The causal involvement of the visual cortex in visual working memory remains uncertain.

The role of the early visual cortex in visual working memory (VWM) is a matter of current debate. Neuroimaging studies have consistently shown that visual areas encode the content of working memory, while transcranial magnetic stimulation (TMS) studies have presented incongruent results. Thus, we lack conclusive evidence supporting the causal role of early visual areas in VWM. In a recent registered report, Phylactou et al. (Phylactou P, Shimi A, Konstantinou N 2023 R. Soc. Open Sci. 10, 230321 (doi:10.1098/rsos.230321)) sought to tackle this controversy via two well-powered TMS experiments, designed to correct possible methodological issues of previous attempts identified in a preceding systematic review and meta-analysis (Phylactou P, Traikapi A, Papadatou-Pastou M, Konstantinou N 2022 Psychon. Bull. Rev. 29, 1594-1624 (doi:10.3758/s13423-022-02107-y)). However, a key part of their critique and experimental design was based on a misunderstanding of the visual system. They disregarded two important anatomical facts, namely that early visual areas of each hemisphere represent the contralateral visual hemifield, and that each hemisphere receives equally strong input from each eye-both leading to confounded conditions and artefactual effects in their studies. Here, we explain the correct anatomy, describe why their experiments failed to address current issues in the literature and perform a thorough reanalysis of their TMS data revealing important null results. We conclude that the causal role of the visual cortex in VWM remains uncertain.

How Conductivity Boundaries Influence the Electric Field Induced by Transcranial Magnetic Stimulation in in vitro Experiments.

BACKGROUND: Although transcranial magnetic stimulation (TMS) has become a valuable method for non-invasive brain stimulation, the cellular basis of TMS activation of neurons is still not fully understood. In vitro preparations have been used to understand the biophysical mechanisms of TMS, but in many cases these studies have encountered substantial difficulties in activating neurons. OBJECTIVE/HYPOTHESIS: The hypothesis of this work is that conductivity boundaries can have large effects on the electric field in commonly used in vitro preparations. Our goal was to analyze the resulting difficulties in in vitro TMS using a simulation study, using a charge-based boundary element model. METHODS: We decomposed the total electric field into the sum of the primary electric field, which only depends on coil geometry and current, and the secondary electric field arising from conductivity boundaries, which strongly depends on tissue and chamber geometry. We investigated the effect of the conductivity boundaries on the electric field strength for a variety of in vitro experimental settings to determine the sources of difficulty. RESULTS: We showed that conductivity boundaries can have large effects on the electric field in in vitro preparations. Depending on the geometry of the air-saline and the saline-tissue interfaces, the secondary electric field can significantly enhance, or attenuate the primary electric field, resulting in a much stronger or weaker total electric field inside the tissue; we showed this using a realistic preparation. Submerged chambers are generally much more efficient than interface chambers since the secondary field due to the thin film of saline covering the tissue in the interface chamber opposes the primary field and significantly reduces the total field in the tissue placed in the interface chamber. The relative dimensions of the chamber and the TMS coil critically determine the total field; the popular setup with a large coil and a small chamber is particularly sub-optimal because the secondary field due to the air-chamber boundary opposes the primary field, thereby attenuating the total field. The form factor (length vs width) of the tissue in the direction of the induced field can be important since a relatively narrow tissue enhances the total field at the saline-tissue boundary. CONCLUSIONS: Overall, we found that the total electric field in the tissue is higher in submerged chambers, is higher if the chamber size is larger than the coil and if the shorter tissue dimension is in the direction of the electric field. Decomposing the total field into the primary and secondary fields is useful for designing in vitro experiments and interpreting the results.

Modeling the stress and forces on multi-channel TMS coil arrays in high-field MRI scanners.

Transcranial magnetic stimulation (TMS) is a non-invasive method for stimulating the cortex. Concurrent functional magnetic resonance imaging can show changes in TMS-induced activity in the whole brain, with the potential to inform brain function research and to guide the development of TMS therapy. However, the interaction of the strong current pulses in the TMS coil in the static main magnetic field of the MRI produces high Lorentz forces, which may damage the coil enclosure and compromise the patient's safety. We studied the time-dependent mechanical behavior and durability of two multi-locus TMS (mTMS) coil arrays inside a high-field MRI bore with finite element modeling. In addition, coil arrays were built and tested based on the simulation results. We found that the current pulses produce shock waves and time-dependent stress distribution in the coil plates. The intensity and location of the maximum stress depend on the current waveform, the coil combination, and the transducer orientation relative to the MRI magnetic field. We found that 30% glass-fiber-filled polyamide is the most durable material out of the six options studied. In addition, novel insights for more durable TMS coil designs were obtained. Our study contributes to a comprehensive understanding of the underlying mechanisms responsible for the structural failure of mTMS coil arrays during stimulation within high static magnetic fields. This knowledge is essential for developing mechanically stable and safe mTMS-MRI transducers.

