Comprehensive assessment of HF-rTMS treatment mechanism for post-stroke dysphagia in rats by integration of fecal metabolomics and 16S rRNA sequencing.

Background: The mechanism by which high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) improves swallowing function by regulating intestinal flora remains unexplored. We aimed to evaluate this using fecal metabolomics and 16S rRNA sequencing. Methods: A Post-stroke dysphagia (PSD) rat model was established by middle cerebral artery occlusion. The magnetic stimulation group received HF-rTMS from the 7th day post-operation up to 14th day post-surgery. Swallowing function was assessed using a videofluoroscopic swallowing study (VFSS). Hematoxylin-eosin (H&E) staining was used to assess histopathological changes in the intestinal tissue. Intestinal flora levels were evaluated by sequencing the 16S rRNA V3-V4 region. Metabolite changes within the intestinal flora were evaluated by fecal metabolomics using liquid chromatography-tandem mass spectrometry. Results: VFSS showed that the bolus area and pharyngeal bolus speed were significantly decreased in PSD rats, while the bolus area increased and pharyngeal transit time decreased after HF-rTMS administration (p < 0.05). In the PSD groups, H&E staining revealed damaged surface epithelial cells and disrupted cryptal glands, whereas HF-rTMS reinforced the integrity of the intestinal epithelial cells. 16S rRNA sequencing indicated that PSD can disturb the intestinal flora and its associated metabolites, whereas HF-rTMS can significantly regulate the composition of the intestinal microflora. Firmicutes and Lactobacillus abundances were lower in the PSD group than in the baseline group at the phylum and genus levels, respectively; however, both increased after HF-rTMS administration. Levels of ceramides (Cer), free fatty acids (FA), phosphatidylethanolamine (PE), triacylglycerol (TAG), and sulfoquinovosyl diacylglycerol were increased in the PSD group. The Cer, FA, and DG levels decreased after HF-rTMS treatment, whereas the TAG levels increased. Peptococcaceae was negatively correlated with Cer, Streptococcus was negatively correlated with DG, and Acutalibacter was positively correlated with FA and Cer. However, these changes were effectively restored by HF-rTMS, resulting in recovery from dysphagia. Conclusion: These findings suggest a synergistic role for the gut microbiota and fecal metabolites in the development of PSD and the therapeutic mechanisms underlying HF-rTMS.

Cost-utility analysis of adjunct repetitive transcranial magnetic stimulation for treatment resistant bipolar depression.

OBJECTIVE: To evaluate the cost-effectiveness of repetitive transcranial magnetic stimulation (rTMS) as an adjunct to standard care from an Australian health sector perspective, compared to standard care alone for adults with treatment-resistant bipolar depression (TRBD). METHODS: An economic model was developed to estimate the cost per disability-adjusted life-year (DALY) averted and quality-adjusted life-year (QALY) gained for rTMS added to standard care compared to standard care alone, for adults with TRBD. The model simulated the time in three health states (mania, depression, residual) over one year. Response to rTMS was sourced from a meta-analysis, converted to a relative risk and used to modify the time in the depressed state. Uncertainty and sensitivity tested the robustness of results. RESULTS: Base-case incremental cost-effectiveness ratios (ICERs) were $72,299 per DALY averted (95 % Uncertainty Interval (UI): $60,915 to $86,668) and $46,623 per QALY gained (95 % UI: $39,676 - $55,161). At a willingness to pay (WTP) threshold of $96,000 per DALY averted, the base-case had a 100 % probability of being marginally cost-effective. At a WTP threshold of $64,000 per QALY gained, the base-case had a 100 % probability of being cost-effective. Sensitivity analyses decreasing the number of sessions provided, increasing the disability weight or the time spent in the depression state for standard care improved the ICERs for rTMS. CONCLUSIONS: Dependent on the outcome measure utilised and assumptions, rTMS would be considered a very cost-effective or marginally cost-effective adjunct to standard care for TRBD compared to standard care alone.

Assessment of rTMS treatment effects for methamphetamine use disorder based on EEG microstates.

