Intermittent theta burst stimulation of the left dorsolateral prefrontal cortex has no additional effect on the efficacy of virtual reality exposure therapy for acrophobia. A randomized double-blind placebo-controlled study.

Anxiety disorders are among the most common mental disorders. Treatment guidelines recommend pharmacotherapy and cognitive behavioral therapy as standard treatment. Although cognitive behavioral therapy is an effective therapeutic approach, not all patients benefit sufficiently from it. In recent years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, have been investigated as promising adjuncts in the treatment of affective disorders. The aim of this study is to investigate whether a combination of intermittent theta burst stimulation (iTBS) and virtual reality exposure therapy leads to a significantly greater reduction in acrophobia than virtual reality exposure with sham stimulation. In this randomized double-blind placebo-controlled study, 43 participants with acrophobia received verum or sham iTBS over the left dorsolateral prefrontal cortex prior to two sessions of virtual reality exposure therapy. Stimulation of the left dorsolateral prefrontal cortex with iTBS was motivated by an experimental study showing a positive effect on extinction memory retention. Acrophobic symptoms were assessed using questionnaires and two behavioral approach tasks one week before, after treatment and six months after the second diagnostic session. The results showed that two sessions of virtual reality exposure therapy led to a significant reduction in acrophobic symptoms, with an overall remission rate of 79 %. However, there was no additional effect of iTBS of the left dorsolateral prefrontal cortex on the therapeutic effects. Further research is needed to determine how exactly a combination of transcranial magnetic stimulation and exposure therapy should be designed to enhance efficacy.

Novel perspective of therapeutic modules to overcome motor and nonmotor symptoms in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that involves the loss of dopaminergic neurons, which leads to motor and non-motor symptoms that have a significant impact. The pathophysiology of PD is complex and involves environmental and genetic factors that contribute to alpha-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The current treatments of PD primarily focus on symptom management and have limitations in addressing disease progression and non-motor symptoms. Epidemiological data indicates a rise in PD cases worldwide, which highlights the need for effective treatments. Pathophysiological insights point out the involvement of various factors in PD progression, such as dopamine dysregulation, genetic mutations, oxidative stress, mitochondrial damage, alpha-synuclein aggregation, and neuroinflammation. Although current treatments, which include dopamine precursors, monoamine oxidase (MAO) inhibitors, and non-dopaminergic drugs, can alleviate motor symptoms, they are not effective in preventing disease progression or managing non-motor symptoms. Additionally, they can lead to adverse effects and become less effective over time. Novel therapeutic approaches, including cell-based therapies, gene therapies, targeted drug delivery therapies, and magnetic field therapies, are promising in improving symptom management and providing personalized treatment. Additionally, emerging therapies that target alpha-synuclein aggregation, mitochondrial dysfunction, and neuroinflammation may have potential disease-modifying effects. To sum up, for dealing with the multiple aspects of PD, there is a great need to come up with new and creative therapeutic approaches that not only relieve symptoms, but also prevent the progression of disease and non-motor symptoms. The progress made in comprehending the underlying mechanisms of PD provides optimism for developing successful treatments that can enhance the outcomes and quality of life.

Vagus nerve stimulation in dementia: A scoping review of clinical and pre-clinical studies.

