest that corticostriatal activity can be targeted, monitored, and modulated noninvasively in humans.

Mapping a network for tics in Tourette syndrome using causal lesions and structural alterations.

Tics are sudden stereotyped movements or vocalizations. Cases of lesion-induced tics are invaluable, allowing for causal links between symptoms and brain structures. While a lesion network for tics has recently been identified, the degree to which this network translates to Tourette syndrome has not been fully elucidated. This is important given that patients with Tourette syndrome make up a large portion of tic cases; therefore, existing and future treatments should apply to these patients. The aim of this study was to first localize a causal network for tics from lesion-induced cases and then refine and validate this network in patients with Tourette syndrome. We independently performed 'lesion network mapping' using a large normative functional connectome (n = 1000) to isolate a brain network commonly connected to lesions causing tics (n = 19) identified through a systematic search. The specificity of this network to tics was assessed through comparison to lesions causing other movement disorders. Using structural brain coordinates from prior neuroimaging studies (n = 7), we then derived a neural network for Tourette syndrome. This was done using standard anatomical likelihood estimation meta-analysis and a novel method termed 'coordinate network mapping', which uses the same coordinates, yet maps their connectivity using the aforementioned functional connectome. Conjunction analysis was used to refine the network for lesion-induced tics to Tourette syndrome by identifying regions common to both lesion and structural networks. We then tested whether connectivity from this common network is abnormal in a separate resting-state functional connectivity MRI data set from idiopathic Tourette syndrome patients (n = 21) and healthy controls (n = 25). Results showed that lesions causing tics were distributed throughout the brain; however, consistent with a recent study, these were part of a common network with predominant basal ganglia connectivity. Using conjunction analysis, coordinate network mapping findings refined the lesion network to the posterior putamen, caudate nucleus, globus pallidus externus (positive connectivity) and precuneus (negative connectivity). Functional connectivity from this positive network to frontal and cingulate regions was abnormal in patients with idiopathic Tourette syndrome. These findings identify a network derived from lesion-induced and idiopathic data, providing insight into the pathophysiology of tics in Tourette syndrome. Connectivity to our cortical cluster in the precuneus offers an exciting opportunity for non-invasive brain stimulation protocols.

Brain perfusion alterations induced by standalone and combined non-invasive brain stimulation over the dorsolateral prefrontal cortex

Abstract Non-invasive brain stimulation (NIBS) interventions are promising for the treatment of psychiatry disorders. Notwithstanding, the mechanisms of action of NIBS over the dorsolateral prefrontal cortex (DLPFC), a hub that modulates affective and cognitive processes, have not been completely mapped. We aimed to investigate regional cerebral blood flow (rCBF) changes over the DLPFC and the interconnected subgenual anterior cingulate cortex (sgACC) of different NIBS protocols using a Single Photon Emission Computed Tomography (SPECT). Twenty-three healthy subjects were allocated to randomly undergo four sessions of NIBS applied once a week: transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), combined tDCS+iTBS and placebo. The radiotracer 99m-Technetium-ethylene-cysteine-dimer (99m-ECD) was injected intravenously during the NIBS session, and SPECT images were acquired after the session. Results revealed none of the active interventions changing rCBF on the targeted DLPFC, but the combination tDCS+iTBS increased rCBF on the right sgACC. TDCS respectively increased and decreased rCBF on DLPFC sub-regions under the cathode and anode, while iTBS did not show any significant changes compared to placebo. Our findings encourage future clinical trials combining tDCS+iTBS for psychiatric population and mechanistic studies to investigate the effects of tDCS and iTBS over the DLPFC. Research Category and Technology and Methods Basic Research: 9. Transcranial Direct Current Stimulation (tDCS)

Non-invasive brain stimulation and cognitive function in patients with major depressive disorder or bipolar depression: systematic review and meta-analysis

IntroductionNon-invasive brain stimulation protocols are effective treatments for depressive episodes. Although the cognitive adverse effects of electroconvulsive therapy (ECT) are well documented, evidence regarding the cognitive effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) is mixed.ObjectivesThe aim of this study was to synthesize research on the cognitive effects of non-invasive brain stimulation protocols and to differentiate between studies of major depressive disorder (MDD), bipolar depression and mixed populations.MethodsFollowing a systematic literature search of multiple electronic databases, a series of meta-analyses were conducted to estimate standardized mean differences (SMD) between pre- and post-treatment cognitive functioning across nine cognitive domains. Where possible, SMDs were estimated separately for MDD, bipolar depression and mixed populations. In studies that included both patients with MDD and bipolar depression, the percentage of patients with a diagnosis of bipolar depression was tested as a potential moderator.ResultsMore than 150 treatment arms were included in the analyses. For ECT, we observed a small decline in language functioning and a decrease in autobiographical memory scores. There was no evidence of pre-post differences across other cognitive domains. For rTMS and tDCS, small to moderate cognitive improvements were observed for several cognitive domains, for example for executive functioning. Across most analyses, between-study heterogeneity was high and could not be accounted for by differences between MDD, bipolar depression or mixed populations.ConclusionsThere was limited evidence that differentiation between studies of MDD, bipolar depression and mixed populations accounted for between-study heterogeneity in analyses of pre-post differences in cognitive functioning. Given that most studies included both patients with MDD and bipolar depression, this finding should be treated as preliminary. Across all the treatment protocols examined, more data are needed to investigate the cognitive effects of non-invasive brain stimulation in patients with bipolar depression.Disclosure of InterestNone Declared