Microstates have been proposed as topographical maps representing large-scale resting-state networks and have recently been suggested as markers for methamphetamine use disorder (MUD). However, it is unknown whether and how they change after repetitive transcranial magnetic stimulation (rTMS) intervention. This study included a comprehensive subject population to investigate the effect of rTMS on MUD microstates. 34 patients with MUD underwent a 4-week randomized, double-blind rTMS intervention (active=17, sham=17). Two resting-state EEG recordings and VAS evaluations were conducted before and after the intervention period. Additionally, 17 healthy individuals were included as baseline controls. The modified k-means clustering method was used to calculate four microstates (MS-A∼MS-D) of EEG, and the FC network was also analyzed. The differences in microstate indicators between groups and within groups were compared. The durations of MS-A and MS-B microstates in patients with MUD were significantly lower than that in HC but showed significant improvements after rTMS intervention. Changes in microstate indicators were found to be significantly correlated with changes in craving level. Furthermore, selective modulation of the resting-state network by rTMS was observed in the FC network. The findings indicate that changes in microstates in patients with MUD are associated with craving level improvement following rTMS, suggesting they may serve as valuable evaluation markers.

Single-pulse transcranial magnetic stimulation for assessment of motor development in infants with early brain injury.

INTRODUCTION: Single-pulse transcranial magnetic stimulation (TMS) has many applications for pediatric clinical populations, including infants with perinatal brain injury. As a noninvasive neuromodulation tool, single-pulse TMS has been used safely in infants and children to assess corticospinal integrity and circuitry patterns. TMS may have important applications in early detection of atypical motor development or cerebral palsy. AREAS COVERED: The authors identified and summarized relevant studies incorporating TMS in infants, including findings related to corticospinal development and circuitry, motor cortex localization and mapping, and safety. This special report also describes methodologies and safety considerations related to TMS assessment in infants, and discusses potential applications related to diagnosis of cerebral palsy and early intervention. EXPERT OPINION: Single-pulse TMS has demonstrated safety and feasibility in infants with perinatal brain injury and may provide insight into neuromotor development and potential cerebral palsy diagnosis. Additional research in larger sample sizes will more fully evaluate the utility of TMS biomarkers in early diagnosis and intervention. Methodological challenges to performing TMS in infants and technical/equipment limitations require additional consideration and innovation toward clinical implementation. Future research may explore use of noninvasive neuromodulation techniques as an intervention in younger children with perinatal brain injury to improve motor outcomes.

Single pulse transcranial magnetic stimulation (TMS) is a safe and noninvasive way to study brain activity in infants and children who have experienced brain injuries around the time of birth. Infants who have had an early brain injury may develop cerebral palsy, a developmental disability that affects movement. TMS uses a device that gives single pulses of energy to activate specific areas of the brain. This can be used to study how the brain connects to the muscles in the body through paths or 'tracts.' TMS helps researchers understand the development of the tracts and the potential need for therapy. This article reviews research studies that used TMS in infants and explains how TMS can be used to assess brain development. It also reviews safety considerations and challenges related to using TMS in infants. TMS could be a valuable tool for early diagnosis of cerebral palsy and could also help guide treatments for infants with brain injuries. However, more research is needed, using larger groups of infants, to potentially expand the use of TMS in clinical practice. Future directions include developing infant-specific research tools and using noninvasive brain stimulation to improve recovery for infants with brain injuries.

Cost-effectiveness analysis comparing repetitive transcranial magnetic stimulation therapy with antidepressant treatment in patients with treatment-resistant depression in Japan.

Repetitive transcranial magnetic stimulation (rTMS) for patients with treatment-resistant depression (TRD) became covered by the National Health Insurance (NHI) in Japan since 2019. Although the evidence of rTMS for TRD is well established, the cost-effectiveness of rTMS versus antidepressants has not been thoroughly analyzed in Japan. Thus, we aimed to evaluate the cost-effectiveness of rTMS for TRD under the NHI system using a microsimulation model to compare the direct costs and quality-adjusted life years (QALYs). Model inputs of clinical parameters and the utility were derived from published literature. Cost parameters were estimated from the Japanese Claim Database. The robustness of the analyses was evaluated with sensitivity analysis and scenario analysis. The analysis estimated that rTMS increased effectiveness by 0.101QALYs and total cost by ¥94,370 ($689) compared with antidepressant medications. As a result, the incremental cost-effectiveness ratio (ICER) of rTMS was estimated to be ¥935,984 ($6,832)/QALY. In the sensitivity and scenario analyses, ICER did not exceed ¥5 million ($36,496)/QALY as the reference value of the Japanese public cost-effectiveness evaluation system. rTMS therapy for TRD can be a cost-effective treatment strategy compared to antidepressant medication under the NHI system in Japan.