Background: Dementia is a prevalent, progressive, neurodegenerative condition with multifactorial causes. Due to the lack of effective pharmaceutical treatments for dementia, there are growing clinical and research interests in using vagus nerve stimulation (VNS) as a potential non-pharmacological therapy for dementia. However, the extent of the research volume and nature into the effects of VNS on dementia is not well understood. This study aimed to examine the extent and nature of research activities in relation to the use of VNS in dementia and disseminate research findings for the potential utility in dementia care. Methods: We performed a scoping review of literature searches in PubMed, HINARI, Google Scholar, and the Cochrane databases from 1980 to November 30th, 2023, including the reference lists of the identified studies. The following search terms were utilized: brain stimulation, dementia, Alzheimer's disease, vagal stimulation, memory loss, Deme*, cognit*, VNS, and Cranial nerve stimulation. The included studies met the following conditions: primary research articles pertaining to both humans and animals for both longitudinal and cross-sectional study designs and published in English from January 1st, 1980, to November 30th, 2023; investigated VNS in either dementia or cognitive impairment; and were not case studies, conference proceedings/abstracts, commentaries, or ordinary review papers. Findings and conclusions: We identified 8062 articles, and after screening for eligibility (sequentially by titles, abstracts and full text reading, and duplicate removal), 10 studies were included in the review. All the studies included in this literature review were conducted over the last three decades in high-income geographical regions (i.e., Europe, the United States, the United Kingdom, and China), with the majority of them (7/10) being performed in humans. The main reported outcomes of VNS in the dementia cases were enhanced cognitive functions, an increased functional connectivity of various brain regions involved in learning and memory, microglial structural modifications from neurodestructive to neuroprotective configurations, a reduction of cerebral spinal fluid tau-proteins, and significant evoked brain tissue potentials that could be utilized to diagnose neurodegenerative disorders. The study outcomes highlight the potential for VNS to be used as a non-pharmacological therapy for cognitive impairment in dementia-related diseases such as Alzheimer's disease.

Single-center experience of utilization and clinical efficacy of segmented leads for subthalamic deep brain stimulation in Parkinson's disease.

Background: Segmented electrodes for deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) enable directional current steering leading to expanded programming options. Objective: This retrospective study covering a longitudinal period of up to 7 years compares the efficacy of segmented and non-segmented leads in motor symptom alleviation and reduction of dopaminergic medication in PD patients treated in a specialized center and assesses the long-term use of directional steering in clinical routine. Methods: Demographic data and clinical scores before surgery and at 12-month follow-up (12MFU) as well as stimulation parameters at 12MFU and last follow-up (LFU) were assessed in all patients implanted with segmented leads between 01/2016 and 12/2019 and non-segmented leads in a corresponding time-period. Patients were classified as very good (>60 %), good (30-60 %) and poor (<30 %) responders according to DBS-induced motor improvement. Results: Clinical data at 12MFU was available for 61/96 patients with segmented (SEG) and 42/53 with non-segmented leads (N-SEG). Mean DBS-induced motor improvement and reduction of medication at 12MFU did not differ significantly between SEG and N-SEG groups or in a subgroup analysis of steering modes. There was a lower proportion of poor responders in the SEG compared with the N-SEG group (23% vs. 31%), though not statistically significant. At LFU, the percentage of patients set at directional steering increased from 54% to 70%. Conclusion: Efficacy in reduction of motor symptoms and medication does not differ between electrode types for STN-DBS at 12 months follow-up. The use of directional steering increases over time and may account for a lower proportion of poor responders.

Levodopa / opicapone as a complement to STN-DBS in clinical practice. A retrospective single-centre analysis.

Objective: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a well-established treatment option in Parkinson's disease with motor and non-motor fluctuations allowing for postoperative reduction of dopaminergic medication. However, evidence is scarce on optimal medication adjustments following STN-DBS implantation. Opicapone allows for long-lasting inhibition of the catechol-O-methyltransferase (COMT) thereby enabling more constant dopaminergic stimulation compared to levodopa alone. However, especially COMT inhibitors are regularly discontinued after STN-DBS surgery. In this single-centre retrospective analysis, we aimed to analyse the clinical phenotype of patients selected for opicapone treatment following STN-DBS implantation and to define clinical determinants of patients requiring more intense dopamine-stabilising strategies after STN-DBS implantation. Methods: A patient cohort treated with STN-DBS + levodopa + opicapone (n = 16) was compared to an age-matched control cohort without opicapone treatment at baseline before and ≥ 5 months post-surgery. As main outcomes we assessed the MDS-UPDRS III and IV scores and reduction of the cumulative dopaminergic medication quantified by the levodopa equivalent dosages (LED). Results: Whilst the MDS-UPDRS III (median [min - max]) in patients with STN-DBS as well as anatomical electrode positions did not differ significantly between the opicapone 20 [4-40] and control cohort 14 [1-44], the patients selected for opicapone treatment showed a significantly higher degree of dyskinesias already preoperatively as reflected by a UPDRS-IV A subscore of 2 [0-4] compared to controls 0 [0-4]. Postoperatively, the opicapone cohort showed stronger motor fluctuations MDS-UPDRS IV 6 [0-14] compared to the controls 0 [0-10], albeit without statistical significance. Moreover, the opicapone cohort showed significantly less reduction of dopaminergic medication (-36.4 % vs. -46.2 % in the control cohort) following STN-DBS implantation independent from the intake of dopamine agonists. Conclusion: These results indicate a clinical phenotype characterised by more motor fluctuations requiring a more stable dopamine replacement therapy to address the patients' disease biology. In these cases, levodopa + COMT inhibition by opicapone represents a therapeutic approach but determination of the potential clinical benefit requires further prospective studies.