Machine learning approaches to predict whether MEPs can be elicited via TMS.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a valuable technique for assessing the function of the motor cortex and cortico-muscular pathways. TMS activates the motoneurons in the cortex, which after transmission along cortico-muscular pathways can be measured as motor-evoked potentials (MEPs). The position and orientation of the TMS coil and the intensity used to deliver a TMS pulse are considered central TMS setup parameters influencing the presence/absence of MEPs. NEW METHOD: We sought to predict the presence of MEPs from TMS setup parameters using machine learning. We trained different machine learners using either within-subject or between-subject designs. RESULTS: We obtained prediction accuracies of on average 77 % and 65 % with maxima up to up to 90 % and 72 % within and between subjects, respectively. Across the board, a bagging ensemble appeared to be the most suitable approach to predict the presence of MEPs. CONCLUSIONS: Although within a subject the prediction of MEPs via TMS setup parameter-based machine learning might be feasible, the limited accuracy between subjects suggests that the transfer of this approach to experimental or clinical research comes with significant challenges.

Elevated allostatic load is associated with poorer response to repetitive transcranial magnetic stimulation in treatment-resistant depression.

This cohort study investigated whether allostatic load (AL) is associated with treatment response to repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD). Pre-treatment blood samples measured AL across multiple systems. Pre- and post-treatment mood changes were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Associations between AL and treatment outcomes were explored. Higher pre-treatment AL was significantly associated with poorer post-treatment response status but was not significantly associated with smaller reduction in MADRS score after 4 weeks of treatment. Identifying biomarker profiles informed by the AL model could enhance treatment decisions in TRD, reducing risks associated with prolonged, ineffective rTMS trials and emphasizing the need for reliable predictive biomarkers.

A computational model elucidating mechanisms and variability in theta burst stimulation responses.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (rTMS) with unknown underlying mechanisms and highly variable responses across subjects. To investigate these issues, we developed a simple computational model. Our model consisted of two neurons linked by an excitatory synapse that incorporates two mechanisms: short-term plasticity (STP) and spike-timing-dependent plasticity (STDP). We applied a variable-amplitude current through I-clamp with a TBS time pattern to the pre- and post-synaptic neurons, simulating synaptic plasticity. We analyzed the results and provided an explanation for the effects of TBS, as well as the variability of responses to it. Our findings suggest that the interplay of STP and STDP mechanisms determines the direction of plasticity, which selectively affects synapses in extended neurons and underlies functional effects. Our model describes how the timing, number, and intensity of pulses delivered to neurons during rTMS contribute to induced plasticity. This not only successfully explains the different effects of intermittent TBS (iTBS) and continuous TBS (cTBS), but also predicts the results of other protocols such as 10 Hz rTMS. We propose that the variability in responses to TBS can be attributed to the variable span of neuronal thresholds across individuals and sessions. Our model suggests a biologically plausible mechanism for the diverse responses to TBS protocols and aligns with experimental data on iTBS and cTBS outcomes. This model could potentially aid in improving TBS and rTMS protocols and customizing treatments for patients, brain areas, and brain disorders.

Hebbian plasticity induced by temporally coincident BCI enhances post-stroke motor recovery.

Functional electrical stimulation (FES) can support functional restoration of a paretic limb post-stroke. Hebbian plasticity depends on temporally coinciding pre- and post-synaptic activity. A tight temporal relationship between motor cortical (MC) activity associated with attempted movement and FES-generated visuo-proprioceptive feedback is hypothesized to enhance motor recovery. Using a brain-computer interface (BCI) to classify MC spectral power in electroencephalographic (EEG) signals to trigger FES-delivery with detection of movement attempts improved motor outcomes in chronic stroke patients. We hypothesized that heightened neural plasticity earlier post-stroke would further enhance corticomuscular functional connectivity and motor recovery. We compared subcortical non-dominant hemisphere stroke patients in BCI-FES and Random-FES (FES temporally independent of MC movement attempt detection) groups. The primary outcome measure was the Fugl-Meyer Assessment, Upper Extremity (FMA-UE). We recorded high-density EEG and transcranial magnetic stimulation-induced motor evoked potentials before and after treatment. The BCI group showed greater: FMA-UE improvement; motor evoked potential amplitude; beta oscillatory power and long-range temporal correlation reduction over contralateral MC; and corticomuscular coherence with contralateral MC. These changes are consistent with enhanced post-stroke motor improvement when movement is synchronized with MC activity reflecting attempted movement.