The VLPFC-Engaged Voluntary Emotion Regulation: Combined TMS-fMRI Evidence for the Neural Circuit of Cognitive Reappraisal.

A clear understanding of the neural circuit underlying emotion regulation (ER) is important for both basic and translational research. However, a lack of evidence based on combined neuroimaging and neuromodulation techniques calls into question (1) whether the change of prefrontal-subcortical activity intrinsically and causally contributes to the ER effect; and (2) whether the prefrontal control system directly modulates the subcortical affective system. Accordingly, we combined fMRI recordings with transcranial magnetic stimulation (TMS) to map the causal connections between the PFC and subcortical affective structures (amygdala and insula). A total of 117 human adult participants (57 males and 60 females) were included in the study. The results revealed that TMS-induced ventrolateral PFC (VLPFC) facilitation led to enhanced activity in the VLPFC and ventromedial PFC (VMPFC) as well as attenuated activity in the amygdala and insula during reappraisal but not during nonreappraisal (i.e., baseline). Moreover, the activated VLPFC intensified the prefrontal-subcortical couplings via the VMPFC during reappraisal only. This study provides combined TMS-fMRI evidence that downregulating negative emotion involves the prefrontal control system suppressing the subcortical affective system, with the VMPFC serving as a crucial hub within the VLPFC-subcortical network, suggesting an indirect pathway model of the ER circuit. Our findings outline potential protocols for improving ER ability by intensifying the VLPFC-VMPFC coupling in patients with mood and anxiety disorders.SIGNIFICANCE STATEMENT Using fMRI to examine the TMS effect, we uncovered that the opposite neural changes in prefrontal (enhanced) and subcortical (attenuated) regions are not a byproduct of emotion regulation (ER); instead, this prefrontal-subcortical activity per se causally contributes to the ER effect. Furthermore, using TMS to amplify the neural changes within the ER circuit, the "bridge" role of the VMPFC is highlighted under the reappraisal versus nonreappraisal contrast. This "perturb-and-measure" approach overcomes the correlational nature of fMRI data, helping us to identify brain regions that causally support reappraisal (the VLPFC and VMPFC) and those that are modulated by reappraisal (the amygdala and insula). The uncovered ER circuit is important for understanding the neural systems underlying reappraisal and valuable for translational research.

Neural bases of motor fatigue in multiple sclerosis: A multimodal approach using neuromuscular assessment and TMS-EEG.

Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in MS are still unclear. This paper investigated whether central motor fatigue in MS reflects impaired corticospinal transmission or suboptimal primary motor cortex (M1) output (supraspinal fatigue). Furthermore, we sought to identify whether central motor fatigue is associated with abnormal M1 excitability and connectivity within the sensorimotor network. Twenty-two patients affected by relapsing-remitting MS and 15 healthy controls (HCs) performed repeated blocks of contraction at different percentages of maximal voluntary contraction with the right first dorsal interosseus muscle until exhaustion. Peripheral, central, and supraspinal components of motor fatigue were quantified by a neuromuscular assessment based on the superimposed twitch evoked by peripheral nerve and transcranial magnetic stimulation (TMS). Corticospinal transmission, excitability and inhibition during the task were tested by measurement of motor evoked potential (MEP) latency, amplitude, and cortical silent period (CSP). M1 excitability and connectivity was measured by TMS-evoked electroencephalography (EEG) potentials (TEPs) elicited by M1 stimulation before and after the task. Patients completed fewer blocks of contraction and showed higher values of central and supraspinal fatigue than HCs. We found no MEP or CSP differences between MS patients and HCs. Patients showed a post-fatigue increase in TEPs propagation from M1 to the rest of the cortex and in source-reconstructed activity within the sensorimotor network, in contrast to the reduction observed in HCs. Post-fatigue increase in source-reconstructed TEPs correlated with supraspinal fatigue values. To conclude, MS-related motor fatigue is caused by central mechanisms related explicitly to suboptimal M1 output rather than impaired corticospinal transmission. Furthermore, by adopting a TMS-EEG approach, we proved that suboptimal M1 output in MS patients is associated with abnormal task-related modulation of M1 connectivity within the sensorimotor network. Our findings shed new light on the central mechanisms of motor fatigue in MS by highlighting a possible role of abnormal sensorimotor network dynamics. These novel results may point to new therapeutical targets for fatigue in MS.