Deep brain stimulation for post-stroke rehabilitation in Pakistan.

Stroke has a high prevalence in Pakistan, at an alarming rate of 250 per 100 000 people. Although various treatment options are available, they are not ideal for Pakistan due to their high cost, restricted availability, and time sensitivity. In 1997, the FDA-approved deep brain stimulation (DBS) for Parkinson's disease and it was first performed in Pakistan in 2014. DBS has also proved effective for restoring post-stroke mobility, according to a trial from August 2023. DBS has the potential to revolutionize post-stroke rehabilitation in Pakistan; however, further research is required into its effectiveness and its limitations must be addressed first.

A historical perspective on the neurobiology of speech and language: from the 19th century to the present.

In this essay, we review 19th century conceptions on the neurobiology of speech and language, including the pioneer work of Franz Gall, Jean-Baptiste Bouillaud, Simon Alexandre Ernest Aubertin, Marc Dax, Paul Broca, and Carl Wernicke. We examine how these early investigations, anchored in the study of neurological disorders, have broadened their scope via neuropsychological and psycholinguistic theories and models. Then, we discuss how major technological advances have led to an important paradigm shift, through which the study of the brain slowly detached from the study of disease to become the study of individuals of all ages, with or without brain pathology or language disorders. The profusion of neuroimaging studies that were conducted in the past four decades, inquiring into various aspects of language have complemented-and often challenged-classical views on language production. Our understanding of the "motor speech center," for instance, has been entirely transformed. The notion of cerebral dominance has also been revisited. We end this paper by discussing the challenges and controversies of 21st century neurobiology of speech and language as well as modern views of the neural architecture supporting speech and language functions.

Advances in Repetitive Transcranial Magnetic Stimulation for the Treatment of Post-traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that develops and persists after an individual experiences a major traumatic or life-threatening event. While pharmacological treatment and psychological interventions can alleviate some symptoms, pharmacotherapy is time-consuming with low patient compliance, and psychological interventions are costly. Repetitive Transcranial Magnetic Stimulation (rTMS) is a safe and effective technique for treating PTSD, with advantages such as high compliance, low cost, and simplicity of implementation. It can even simultaneously improve depressive symptoms in some patients. Current research indicates that high-frequency rTMS shows better therapeutic effects compared to low-frequency rTMS, with no significant difference in the likelihood of adverse reactions between the two. Theta Burst Stimulation (TBS) exhibits similar efficacy to high-frequency rTMS, with shorter duration and significant improvement in depressive symptoms. However, it carries a slightly higher risk of adverse reactions compared to traditional high-frequency rTMS. Combining rTMS with psychological therapy appears to be more effective in improving PTSD symptoms, with early onset of effects and longer duration, albeit at higher cost and requiring individualized patient control. The most common adverse effect of treatment is headache, which can be improved by stopping treatment or using analgesics. Despite these encouraging data, several aspects remain unknown. Given the highly heterogeneous nature of PTSD, defining unique treatment methods for this patient population is quite challenging. There are also considerable differences between trials regarding stimulation parameters, therapeutic effects, and the role of combined psychological therapy, which future research needs to address.

Vagus nerve stimulation (VNS): recent advances and future directions.