Investigating the Effects of Repetitive Paired-Pulse Transcranial Magnetic Stimulation on Visuomotor Training Using TMS-EEG.

I-wave periodicity repetitive paired-pulse transcranial magnetic stimulation (iTMS) can modify acquisition of a novel motor skill, but the associated neurophysiological effects remain unclear. The current study therefore used combined TMS-electroencephalography (TMS-EEG) to investigate the neurophysiological effects of iTMS on subsequent visuomotor training (VT). Sixteen young adults (26.1 ± 5.1 years) participated in three sessions including real iTMS and VT (iTMS + VT), control iTMS and VT (iTMSControl + VT), or iTMS alone. Motor-evoked potentials (MEPs) and TMS-evoked potentials (TEPs) were measured before and after iTMS, and again after VT, to assess neuroplastic changes. Irrespective of the intervention, MEP amplitude was not changed after iTMS or VT. Motor skill was improved compared with baseline, but no differences were found between stimulus conditions. In contrast, the P30 peak was altered by VT when preceded by control iTMS (P < 0.05), but this effect was not apparent when VT was preceded by iTMS or following iTMS alone (all P > 0.15). In contrast to expectations, iTMS was unable to modulate MEP amplitude or influence motor learning. Despite this, changes in P30 amplitude suggested that motor learning was associated with altered cortical reactivity. Furthermore, this effect was abolished by priming with iTMS, suggesting an influence of priming that failed to impact learning.

Water and Brain Function - Effects of Hydration Status on Neurostimulation with Transcranial Magnetic Stimulation.

INTRODUCTION: Neurostimulation/neurorecording are tools to study, diagnose, and treat neurologic/psychiatric conditions. Both techniques depend on volume conduction between scalp and excitable brain tissue. We examine how neurostimulation with TMS is affected by hydration status, a physiologic variable which can influence the volume of fluid spaces/cells, excitability and cellular/global brain functioning. Compared to dehydration, we expected rehydration to show signs of macroscopic and microscopic volume changes including decreased scalp-cortex distance (brain closer to stimulator) and astrocyte swelling-induced glutamate release. METHODS: Normal healthy adult participants (32, 9 male) had common motor TMS measures taken in a repeated measures design from dehydrated (12-hour overnight fast/thirst) and rehydrated (identical dehydration protocol followed by rehydration with 1 L water in 1 hour) testing days. The target region was left primary motor cortex hand area. Response at the target muscle was recorded with electromyography. Urinalysis confirmed hydration status. RESULTS: Motor hotspot shifted in half of participants. Motor threshold decreased in rehydration, indicating increased excitability. Even after re-dosing/re-localizing TMS to the new threshold/hotspot, rehydration still showed evidence of increased excitability: recruitment curve measures generally shifted upwards and SICF was increased. SICI, LICI, LICF, and CSP were relatively unaffected. The hydration perturbations were mild/subclinical, based on the magnitude/speed and urinalysis. DISCUSSION: Motor TMS measures showed evidence of expected physiologic changes of osmotic challenges. Hydration may be a source of variability affecting techniques dependant on brain volumes/volume conduction. These concepts are important for researchers/clinicians using such techniques or dealing with the wide variety of disease processes involving water balance.

Local neuronal sleep after stroke: The role of cortical bistability in brain reorganization.