Assessment of Motor Evoked Potentials in Multiple Sclerosis.

Transcranial magnetic stimulation (TMS) is a noninvasive technique mainly used for the assessment of corticospinal tract integrity and excitability of the primary motor cortices. Motor evoked potentials (MEPs) play a pivotal role in TMS studies. TMS clinical guidelines, concerning the use and interpretation of MEPs in diagnosing and monitoring corticospinal tract integrity in people with multiple sclerosis (pwMS), were established almost ten years ago and refer mainly to the use of TMS implementation; this comprises the magnetic stimulator connected to a standard EMG unit, with the positioning of the coil performed by using the external landmarks on the head. The aim of the present work was to conduct a narrative literature review on the MEP assessment and outcome measures in clinical and research settings, assessed by TMS Methodological characteristics of different TMS system implementations (TMS without navigation, line-navigated TMS and e-field-navigated TMS); these were discussed in the context of mapping the corticospinal tract integrity in MS. An MEP assessment of two case reports, by using an e-field-navigated TMS, was presented; the results of the correspondence between the e-field-navigated TMS with MRI, and the EDSS classifications were presented. Practical and technical guiding principles for the improvement of TMS studies in MEP assessment for MS are discussed, suggesting the use of e-field TMS assessment in the sense that it can improve the accuracy of corticospinal tract integrity testing by providing a more objective correspondence of the neurophysiological (e-field-navigated TMS) and clinical (Expanded Disability Status Scale-EDSS) classifications.

Multimodal assessment of the GABA system in patients with fragile-X syndrome and neurofibromatosis of type 1.

Fragile-X syndrome (FXS) and Neurofibromatosis of type 1 (NF-1) are two monogenic disorders sharing neurobehavioral symptoms and pathophysiological mechanisms. Namely, preclinical models of both conditions show overactivity of the mTOR signaling pathway as well as GABAergic alterations. However, despite its potential clinical relevance for these disorders, the GABAergic system has not been systematically studied in humans. In the present study, we used an extensive transcranial magnetic stimulation (TMS) assessment battery in combination with magnetic resonance spectroscopy (MRS) to provide a comprehensive picture of the main inhibitory neurotransmitter system in patients with FXS and NF1. Forty-three participants took part in the TMS session (15 FXS, 10 NF1, 18 controls) and 36 in the MRS session (11 FXS, 14 NF1, 11 controls). Results show that, in comparison to healthy control participants, individuals with FXS and NF1 display lower GABA concentration levels as measured with MRS. TMS result show that FXS patients present increased GABAB-mediated inhibition compared to controls and NF1 patients, and that GABAA-mediated intracortical inhibition was associated with increased excitability specifically in the FXS groups. In line with previous reports, correlational analyses between MRS and TMS measures did not show significant relationships between GABA-related metrics, but several TMS measures correlated with glutamate+glutamine (Glx) levels assessed with MRS. Overall, these results suggest a partial overlap in neurophysiological alterations involving the GABA system in NF1 and FXS, and support the hypothesis that MRS and TMS assess different aspects of the neurotransmitter systems.

Research and application advances in rehabilitation assessment of stroke.

Stroke has a high incidence and disability rate, and rehabilitation is an effective means to reduce the disability rate of patients. To systematize rehabilitation assessment, which is the foundation for rehabilitation therapy, we summarize the assessment methods commonly used in research and clinical applications, including the various types of stroke rehabilitation scales and their applicability, and related biomedical detection technologies, including surface electromyography (sEMG), motion analysis systems, transcranial magnetic stimulation (TMS), magnetic resonance imaging (MRI), and combinations of different techniques. We also introduce some assessment techniques that are still in the experimental phase, such as the prospective application of artificial intelligence (AI) with optical correlation tomography (OCT) in stroke rehabilitation. This review provides a useful bibliography for the assessment of not only the severity of stroke injury, but also the therapeutic effects of stroke rehabilitation, and establishes a solid base for the future development of stroke rehabilitation skills.

The assessment of biceps voluntary activation with transcranial magnetic stimulation in individuals with tetraplegia.