PURPOSE: Vagus nerve stimulation (VNS) is emerging as a unique and potent intervention, particularly within neurology and psychiatry. The clinical value of VNS continues to grow, while the development of noninvasive options promises to change a landscape that is already quickly evolving. In this review, we highlight recent progress in the field and offer readers a glimpse of the future for this bright and promising modality. METHODS: We compiled a narrative review of VNS literature using PubMed and organized the discussion by disease states with approved indications (epilepsy, depression, obesity, post-stroke motor rehabilitation, headache), followed by a section highlighting novel, exploratory areas of VNS research. In each section, we summarized the current role, recent advancements, and future directions of VNS in the treatment of each disease. RESULTS: The field continues to gain appreciation for the clinical potential of this modality. VNS was initially developed for treatment-resistant epilepsy, with the first depression studies following shortly thereafter. Overall, VNS has gained approval or clearance in the treatment of medication-refractory epilepsy, treatment-resistant depression, obesity, migraine/cluster headache, and post-stroke motor rehabilitation. CONCLUSION: Noninvasive VNS represents an opportunity to bridge the translational gap between preclinical and clinical paradigms and may offer the same therapeutic potential as invasive VNS. Further investigation into how VNS parameters modulate behavior and biology, as well as how to translate noninvasive options into the clinical arena, are crucial next steps for researchers and clinicians studying VNS.

Neuromodulation effect of temporal interference stimulation based on network computational model.

Deep brain stimulation (DBS) has long been the conventional method for targeting deep brain structures, but noninvasive alternatives like transcranial Temporal Interference Stimulation (tTIS) are gaining traction. Research has shown that alternating current influences brain oscillations through neural modulation. Understanding how neurons respond to the stimulus envelope, particularly considering tTIS's high-frequency carrier, is vital for elucidating its mechanism of neuronal engagement. This study aims to explore the focal effects of tTIS across varying amplitudes and modulation depths in different brain regions. An excitatory-inhibitory network using the Izhikevich neuron model was employed to investigate responses to tTIS and compare them with transcranial Alternating Current Stimulation (tACS). We utilized a multi-scale model that integrates brain tissue modeling and network computational modeling to gain insights into the neuromodulatory effects of tTIS on the human brain. By analyzing the parametric space, we delved into phase, amplitude, and frequency entrainment to elucidate how tTIS modulates endogenous alpha oscillations. Our findings highlight a significant difference in current intensity requirements between tTIS and tACS, with tTIS requiring notably higher intensity. We observed distinct network entrainment patterns, primarily due to tTIS's high-frequency component, whereas tACS exhibited harmonic entrainment that tTIS lacked. Spatial resolution analysis of tTIS, conducted via computational modeling and brain field distribution at a 13 Hz stimulation frequency, revealed modulation in deep brain areas, with minimal effects on the surface. Notably, we observed increased power within intrinsic and stimulation bands beneath the electrodes, attributed to the high stimulus signal amplitude. Additionally, Phase Locking Value (PLV) showed slight increments in non-deep areas. Our analysis indicates focal stimulation using tTIS, prompting further investigation into the necessity of high amplitudes to significantly affect deep brain regions, which warrants validation through clinical experiments.

Noninvasive modulation of subcallosal cingulate and depression with focused ultrasonic waves.

BACKGROUND: Severe forms of depression have been linked to excessive subcallosal cingulate (SCC) activity. Stimulation of SCC with surgically implanted electrodes can alleviate depression, but current noninvasive techniques cannot directly and selectively modulate deep targets. We developed a new noninvasive neuromodulation approach that can deliver low-intensity focused ultrasonic waves to the SCC. METHODS: Twenty-two subjects with treatment-resistant depression participated in a randomized, double-blind, sham-controlled study. Ultrasonic stimulation was delivered to bilateral SCC during concurrent functional MRI to quantify target engagement. Mood state was measured with the Sadness subscale of the Positive and Negative Affect Schedule before and after 40 minutes of real or sham SCC stimulation. Change in depression severity was measured with the 6-item Hamilton Depression Rating Scale (HDRS- 6) at 24 hours and 7 days. RESULTS: Functional MRI demonstrated a target-specific decrease in SCC activity during stimulation (p=0.028, n=16). In 7 of 16 participants, SCC neuromodulation was detectable at the individual-subject level with a single 10-minute scan (p<0.05, small-volume-correction). Mood and depression scores improved more with real than with sham stimulation. In the per-protocol sample (n=19), real stimulation was superior to sham for HDRS-6 at 24 hours and for Sadness (both p<0.05, d>1). Non-significant trends were found in the intent-to-treat sample. CONCLUSIONS: This small pilot study indicates that ultrasonic stimulation modulates SCC activity and can rapidly reduce depressive symptoms. The capability to noninvasively and selectively target deep brain areas creates new possibilities for future development of circuit-directed therapeutics, and for the dissection of deep-brain circuit function in humans.

