Brain Stimulation

BackgroundTranscranial magnetic stimulation (TMS) can entrain oscillatory brain activity, offering a promising approach to study motor-related neural oscillations such as beta rhythms. However, how TMS-induced corticospinal oscillations are generated, propagated, and related to endogenous activity remains unclear, partly due to limitations in brain recording techniques. Recording muscle activity provides an alternative and physiologically grounded window into corticospinal dynamics. MethodsWe investigated whether subthreshold TMS over the motor cortex induces corticospinal oscillatory activity detectable in muscles, and whether these responses share neural generators with endogenous beta rhythms. Single-pulse subthreshold TMS was applied over the motor cortex in healthy participants while electromyography (EMG) was recorded from tonically active muscles. Stimulation intensity, coil orientation, and stimulation site were systematically varied. Concurrent electroencephalography (EEG) was used to assess cortical responses and corticomuscular transmission. In additional experiments, advanced EMG techniques were employed to track motor neuron pools and characterize how TMS-evoked oscillations are transmitted at the motor unit level. ResultsTMS elicited a robust and short-latency increase in beta-band activity in the EMG. The analysis of the elicited muscle responses and the comparison of results across different TMS configurations indicate that the beta responses resulted from activation of inhibitory interneurons in the targeted primary motor cortex. Importantly, the characteristics of cortico-muscular coherence and beta projection to the muscles indicate that the elicited beta responses with TMS have same cortical sources as endogenously generated beta activity. ConclusionsThese findings demonstrate that muscle recordings provide a sensitive and physiologically meaningful readout of TMS-induced corticospinal beta oscillations.

ObjectiveMany deep brain stimulation (DBS) systems sense local field potentials (LFPs) for patient monitoring or closed-loop therapy (CL-DBS). LFPs can be impacted by artifacts, including a recently discovered cardiac non-electrocardiographic pulse signal that can be visually masked by commercial device filters. We aimed to establish its prevalence across patient groups and brain areas, and to investigate its spectral impact. MethodsWe performed a cross-sectional analysis of LFPs recorded from the cranially mounted Picostim from the pedunculopontine nucleus in multiple systems atrophy patients, periacqueductal gray and sensory thalamus in chronic pain patients, and the centromedian thalamic nucleus (CMT) in paediatric epilepsy patients. For comparison, we analyse externalised recordings from the subthalamic nucleus in Parkinsons disease patients. The PulsAr algorithm was developed to detect and extract pulsatile signals, and we characterised contamination level and spectral content. ResultsThough not visually obvious in CMT, the pulsatile signal was algorithmically detected in all targets, with 33% of LFPs across targets classed as contaminated. Pulse signal power was similar across targets and may have been masked by higher endogenous activity in CMT. While its dominant frequencies were in the heartbeat range, the signal had spectral content extending up to >10Hz. ConclusionsA heart pulse signal affects LFP recordings from DBS leads across brain regions and patient groups. While masked by some device filters, spectral content can extend into higher (clinically relevant) frequencies. Researchers and clinicians should exercise caution when sensing lower LFP frequencies, especially for automated control of therapy in CL-DBS. HighlightsO_LIHistorically, electrocardiographic artifacts have been a major source of artifact affecting deep brain stimulation recordings, however pulsatile artifact is less well described. C_LIO_LIA cardiac pulse signal affects local field potentials recorded from deep brain stimulation electrodes across clinical targets. C_LIO_LIWe introduce an ECG-independent algorithm that detects and extracts this pulsatile signal. C_LIO_LIThe heart pulse signal looks like the intracranial pressure waveform and affects spectral frequencies above the heart rate range up to >10Hz. C_LIO_LIClinicians should incorporate screening and procedures to ensure accurate biomarker detection for clinical decision making. C_LI

Neural excitability fluctuates with sensory events, creating windows of opportunity to enhance brain stimulation. Repetitive transcranial magnetic stimulation (TMS), including intermittent theta burst stimulation (iTBS), is a promising treatment for neurological and psychiatric disorders, but does not account for fluctuations in neural excitability, likely contributing to variable outcomes. Sensory Entrained TMS (seTMS) leverages sensorimotor oscillations to enhance corticospinal responses, but the sustained effects as a repetitive protocol are unknown. We extend seTMS to iTBS, measuring motor-evoked potentials (MEPs) as a physiological readout. In a randomized crossover study comparing standard iTBS with sensory entrained iTBS (se-iTBS; n=20), we found that se-iTBS more than doubled the MEP effect (55% vs 26% MEP enhancement) and persisted for at least 30 minutes. Notably, at least 80% of participants showed larger responses with se-iTBS at all time points. se-iTBS may provide a robust and practical framework for optimizing TMS that bridges electrophysiological mechanisms and clinical applications.