BACKGROUND: Assessment of voluntary activation is useful in the study of neuromuscular impairments, particularly after spinal cord injury (SCI). Measurement of voluntary activation with transcranial magnetic stimulation (VATMS) is limited by technical challenges, including the difficulty in preferential stimulation of cortical neurons projecting to the target muscle and minimal stimulation of antagonists. Thus, the motor evoked potential (MEP) response to TMS in the target muscle compared to its antagonist may be an important parameter in the assessment of VATMS. OBJECTIVE: The purpose of this study was to evaluate the effect of isometric elbow flexion angle on two metrics in individuals with tetraplegia following SCI: 1) the ratio of biceps/triceps MEP amplitude across a range of voluntary efforts, and 2) VATMS. METHODS: Ten individuals with tetraplegia and ten nonimpaired individuals were recruited to participate in three sessions wherein VATMS was assessed at 45°, 90°, and 120° of isometric elbow flexion. RESULTS: In SCI participants, the biceps/triceps MEP ratio was not modulated by elbow angle. In nonimpaired participants, the biceps/triceps MEP ratio was greater in the more flexed elbow angle (120° flexion) compared to 90° during contractions of 50% and 75% MVC, but VATMS was not different. VATMS assessed in the more extended elbow angle (45° flexion) was lower relative to 90° elbow flexion; this effect was dependent on the biceps/triceps MEP ratio. In both groups, VATMS was sensitive to the linearity of the voluntary moment and superimposed twitch relationship, regardless of elbow angle. Linearity was lower in SCI relative to nonimpaired participants. CONCLUSIONS: Increasing the MEP ratio via elbow angle did not enable estimation of VATMS in SCI participants. VATMS may not be a viable approach to assess neuromuscular function in individuals with tetraplegia.

Neurophysiological assessment of juvenile parkinsonism due to primary monoamine neurotransmitter disorders.

No studies have investigated voluntary movement abnormalities and their neurophysiological correlates in patients with parkinsonism due to inherited primary monoamine neurotransmitter (NT) disorders. Nine NT disorders patients and 16 healthy controls (HCs) were enrolled. Objective measurements of repetitive finger tapping were obtained using a motion analysis system. Primary motor cortex (M1) excitability was assessed by recording the input/output (I/O) curve of motor-evoked potentials (MEP) and using a conditioning test paradigm for short-interval intracortical inhibition (SICI) assessment. M1 plasticity-like mechanisms were indexed according to MEPs amplitude changes after the paired associative stimulation protocol. Patient values were considered abnormal if they were greater or lower than two standard deviations from the average HCs value. Patients with aromatic amino acid decarboxylase, tyrosine hydroxylase, and 6-pyruvoyl-tetrahydropterin synthase defects showed markedly reduced velocity (5/5 patients), reduced movement amplitude, and irregular rhythm (4/5 patients). Conversely, only 1 out of 3 patients with autosomal-dominant GTPCH deficiency showed abnormal movement parameters. Interestingly, none of the patients had a progressive reduction in movement amplitude or velocity during the tapping sequence (no sequence effect). Reduced SICI was the most prominent neurophysiological abnormality in patients (5/9 patients). Finally, the I/O curve slope correlated with movement velocity and rhythm in patients. We provided an objective assessment of finger tapping abnormalities in monoamine NT disorders. We also demonstrated M1 excitability changes possibly related to alterations in motor execution. Our results may contribute to a better understanding of the pathophysiology of juvenile parkinsonism due to dopamine deficiency.

Safety of Special Waveform of Transcranial Electrical Stimulation (TES): In Vivo Assessment.

Intermittent theta burst (iTBS) powered by direct current stimulation (DCS) can safely be applied transcranially to induce neuroplasticity in the human and animal brain cortex. tDCS-iTBS is a special waveform that is used by very few studies, and its safety needs to be confirmed. Therefore, we aimed to evaluate the safety of tDCS-iTBS in an animal model after brain stimulations for 1 h and 4 weeks. Thirty-one Sprague Dawley rats were divided into two groups: (1) short-term stimulation for 1 h/session (sham, low, and high) and (2) long-term for 30 min, 3 sessions/week for 4 weeks (sham and high). The anodal stimulation applied over the primary motor cortex ranged from 2.5 to 4.5 mA/cm2. The brain biomarkers and scalp tissues were assessed using ELISA and histological analysis (H&E staining) after stimulations. The caspase-3 activity, cortical myelin basic protein (MBP) expression, and cortical interleukin (IL-6) levels increased slightly in both groups compared to sham. The serum MBP, cortical neuron-specific enolase (NSE), and serum IL-6 slightly changed from sham after stimulations. There was no obvious edema or cell necrosis seen in cortical histology after the intervention. The short- and long-term stimulations did not induce significant adverse effects on brain and scalp tissues upon assessing biomarkers and conducting histological analysis.