Noise-modulated multistable synapses in a Wilson-Cowan-based model of plasticity.

Frequency-dependent plasticity refers to changes in synaptic strength in response to different stimulation frequencies. Resonance is a factor known to be of importance in such frequency dependence, however, the role of neural noise in the process remains elusive. Considering the brain is an inherently noisy system, understanding its effects may prove beneficial in shaping therapeutic interventions based on non-invasive brain stimulation protocols. The Wilson-Cowan (WC) model is a well-established model to describe the average dynamics of neural populations and has been shown to exhibit bistability in the presence of noise. However, the important question of how the different stable regimes in the WC model can affect synaptic plasticity when cortical populations interact has not yet been addressed. Therefore, we investigated plasticity dynamics in a WC-based model of interacting neural populations coupled with activity-dependent synapses in which a periodic stimulation was applied in the presence of noise of controlled intensity. The results indicate that for a narrow range of the noise variance, synaptic strength can be optimized. In particular, there is a regime of noise intensity for which synaptic strength presents a triple-stable state. Regulating noise intensity affects the probability that the system chooses one of the stable states, thereby controlling plasticity. These results suggest that noise is a highly influential factor in determining the outcome of plasticity induced by stimulation.

Comparative efficacy of different noninvasive brain stimulation therapies for recovery of global cognitive function, attention, memory, and executive function after stroke: a network meta-analysis of randomized controlled trials.

Which noninvasive brain stimulation (NIBS) treatment - transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) - is more beneficial for stroke patients' cognitive rehabilitation is still up for debate. Our goal is to provide an overview of the research on the effectiveness and safety of various NIBS protocols. Systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs). This NMA compared any active NIBS versus sham stimulation in adult stroke survivors to enhance cognitive function, with a focus on global cognitive function (GCF), attention, memory, and executive function (EF) using the databases MEDLINE, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov. The NMA statistical approach was built on a frequency framework. The effect size was estimated by the standardized mean difference (SMD) and a 95% confidence interval (CI). We compiled a relative ranking of the competing interventions based on their surface under the cumulative ranking curve (SUCRA). NMA showed that high-frequency repeated TMS (HF-rTMS) improved GCF compared with sham stimulation (SMD = 1.95; 95% CI: 0.47-3.43), while dual-tDCS improved memory performance versus sham stimulation significantly (SMD = 6.38; 95% CI: 3.51-9.25). However, various NIBS stimulation protocols revealed no significant impact on enhancing attention, executive function, or activities of daily living. There was no significant difference between the active stimulation protocols for TMS and tDCS and sham stimulation in terms of safety. Subgroup analysis demonstrated an effect favoring activation site of the left dorsolateral prefrontal cortex (DLPFC) (SUCRA = 89.1) for enhancing GCF and bilateral DLPFC (SUCRA = 99.9) stimulation for enhancing memory performance. The HF-rTMS over the left DLPFC appears to be the most promising NIBS therapeutic option for improving global cognitive performance after stroke, according to a comparison of numerous NIBS protocols. Furthermore, for patients with post-stroke memory impairment, dual-tDCS over bilateral DLPFC may be more advantageous than other NIBS protocols. Both tDCS and TMS are reasonably safe. PROSPERO ID: CRD42022304865.