Transcranial focused ultrasound (tFUS) can noninvasively modulate sensory pathways, but the cell-type-specific mechanisms underlying excitatory or inhibitory effects remain unclear. Here, we investigate how tFUS applied to the somatosensory cortex (S1) influences S1 and posterior medial thalamic nucleus (POm) responses to hind paw vibration-tactile stimulation and which neuronal populations mediate these effects. Vibration-tactile stimulation evoked potentials (TEPs) and multi-unit activities (MUA) in S1 and POm were recorded from male rats. Optogenetic tagging was used to identify S1 CaMKII-positive, PV-positive, and SST-positive neurons, while waveform features were used to classify putative excitatory (i.e., regular-spiking units - RSUs) and inhibitory neurons (i.e., fast-spiking units - FSUs) in POm. We found that only S1 CaMKII-positive neurons and POm RSUs responded robustly to tactile stimulation. When tFUS was applied to S1, high pulse repetition frequency (PRF), high duty cycle, and high-pressure stimulation (etFUS) produced excitatory modulation of the sensory pathway, whereas low PRF, low duty cycle, and low-pressure stimulation (itFUS) induced inhibitory effects. Further analyses revealed that excitatory modulation was mediated by activation of S1 CaMKII-positive neurons, while the inhibitory effect arose from their deactivation. These findings demonstrate that tFUS exerts bidirectional, parameter-dependent modulation of a sensory pathway and highlight the critical role of CaMKII-positive neurons in mediating these effects. This study provides mechanistic insight into cell-type-specific neuromodulation by tFUS, particularly in bidirectional modulation of a sensory pathway, and informs the optimization of stimulation parameters for targeted therapeutic interventions.

ObjectiveComputational models and visualization toolboxes for Deep Brain Stimulation (DBS) increasingly rely on pre-computed electric field libraries to estimate the Volume of Tissue Activated (VTA). However, the boundary conditions (BCs) and source models used to generate these fields vary widely across studies, and there is currently no experimental consensus regarding which parameters most accurately reflect the physical device output. The objective of this study was to experimentally validate the electric potential distribution of directional DBS leads in order to determine the optimal Finite Element Method (FEM) configuration. ApproachThe voltage distribution surrounding a Boston Scientific Vercise Gevia directional lead was mapped in a saline phantom using a custom high-precision robotic scanning system. Experimental measurements were compared against six FEM configurations that varied in source formulation (Dirichlet vs. Neumann boundary conditions) and ground definitions. For each configuration, the resulting VTA volume was computed to assess the clinical impact of modeling assumptions. ResultsThe FEM configuration implementing a Dirichlet (voltage) boundary condition on the active contact with a grounded implantable pulse generator (IPG) surface demonstrated the highest accuracy, achieving a Symmetric Mean Absolute Percent Error (SMAPE) of less than 9% across all contact levels. In contrast, conventional current-controlled simulations employing Neumann boundary conditions with disparate ground definitions substantially overestimated electric field spread. Suboptimal boundary condition selection resulted in an approximate 67% overestimation of VTA volume (137 mm3 vs. 82 mm3) relative to the experimentally validated model. SignificanceAlthough clinical DBS systems operate as current sources, standard Neumann (current density) boundary conditions do not adequately represent the equipotential behavior of the electrode-tissue interface, resulting in nearly a two-fold error in predicted VTA volume. To improve the validity of predictive clinical models, we recommend the use of Dirichlet boundary conditions derived from the device operating impedance (V = Itarget x Zmeasured) rather than conventional current density specifications.

Optimization of deep brain stimulation (DBS) therapy for neurological and neuropsychiatric disorders depends on objective quantitative biomarkers that can guide stimulation parameter adjustments. With the recent introduction of new-generation DBS systems capable of simultaneously stimulating brain activity and recording local field potentials (LFP), there is increasing demand for platforms that enable efficient visualization and analysis of these signals for electrophysiological biomarkers identification. To address the limitations of currently available toolboxes that require advanced signal processing skills and rely on proprietary software, we present NeoDBS, an open-source Python platform designed for ingestion and advance signal visualization and processing of LFP signals from DBS systems through an easy-to-use graphical interface. NeoDBS is a user-centered platform that offers predefined analysis pipelines with the aim of facilitating electrophysiological biomarker investigation for DBS across different brain disorders. Custom analysis pipelines are also available for users to leverage the signal analysis tools to their research needs. Critical functionalities for longitudinal biomarker research are featured in NeoDBS, such as batch file processing and event-locked analysis for in-clinic and at-home recordings. This combination of accessibility, user-experience and advanced signal processing tools makes NeoDBS an environment that propels easy and fast electrophysiological biomarker research for DBS, across patients, sessions, and stimulation parameters.