[Contribution of central motion conduction time to the assessment of corticospinal tract lesions and its clinical significance].

Objective: To investigate the association of central motion conduction time (CMCT) with corticospinal tract lesions and its clinical application. Methods: Patients who completed transcranial magnetic stimulation-motor evoked potentials were included from Department of Neurology, Xuanwu Hospital between June 2020 and June 2021. The differences of CMCT values between corticospinal tract sign-positive group and tendon reflex-positive group and the relevant negative groups were compared. The consistency between increased CMCT values and the positive signs of corticospinal tract damage, as well as the significance of CMCT in different neurological diseases were further evaluated. Results: A total of 271 patients were included in the study, aged 12-86 (49±16) years, with 137 males (50.55%) and 134 females (49.45%). The CMCT valuesï¼»M（Q1，Q3）］from Hoffmann's sign-positive group [9.52 (8.54, 10.99) ms vs 9.03 (8.30, 9.53) ms], Babinski's sign-positive group [19.54 (16.97, 24.43) ms vs 16.85(15.63, 18.55) ms] and tendon reflex-positive group [15.38 (9.27, 19.28) ms vs 10.49(8.79, 16.60) ms] were larger than those of relevant negative groups (all P<0.01). In the Babinski sign-positive group, 78.01%(181/232) of the patients had increased CMCT, while in the Hoffmann's sign-positive group, only 26.03%(19/73) of the patients had increased CMCT, indicating that the contribution of CMCT from the lower extremities to the assessment of corticospinal tract lesions was better than that of the upper extremities. With the increase of CMCT values in lower limbs, Babinski sign positive rate increased, the difference was statistically significant(P<0.001). In nervous system diseases, the consistency between CMCT and pathological signs was 75.65% (205/271). Conclusions: The contribution of CMCT from the lower extremities to the assessment of corticospinal tract lesions is superior to that of upper limbs. The higher increase of CMCT values are more reliable for corticospinal tract damage. CMCT has a good concordance with corticospinal tract lesions in some neurological diseases, which can be used to assist clinical diagnosis.

A TMS/EEG protocol for the causal assessment of the functions of the oscillatory brain rhythms in perceptual and cognitive processes.

The combined use of transcranial magnetic stimulation (TMS), electroencephalogram (EEG), and behavioral performance allows investigation of causal relationships between neural markers and their functional relevance across a number of perceptual and cognitive processes. Here, we present a protocol for combining and applying these techniques on human subjects. We describe correlation approach and causal approach to disentangle the role of different oscillatory parameters, namely alpha frequency and amplitude that control for accuracy and metacognitive abilities, respectively, in a visual detection task. For complete details on the use and execution of this protocol, please refer to Di Gregorio et al. (2022).

Assessment of cortical inhibition depends on inter individual differences in the excitatory neural populations activated by transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is used to probe inhibitory intracortical neurotransmission and has been used to infer the neurobiological dysfunction that may underly several neurological disorders. One technique, short-interval intracortical inhibition (SICI), indexes gamma-aminobutyric acid (GABA) mediated inhibitory activity and is a promising biomarker. However emerging evidence suggests SICI does not exclusively represent GABAergic activity because it may be influenced by inter-individual differences in the specific excitatory neural populations activated by TMS. Here we used the latency of TMS motor evoked potentials (MEPs) to index these inter-individual differences, and found that a significant proportion of the observed variability in SICI magnitude was accounted for by MEP latency, r = - 0.57, r2 = 0.33, p = .014. We conclude that SICI is influenced by inter-individual differences in the excitatory neural populations activated by TMS, reducing the precision of this GABAergic probe. Interpreting SICI measures in the context of MEP latency may facilitate a more precise assessment of GABAergic intracortical inhibition. The reduced cortical inhibition observed in some neuropathologies could be influenced by reduced activity in specific excitatory neural populations. Including MEP latency assessment in research investigating SICI in clinical groups could assist in differentiating the cortical circuits impacted by neurological disorders.