Non-invasive brain stimulation therapy on neurological symptoms in patients with multiple sclerosis: A network meta analysis

The aim of the study was to evaluate non-invasive brain stimulation (NIBS) [including transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES)] on neurological symptoms in patients with multiple sclerosis (PwMS). We searched PubMed, Embase, Cochrane Library, Web of Science and Ovid MEDLINE until February 2022. And we evaluated the included studies for methodological quality by the Cochrane bias risk assessment tool and assessed the studies' certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. We performed network meta analysis (NMA) by using Stata 15 and ranked the results of the NMA by using the surface under the cumulative ranking curve (SUCRA) ranking chart. Twenty seven clinical trials were finally included (N = 596, 66.4% women). For the immediate effects, rTMS over M1 yielded the most optimal scheme for fatigue reduction among all the interventions compared to the sham stimulation groups [MD = -0.85, 95% CI (-1.57, -0.14)] (SUCRA = 82.6%). iTBS over M1 yielded the most signifcant reduced pain level than the sham groups did [MD = -1.26, 95% CI (-2.40, -0.11)] (SUCRA = 98.4%). tDCS over F3 was the best protocol of NIBS to improve quality of life (QOL) [MD = 1.41, 95% CI = (0.45,2.36)] (SUCRA = 76.7%), and iTBS over M1 may significantly reduce spasticity compared to sham stimulation [MD = -1.20, 95% CI = (-1.99, -0.41)] (SUCRA = 90.3%). Furthermore, rTMS, tRNS, and tDCS on certain areas may improve PwMS accuracy, response time, manual dexterity, pain relief and QOL, but does not show statistically significant differences. The evidence assessed using GRADE is very low. Based on the NMA and SUCRA ranking, we can conclude that symptoms including fatigue, pain, spasticity, and QOL can be improved by following NIBS protocol after treatment. Nonetheless, most of the included studies lack a good methodology, and more high-quality randomized clinical trials are needed.

Improving Upper Limb and Gait Rehabilitation Outcomes in Post-Stroke Patients: A Scoping Review on the Additional Effects of Non-Invasive Brain Stimulation When Combined with Robot-Aided Rehabilitation.

Robot-aided rehabilitation (RAR) and non-invasive brain stimulation (NIBS) are the two main interventions for post-stroke rehabilitation. The efficacy of both approaches in combination has not been well established yet. The importance of coupling these interventions, which both enhance brain plasticity to promote recovery, lies in augmenting the rehabilitation potential to constrain the limitation in daily living activities and the quality of life following stroke. This review aimed to evaluate the evidence of NIBS coupled with RAR in improving rehabilitation outcomes of upper limb and gait motor impairment in adult individuals with stroke. We included 18 clinical trials in this review. All studies were highly heterogeneous concerning the technical characteristics of robotic devices and NIBS protocols. However, the studies reported a global improvement in body structure and function and activity limitation for the upper limb, which were non-significant between the active and control groups. Concerning gait training protocols, the active group outperformed the control group in improving walking capacity and recovery. According to this review, NIBS and RAR in combination are promising but not yet largely recommendable as a systematic approach for stroke rehabilitation as there is not enough data about this. Therefore, more homogenous clinical trials are required, pointing out the best characteristics of the combined therapeutic protocols.

Intraclass Correlation in Paired Associative Stimulation and Metaplasticity

Paired associative stimulation (PAS) is a widely used noninvasive brain stimulation protocol to assess neural plasticity. Its reproducibility, however, has been rarely tested and with mixed results. With two consecutive studies, we aimed to provide further tests and a more systematic assessment of PAS reproducibility. We measured intraclass correlation coefficients (ICCs)—a widely used tool to assess whether groups of measurements resemble each other—in two PAS studies on healthy volunteers. The first study included five PAS sessions recording 10 MEPS every 10 min for an hour post-PAS. The second study included two PAS sessions recording 50 MEPS at 20 and 50 min post-PAS, based on analyses from the first study. In both studies PAS sessions were spaced one week apart. Within sessions ICC was fair to excellent for both studies, yet between sessions ICC was poor for both studies. We suggest that long term meta-plasticity effects (longer than one week) may interfere with between sessions reproducibility.

Inter-Individual Variability in Motor Output Is Driven by Recruitment Gain in the Corticospinal Tract Rather Than Motor Threshold.

Variability in the response of individuals to various non-invasive brain stimulation protocols is a major problem that limits their potential for clinical applications. Baseline motor-evoked potential (MEP) amplitude is the key predictor of an individual’s response to transcranial magnetic stimulation protocols. However, the factors that predict MEP amplitude and its variability remain unclear. In this study, we aimed to identify the input–output curve (IOC) parameters that best predict MEP amplitude and its variability. We analysed IOC data from 75 subjects and built a general linear model (GLM) using the IOC parameters as regressors and MEP amplitude at 120% resting motor threshold (RMT) as the response variable. We bootstrapped the data to estimate variability of IOC parameters and included them in a GLM to identify the significant predictors of MEP amplitude variability. Peak slope, motor threshold, and maximum MEP amplitude of the IOC were significant predictors of MEP amplitude at 120% RMT and its variability was primarily driven by the variability of peak slope and maximum MEP amplitude. Recruitment gain and maximum corticospinal excitability are the key predictors of MEP amplitude and its variability. Inter-individual variability in motor output may be reduced by achieving a uniform IOC slope.