Combination of or Transition between Deep Brain Stimulation and Responsive Neurostimulation for the Treatment of Drug-Resistant Epilepsy.

INTRODUCTION: Neuromodulation is an important treatment modality for patients with drug-resistant epilepsy who are not candidates for resective or ablative procedures. However, randomized controlled trials and real-world studies reveal that a subset of patients will experience minimal reduction or even an increase in seizure frequency after neuromodulation. We describe our experience with patients who undergo a second intracranial neuromodulation procedure after unsatisfactory initial response to intracranial neuromodulation. METHODS: We performed a retrospective chart review to identify all patients who had undergone deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) or responsive neurostimulation (RNS), followed by additional intracranial neuromodulatory procedures, with at least 12 months of follow-up. Demographic and clinical data, including seizure frequencies, were collected. RESULTS: All patients had temporal lobe epilepsy. Six patients were treated with concurrent ANT DBS and temporal lobe RNS, and 3 patients transitioned between neuromodulation systems. Of the patients treated concurrently with ANT DBS and temporal lobe RNS, 5 of the 6 patients experienced additional reduction in seizure frequency after adding a second neuromodulation system. Of the patients who switched between neuromodulation modalities, all patients experienced further reduction in seizure frequency. CONCLUSIONS: For patients who do not experience adequate benefit from initial therapy with ANT DBS or temporal lobe RNS, the addition of a neuromodulation system or switching to a different form of neuromodulation may allow for additional reduction in seizure frequency. Larger studies will need to be performed to understand whether the use of multiple systems concurrently leads to improved clinical results in patients who are initially treatment resistant to neuromodulation.

Stereotactic radiofrequency lesioning of caudal zona incerta for parkinsonian tremor.

This video showcases stereotactic radiofrequency lesioning of the caudal zona incerta (CZi) for parkinsonian tremor in a 70-year-old patient. The preoperative evaluation, including imaging and frame placement, is detailed. The surgical procedure involves meticulous targeting and trajectory planning. Intraoperative stimulation is utilized for motor response assessment. Two temporary lesioning phases precede the final procedure at 75°C. The postoperative CT scan highlights the lesion site. Immediate tremor relief is observed postoperatively, with the effect persisting at the 1-month follow-up. Supporting readings underscore the efficacy and safety of CZi for tremor management. The video can be found here: https://stream.cadmore.media/r10.3171/2024.7.FOCVID2462.