Assessment of Noninvasive Brain Stimulation Interventions for Negative Symptoms of Schizophrenia: A Systematic Review and Network Meta-analysis.

Importance: Negative symptoms have a detrimental impact on functional outcomes and quality of life in people with schizophrenia, and few therapeutic options are considered effective for this symptomatic dimension. Studies have suggested that noninvasive brain stimulation (NIBS) interventions may be effective in treating negative symptoms. However, the comparative efficacy of different NIBS protocols for relieving negative symptoms remains unclear. Objective: To compare the efficacy and acceptability of different NIBS interventions for treating negative symptoms. Data Sources: The ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, ClinicalTrials.gov, and Web of Science electronic databases were systematically searched from inception through December 7, 2021. Study Selection: A frequentist model network meta-analysis was conducted to assess the pooled findings of trials that evaluated the efficacy of repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation, transcranial random noise stimulation, transcutaneous vagus nerve stimulation, and transcranial direct current stimulation on negative symptoms in schizophrenia. Randomized clinical trials (RCTs) examining NIBS interventions for participants with schizophrenia were included. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were independently extracted by multiple observers. The pair-wise meta-analytic procedures were conducted using a random-effects model. Main Outcomes and Measures: The coprimary outcomes were changes in the severity of negative symptoms and acceptability (ie, dropout rates owing to any reason). Secondary outcomes were changes in positive and depressive symptoms. Results: Forty-eight RCTs involving 2211 participants (mean [range] age, 38.7 [24.0-57.0] years; mean [range] proportion of female patients, 30.6% [0%-70.0%]) were included. Compared with sham control interventions, excitatory NIBS strategies (standardized mean difference [SMD]: high-definition transcranial random noise stimulation, -2.19 [95% CI, -3.36 to -1.02]; intermittent theta-burst stimulation, -1.32 [95% CI, -1.88 to -0.76]; anodal transcranial direct current stimulation, -1.28 [95% CI, -2.55 to -0.02]; high-frequency rTMS, -0.43 [95% CI, -0.68 to -0.18]; extreme high-frequency rTMS, -0.45 [95% CI, -0.79 to -0.12]) over the left dorsolateral prefrontal cortex with or without other inhibitory stimulation protocols in the contralateral regions of the brain were associated with significantly larger reductions in negative symptoms. Acceptability did not significantly differ between the groups. Conclusions and Relevance: In this network meta-analysis, excitatory NIBS protocols over the left dorsolateral prefrontal cortex were associated with significantly large improvements in the severity of negative symptoms. Because relatively few studies were available for inclusion, additional well-designed, large-scale RCTs are warranted.

Repetitive transcranial magnetic stimulation may be a cost-effective alternative to antidepressant therapy after two treatment failures in patients with major depressive disorder.

BACKGROUND: The cost-effectiveness of treatment strategies for patients with Major Depressive Disorder (MDD) who have not responded to two adequate treatments with antidepressants (TRD) are still unclear. The aim of this analysis was to evaluate the cost-effectiveness of add-on repetitive Transcranial Magnetic Stimulation (rTMS) compared with standard treatment. METHODS: A Markov-model simulated clinical events over one year from the perspective of healthcare payer. Third- and fourth-line treatment pathways (augmentation, antidepressant switch or combination, and Electro-Convulsive Therapy (ECT)) were defined based on medical practice guidelines. Transition probabilities were derived from a recent meta-analysis and scientific publications. Resource utilization and cost estimates were based on the patient-level database of a large university hospital. RESULTS: Incremental Quality-Adjusted Life Years (QALYs) and costs were 0.053 and 785 €, respectively, corresponding to an Incremental Cost-Effectiveness Ratio (ICER) of 14,670 € per QALY. The difference in cost between standard treatment and rTMS is explained by the rTMS sessions used in acute (€660) and maintenance (€57/month) treatments, partly offset by lower hospital costs due to higher remission rates in the rTMS arm. Key parameters driving the ICER were incremental utility of remission, unit cost of rTMS treatment and remission rate. At a threshold of €22,243 add-on rTMS is a cost-effective alternative to pharmacotherapy. Evidence on long-term effectiveness is not yet available, so results are estimated for a one-year period. CONCLUSION: Not only does rTMS treatment have beneficial clinical effects compared with drug therapy in TRD, but it also appears to offer good value-for-money, especially in centres with larger numbers of patients where unit costs can be kept low.