BACKGROUND: Acute cerebral ischemia triggers a number of cellular mechanisms not only leading to excitotoxic cell death but also to enhanced neuroplasticity, facilitating neuronal reorganization and functional recovery. OBJECTIVE: Transferring these cellular mechanisms to neurophysiological correlates adaptable to patients is crucial to promote recovery post-stroke. The combination of TMS and EEG constitutes a promising readout of neuronal network activity in stroke patients. METHODS: We used the combination of TMS and EEG to investigate the development of local signal processing and global network alterations in 40 stroke patients with motor deficits alongside neural reorganization from the acute to the chronic phase. RESULTS: We show that the TMS-EEG response reflects information about reorganization and signal alterations associated with persistent motor deficits throughout the entire post-stroke period. In the early post-stroke phase and in a subgroup of patients with severe motor deficits, TMS applied to the lesioned motor cortex evoked a sleep-like slow wave response associated with a cortical off-period, a manifestation of cortical bistability, as well as a rapid disruption of the TMS-induced formation of causal network effects. Mechanistically, these phenomena were linked to lesions affecting ascending activating brainstem fibers. Of note, slow waves invariably vanished in the chronic phase, but were highly indicative of a poor functional outcome. CONCLUSION: In summary, we found evidence that transient effects of sleep-like slow waves and cortical bistability within ipsilesional M1 resulting in excessive inhibition may interfere with functional reorganization, leading to a less favorable functional outcome post-stroke, pointing to a new therapeutic target to improve recovery of function.

Neurophysiological effects of acute aerobic exercise in young adults: a systematic review and meta-analysis.

Evidence continues to accumulate that acute aerobic exercise (AAE) impacts neurophysiological excitability as measured by transcranial magnetic stimulation (TMS). Yet, uncertainty exists about which TMS measures are modulated after AAE in young adults. The influence of AAE intensity and duration of effects are also uncertain. This pre-registered meta-analysis (CRD42017065673) addressed these uncertainties by synthesizing data from 23 studies (including 474 participants) published until February 2024. Meta-analysis was run using a random-effects model and Hedge's g used as effect size. Our results demonstrated a decrease in short-interval intracortical inhibition (SICI) following AAE (g = 0.27; 95 % CI [0.16-0.38]; p <.0001), particularly for moderate (g = 0.18; 95 % CI [0.05-0.31]; p <.01) and high (g = 0.49; 95 % CI [0.27-0.71]; p <.0001) AAE intensities. These effects remained for 30 minutes after AAE. Additionally, increased corticospinal excitability was only observed for high intensity AAE (g = 0.28; 95 % CI, [0.07-0.48]; p <.01). Our results suggest potential mechanisms for inducing a more susceptible neuroplastic environment following AAE.

The Impact of Obesity as a Peripheral Disruptor of Brain Inhibitory Mechanisms in Fibromyalgia: A Cross-Sectional Study.

Background/Objective: Obesity, characterized by chronic inflammation, may serve as a surrogate marker for more dysfunctional peripheral inflammation, potentially exacerbating FM symptomatology. Given this premise, this study aimed to investigate the effects of obesity as an effect modifier on neural and clinical variables, specifically those indexing pain-compensatory mechanisms in FM symptoms. Methods: A cross-sectional study was conducted with 108 participants who underwent a standardized TMS protocol assessment to measure resting motor threshold (MT), intracortical facilitation (ICF), and intracortical inhibition (ICI). Clinical data were collected using Beck's Depression Index (BDI), PROMIS, the Brief Pain Inventory (BPI), and conditioned pain modulation (CPM). Linear regression models were used to explore the relationship between these variables while examining Body Mass Index (BMI) as a potential effect modifier. If it was found to be a modifier, we stratified the sample into two groups with a BMI cutoff of 30 and performed another regression model within the subgroups. Results: BMI was identified as an effect modifier in the relationships between ICI and BDI, PROMIS fatigue, and CPM and in MT versus CPM. After stratification, non-obese fibromyalgia subjects demonstrated significant correlations between clinical symptoms and CPM and ICI activity. However, these correlations were absent in the obese group, suggesting obesity disrupts pain mechanisms and their compensatory effects. Higher MT values were associated with weaker endogenous pain control, particularly evident in the obese group. Conclusions: Obesity appears to be a significant effect modifier and delineates two patient groups across multiple clinical and neural assessments of fibromyalgia. Additionally, it suggests a role for obesity in exacerbating fibromyalgia symptoms and disrupting physiological pain-inhibitory mechanisms.

The mechanism of Sangdantongluo granule in treating post-stroke spasticity based on multimodal fMRI combined with TMS: Study protocol.