Parkinson's Disease Treatment: A Bibliometric Analysis.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by motor symptoms like bradykinesia, tremor, rigidity, and postural instability. Patients also experience non-motor symptoms that greatly affect their quality of life. The global prevalence of PD is increasing, especially among the elderly, necessitating effective treatment strategies. This review provides an overview of the current treatment modalities for PD, including pharmacological and surgical interventions, and employs a bibliometric analysis to evaluate the trends and impact of scientific research in this field. A comprehensive search of the Web of Science Core Collection (WoSCC) database was conducted on July 12, 2024, yielding 3,724 publications related to PD treatment. Bibliometric analysis was performed using Biblioshiny and VOSviewer to assess publication trends, impact, and collaborative networks. Metrics such as the number of publications, citations, h-index, and country/institutional contributions were analyzed to identify key areas of focus and influential research in PD treatment. The analysis revealed a significant increase in PD research output from 2000 onwards, peaking between 2011 and 2016. The United States led in research production, followed by China, Canada, and the United Kingdom. Key researchers included Lang AE, Okun MS, and Lozano AM, with the University of Toronto, University of California System, and Harvard University being the top contributing institutions. The study identified major trends in pharmacological treatments, such as dopamine replacement therapy and deep brain stimulation (DBS) as the most common surgical intervention. Bibliometric analysis highlighted significant international collaborations and identified influential studies shaping the current understanding and treatment of PD. This bibliometric analysis elucidated the trends and impacts of scientific contributions, emphasizing the prolific output from leading countries and institutions in relation to the treatment of Parkinson's disease. Take-home messages for the conclusion of our study are as follows: (1) this study found a substantial increase in Parkinson's disease (PD) research output from 2000 onwards, peaking around 2017-2018, (2) noted a decline in publication output post-2020, (3) the United States had the highest research output, followed by significant contributions from countries like China, Canada, and the United Kingdom, (4) international collaborations played a vital role in advancing PD research, (5) key researchers in the field were Lang AE, Okun MS, and Lozano AM, (6) and established institutions like the University of Toronto, Johns Hopkins University and Harvard University made substantial contributions to the field, emphasizing the role of leading academic centers in driving PD research.

Deep brain stimulation targets in drug-resistant epilepsy: Systematic review and meta-analysis of effectiveness and predictors of response.

PURPOSE: Anterior nucleus of the thalamus (ANT) is the only deep brain stimulation (DBS) target that is approved by the FDA for treatment of drug-resistant epilepsy (DRE). Hippocampus (HC) and centromedian nucleus (CMN) have been reported as potential DBS targets for DRE. This study aimed to assess the effectiveness and predictors of response among DRE patients treated with DBS in general and among ANT, HC and CMN DBS-targets. METHODS: A systematic search was executed on PubMed, SCOPUS and the Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases between Jan 1, 2000 and June 29, 2020. Patients with DRE who underwent DBS treatment with at least three months of follow-up were included. Individual patient data (IPD) meta-analysis was conducted on DBS studies with available IPD. Response was defined as ≥50 % reduction in seizures frequency. Responders group was compared with non-responders group in terms of demographics, epilepsy/seizure characteristics, MRI findings, and DBS targets and duration of use. Subsequently, predictors of response to different DBS targets were investigated. RESULTS: Thirty-nine studies with a total of 296 patients (ANT: 69 %, HC: 11 %, CMN: 21 %) were included. The responders group constituted of 209 patients (70.6 %). The response was significantly higher in patients with generalized seizures compared to those with focal seizures (93.2% vs 63.9 %; p < 0.001). Response was significantly higher with CMN (83.9 %) and HC (77.4 %) compared with ANT (65.5 %) as DBS targets (p = 0.014). Response was also significantly associated with longer duration of DBS use (p = 0.008). The responder rate was higher among the patients with lesional MRIs (76.7 %) than those with non-lesional MRIs (66.7 %), but with no statistically significant difference (p = 0.134). Age, gender, epilepsy etiology, onset zone of focal seizures, and previous use of VNS had no significant differences between the responders and non-responders. A binary logistic regression including the seizure type, MRI findings, DBS targets, and DBS duration showed, after controlling for confounders, that the duration of DBS use was the only significant predictor of response (adjusted OR 1.061; 95 % CI 1.019-1.106; p = 0.005). Regarding DBS targets, the response rate in patients with symptomatic etiology was significantly higher with HC or CMN targets than the ANT (p = 0.003). In patients with non-lesional MRI, response rate was significantly higher with the CMN target compared to the other two targets (p = 0.008). CONCLUSION: DBS proves to be effective in DRE, with progressive success upon longer treatment and possibility of improving quality of life. In addition to focal seizures, DBS has potential for treating generalized seizures as well. While the ANT stands as the most utilized and only approved DBS target for DRE, CMN and HC are alternative targets with high seizure control potential. Patients with symptomatic etiology showed significant seizure reduction when HC or CMN were targeted. Studies revealed noticeable effectiveness of CMN-DBS in treating patients with non-lesional MRI. Despite ANT prominence in research, our findings suggest promising outcomes with CMN and HC, emphasizing the need for future larger-scale comparative clinical trials to better understand the efficacy of different DBS targets.

Non-Invasive Brain Stimulation Beyond the Motor Cortex: A Systematic Review and Meta-Analysis Exploring Effects on Quantitative Sensory Testing in Clinical Pain.

BACKGROUND: Non-invasive brain stimulation (NIBS) has been investigated increasingly as a means of treating pain. The effectiveness of NIBS in the treatment of pain has traditionally focused upon protocols targeting the primary motor cortex (M1). However, over time, the effectiveness of M1 NIBS has been attributed to effects on interconnected cortical and subcortical sites rather than M1 itself. While previous reviews have demonstrated the effectiveness of non-M1 NIBS in improving subjective reports of pain intensity, the neurophysiological mechanisms underlying these effects remain incompletely understood. As chronic pain is associated with pain hypersensitivity and impaired endogenous descending pain modulation, it is plausible that non-M1 NIBS promotes analgesic effects by influencing these processes. OBJECTIVE: The aim of this systematic review and meta-analysis was therefore to evaluate the effect of NIBS over non-M1 sites on quantitative sensory testing measures in clinical pain populations. METHODS: A systematic search of electronic databases was conducted from inception to January 2024. Included articles (13trials, n = 565 participants) were appraised using PEDro and GRADE and a random effects model was used to meta-analyse outcomes where possible. RESULTS: A small number of studies found that NIBS applied to DLPFC may improve pain modulation in patients with fibromyalgia, and that stimulation of the posterior superior insula and prefrontal cortex could improve pain sensitivity in chronic neuropathic and osteoarthritic pain, respectively. However, findings varied between studies and there remains a paucity of primary research. CONCLUSION: This review indicates that current literature does not provide clear evidence that NIBS over non-M1 sites influences pain processing.

Transcranial direct-current stimulation of core language areas facilitates novel word acquisition.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that can alter the state of the stimulated brain area and thereby affect neurocognitive processes and resulting behavioural performance. Previous studies have shown disparate results with respect to tDCS effects on language function, particularly with respect to language learning and word acquisition. To fill this gap, this study aimed at systematically addressing the effects of tDCS of core left-hemispheric language cortices on the brain mechanisms underpinning two main neurocognitive strategies of word learning: implicit inference-based Fast Mapping (FM) and direct instruction-based Explicit Encoding (EE). Prior to a word-learning session, 160 healthy participants were given 15 min of either anodal or cathodal tDCS of Wernicke's or Broca's areas, or a control sham (placebo) stimulation, using a between-group design. Each participant then learned 16 novel words (8 through FM and 8 through EE) in a contextual word-picture association session. Moreover, these words were learnt either perceptually via auditory exposure combined with a graphical image of the novel object, or in an articulatory mode, where the participants additionally had to overtly articulate the novel items. These learning conditions were fully counterbalanced across participants, stimuli and tDCS groups. Learning outcomes were tested at both lexical and semantic levels using two tasks: recognition and word-picture matching. EE and FM conditions produced similar outcomes, indicating comparable efficiency of the respective learning strategies. At the same time, articulatory learning produced generally better results than non-articulatory exposure, yielding higher recognition accuracies and shorter latencies in both tasks. Crucially, real tDCS led to global outcome improvements, demonstrated by faster (compared to sham) reactions, as well as some accuracy changes. There was also evidence of more specific tDCS effects: better word-recognition accuracy for EE vs. FM following cathodal stimulation as well as more expressed improvements in recognition accuracy and reaction times for anodal Broca's and cathodal Wernicke's stimulation, particularly for unarticulated FM items. These learning mode-specific effects support the notion of partially distinct brain mechanisms underpinning these two learning strategies. Overall, numerically largest improvements were observed for anodal Broca's tDCS, whereas the least expressed benefits of tDCS for learning were measured after anodal Wernicke stimulation. Finally, we did not find any inhibitory effects of either tDCS polarity in any of the comparisons. We conclude that tDCS of core language areas exerts a general facilitatory effect on new word acquisition with some limited specificity to learning protocols - the result that may be of potential applied value for future research aimed at ameliorating learning deficits and language disorders.