Introduction: Post-stroke spasticity (PSS) is among the prevalent complications of stroke, greatly affecting motor function recovery and reducing patients' quality of life without timely treatment. Sangdantongluo granule, a modern traditional Chinese patent medicine, has significant clinical efficacy in treating PSS. However, the mechanism of Sangdantongluo granule in treating PSS is still unknown. We designed this study to explore the mechanism of Sangdantongluo granule in treating PSS through multimodal functional magnetic resonance imaging (fMRI) combined with transcranial magnetic stimulation (TMS). Methods and analysis: In a single-center, randomized, double-blind, parallel placebo-controlled study, 60 PSS patients will be recruited in China and randomly assigned to either the experimental or control groups at a ratio of 1:1. For eight weeks, Sangdantongluo granule or placebo will be utilized for intervention. The main outcome is the Modified Ashworth Scale (MAS), the secondary outcome includes the Fugl-Meyer Assessment Scale-upper Extremity (FMA-UE), National Institute of Health Stroke Scale (NIHSS), and Modified Rankin Scale (mRS), the mechanism measure is the changes in cortical excitability and multimodal fMRI at baseline and after eight weeks. Ethics and dissemination: This study was approved by the Ethics Committee of the Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine (approval number: [202364]). Clinical trial registration: Chinese Clinical Trial Registry, identifier: ChiCTR2300074793. Registered on 16 August 2023.

A neural signature for brain compensation in stroke with EEG and TMS: Insights from the DEFINE cohort study.

OBJECTIVE: This study aimed to explore the relationships between potential neurophysiological biomarkers and upper limb motor function recovery in stroke patients, specifically focusing on combining two neurophysiological markers: electroencephalography (EEG) and transcranial magnetic stimulation (TMS). METHODS: This cross-sectional study analyzed neurophysiological, clinical, and demographical data from 102 stroke patients from the DEFINE cohort. We searched for correlations of EEG and TMS measurements combined to build a prediction model for upper limb motor functionality, assessed by five outcomes, across five assessments: Fugl-Meyer Assessment (FMA), Handgrip Strength Test (HST), Finger Tapping Test (FTT), Nine-Hole Peg Test (9HPT), and Pinch Strength Test (PST). RESULTS: Our multivariate models agreed on a specific neural signature: higher EEG Theta/Alpha ratio in the frontal region of the lesioned hemisphere is associated with poorer motor outcomes, while increased MEP amplitude in the non-lesioned hemisphere correlates with improved motor function. These relationships are held across all five motor assessments, suggesting the potential of these neurophysiological measures as recovery biomarkers. CONCLUSION: Our findings indicate a potential neural signature of brain compensation in which lower frequencies of EEG power are increased in the lesioned hemisphere, and lower corticospinal excitability is also increased in the non-lesioned hemisphere. We discuss the meaning of these findings in the context of motor recovery in stroke.

Densely sampled stimulus-response map of human cortex with single pulse TMS-EEG and its relation to whole brain neuroimaging measures.

Large-scale networks underpin brain functions. How such networks respond to focal stimulation can help decipher complex brain processes and optimize brain stimulation treatments. To map such stimulation-response patterns across the brain non-invasively, we recorded concurrent EEG responses from single-pulse transcranial magnetic stimulation (i.e., TMS-EEG) from over 100 cortical regions with two orthogonal coil orientations from one densely-sampled individual. We also acquired Human Connectome Project (HCP)-styled diffusion imaging scans (six), resting-state functional Magnetic Resonance Imaging (fMRI) scans (120 mins), resting-state EEG scans (108 mins), and structural MR scans (T1- and T2-weighted). Using the TMS-EEG data, we applied network science-based community detection to reveal insights about the brain's causal-functional organization from both a stimulation and recording perspective. We also computed structural and functional maps and the electric field of each TMS stimulation condition. Altogether, we hope the release of this densely sampled (n=1) dataset will be a uniquely valuable resource for both basic and clinical neuroscience research.

Theta-burst stimulation over primary somatosensory cortex modulates tactile acuity of tongue.

Background: Emerging studies in humans have established the modulatory effects of repetitive transcranial magnetic stimulation (rTMS) over primary somatosensory cortex (S1) on somatosensory cortex activity and perception. However, to date, research in this area has primarily focused on the hand and fingers, leaving a gap in our understanding of the modulatory effects of rTMS on somatosensory perception of the orofacial system and speech articulators. Objective: The present study aimed to examine the effects of different types of theta-burst stimulation-continuous TBS (cTBS), intermittent TBS (iTBS), or sham-over the tongue representation of left S1 on tactile acuity of the tongue. Methods: In a repeated-measures design, fifteen volunteers participated in four separate sessions, where cTBS, iTBS, sham, or no stimulation was applied over the tongue representation of left S1. Effects of TBS were measured on both temporal and spatial perceptual acuity of tongue using a custom vibrotactile stimulator. Results: CTBS significantly impaired spatial amplitude threshold at the time window of 16-30 minutes after stimulation, while iTBS improved it at the same time window. The effect of iTBS, however, was smaller than cTBS. In contrast, neither cTBS nor iTBS had any effect on the temporal discrimination threshold. Conclusions: The current study establishes the validity of using TBS to modulate somatosensory perception of the orofacial system. Directly modifying somatosensation in the orofacial system has the potential to benefit clinical populations with abnormal tactile acuity, improve our understanding of the role of sensory systems in speech production, and enhance speech motor learning and rehabilitation.

Insight into motor fatigue mechanisms in natalizumab treated multiple sclerosis patients with wearing off.

Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence ('wearing-off') before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab's effect on MS-related fatigue. Forty-five relapsing-remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Prefrontal oscillatory slowing in early-course schizophrenia is associated with worse cognitive performance and negative symptoms: a TMS-EEG study.

BACKGROUND: Abnormalities in dorsolateral prefrontal cortex (DLPFC) oscillations are neurophysiological signatures of schizophrenia thought to underlie its cognitive deficits. Transcranial magnetic stimulation with electroencephalography (TMS-EEG) provides a measure of cortical oscillations unaffected by sensory relay functionality and/or patients' level of engagement, which are important confounding factors in schizophrenia. Previous TMS-EEG work showed reduced fast, gamma-range oscillations and a slowing of the main DLPFC oscillatory frequency, or natural frequency, in chronic schizophrenia. However, it is unclear whether this DLPFC natural frequency slowing is present in early-course schizophrenia (EC-SCZ) and is associated with symptom severity and cognitive dysfunction. METHODS: We applied TMS-EEG to the left DLPFC in 30 EC-SCZ and 28 healthy control (HC) subjects. Goal-directed working memory performance was assessed using the "AX" Continuous Performance Task (AX-CPT). The EEG frequency with the highest cumulative power at the stimulation site, or natural frequency, was extracted. We also calculated the local Relative Spectral Power (RSP) as the average power in each frequency band divided by the broadband power. RESULTS: Compared to HC, EC-SCZ had reduced DLPFC natural frequency (p=0.0000002, Cohen's d=-2.32) and higher DLPFC beta-range RSP (p=0.0003, Cohen's d=0.77). In EC-SCZ, the DLPFC natural frequency was inversely associated with negative symptoms. Across all participants, the beta-band RSP negatively correlated with the AX-CPT performance. CONCLUSIONS: A DLPFC oscillatory slowing is an early pathophysiological biomarker of schizophrenia that is associated with its symptom severity and cognitive impairments. Future work should assess whether non-invasive neurostimulation can ameliorate prefrontal oscillatory deficits and related clinical functions in EC-SCZ.

N100 as a response prediction biomarker for accelerated 1 Hz right DLPFC-rTMS in major depression.

BACKGROUND AND OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective treatment for major depressive disorder (MDD); however, this treatment currently lacks reliable biomarkers of treatment response. TMS-evoked potentials (TEPs), measured using TMS-electroencephalography (TMS-EEG), have been suggested as potential biomarker candidates, with the N100 peak being one of the most promising. This study investigated the association between baseline N100 amplitude and 1 Hz right dorsolateral prefrontal cortex (R-DLPFC) accelerated rTMS (arTMS) treatment in MDD. METHODS: Baseline TMS-EEG sessions were performed for 23 MDD patients. All patients then underwent 40 sessions of 1 Hz R-DLPFC (F4) arTMS over 5 days and a follow-up TMS-EEG session one week after the end of theses arTMS sessions. RESULTS: Baseline N100 amplitude at F4 showed a strong positive association (p < .001) with treatment outcome. The association between the change in N100 amplitude (baseline to follow-up) and treatment outcome did not remain significant after Bonferroni correction (p = .06, corrected; p = .03, uncorrected). Furthermore, treatment responders had a significantly larger mean baseline F4 TEP amplitude during the N100 time frame compared to non-responders (p < .001). Topographically, after Bonferroni correction, F4 is the only electrode at which its baseline N100 amplitude showed a significant positive association (p < .001) with treatment outcome. LIMITATIONS: Lack of control group and auditory masking. CONCLUSION: Baseline N100 amplitude showed a strong association with treatment outcome and thus demonstrated great potential to be utilized as a cost-effective and widely adoptable biomarker of rTMS treatment in MDD.