BackgroundNon-invasive neuromodulation technologies have advanced considerably. Yet, precise and focal activation of deep brain regions remains challenging due to the rapid attenuation of electric fields across the scalp, skull and brain surface. ObjectiveWe present FLOATES (FLOAting Transcranial Electrical Stimulation), a novel approach that employs an untethered wire implanted in the brain which passively relays currents injected transcranially from the brain surface to deep brain regions, achieving focused stimulation deep within the brain. MethodsWe validated FLOATES through a combination of simulations, benchtop testing, and in vivo rodent studies. The benchtop experiments confirmed the ability to relay the field across the floating wire. Rodent studies demonstrated capability to stimulate deep brain regions in vivo. ResultsOur simulation and benchtop testing results indicate that FLOATES can deliver significantly higher electric fields to subcortical regions compared to conventional transcranial stimulation approaches. Further in-vivo results demonstrated deep subthalamic nuclei stimulation to evoke limb motor responses and demonstrated a significantly lower motor threshold compared to transcranial stimulation. Finite element simulations reveal that the efficiency of FLOATES depends on several key parameters including input field strength, wire length and diameter, exposed electrode area, impedance, and tip geometry. Simulations using a human-sized head model suggest that electric fields sufficient for brain stimulation can be obtained with reasonable currents injected to the scalp. ConclusionTogether, these results establish a theoretical and experimental foundation for FLOATES as a minimally invasive and spatially precise brain stimulation platform in modulating deep neural circuits implicated in neuropsychiatric and movement disorders.

ObjectivesDeep brain stimulation (DBS) is an established therapy for neurological disorders such as Parkinsons disease (PD). Modern DBS devices can record local field potentials (LFPs) to guide DBS therapy. LFPs from these devices are typically limited to bipolar configurations to suppress common-mode noise and reject artifacts. However, bipolar recordings also attenuate some local physiological signals. Methods that convert bipolar to monopolar power offer more spatially precise estimates of LFPs. Herein, we develop a model to estimate monopolar power from bipolar recordings. Materials and MethodsThis retrospective study analyzed 64 patients with PD undergoing STN (11) or GPi (53) DBS implantation. Intraoperatively, LFPs were recorded from all contacts and filtered. Bipolar montages were generated for each combination. Power spectral density (PSD) was calculated from each monopolar and bipolar signal, averaged over canonical frequency bands, and processed as log PSD. A common set of bipolar configurations was selected to minimize the Condition Number (CN), maximizing model stability. Monopolar and bipolar powers were related using robust OLS regression. Observations were randomly partitioned into training and validation sets. ResultsSixty-four PD patients yielded 640 observations. The configuration group with the lowest CN (7.45) was {C03, C12, C23}. The models demonstrated adjusted R2s of 0.9015, 0.9055, 0.8853, and 0.8764, and RMSEs (dB) of 3.2663, 3.2801, 3.5815, and 3.7035 when predicting C0, C1, C2, and C3 (N = 500; all p < 0.0001). The STN, GPi, and combined cohorts performed comparably. Weights transferred from the combined model to the validation set retained high performance. ConclusionsThis study demonstrates that monopolar LFP power can be accurately estimated from bipolar power using a linear regression model with strong generalizability across targets and validation sets. This approach offers a hardware-agnostic solution to spatially disambiguate signals and better inform DBS programming and adaptive stimulation in chronically implanted devices.

BackgroundPersonalized optimization of 4x1 high-definition transcranial electrical stimulation (HD-tES) faces inherent trade-offs between montage flexibility, computational efficiency, and implementation accessibility. Conventional 10-10 electrode systems constrain placement to discrete landmark positions, while unconstrained optimization relies on stochastic algorithms that risk converging to local optima and requires neuronavigation equipment often unavailable in rehabilitation settings. Here we introduce a scalp geometry-based parameter space (SGP) that parameterizes 4x1 HD-tES montages using three intuitive scalp-defined parameters--position, radius, and orientation--and characterize parameter-performance regularities through exhaustive electric field simulations across 30 subjects and 624 cortical targets (>3.6 million configurations). ResultsPosition primarily determined proximity to optimal performance, radius governed the intensity-focality trade-off, and orientation served as fine-tuning. Exploiting these regularities, a minimal search space (SGP-MSS) was constructed that reduced computational complexity by over 90% while guaranteeing global optima identification. Compared with standard 10-10 montages, SGP-MSS achieved up to 99% higher targeting intensity and 126% higher focality (all p < 0.0001). Compared with lead-field-free optimization, SGP-MSS achieved comparable performance with greater cross-subject stability. ConclusionsThe SGP framework enables efficient individualized HD-tES optimization without neuronavigation. Its scalp-based parameterization supports electrode positioning via standard cranial landmark measurements, facilitating translation to routine clinical and home-based rehabilitation settings.

IntroductionNoninvasive brain stimulation can help clarify the neural basis of reward processing and potentially inform treatments for disorders involving reward dysfunction. However, widely used methods such as transcranial magnetic and electrical stimulation cannot directly stimulate deep-brain regions like the striatum. Here, we tested whether stimulating the ventrolateral prefrontal cortex (VLPFC)--a cortical region strongly connected to the striatum-- could indirectly influence reward-related neural and physiological responses. MethodsIn a within-subjects design, participants performed a card-guessing task involving monetary rewards for correct guesses and punishments for incorrect guesses. During the task, participants underwent functional magnetic resonance imaging (fMRI) and pupillometry while receiving concurrent 10 Hz transcranial alternating current stimulation (-tACS). Stimulation targeted either the VLPFC or a control region (temporoparietal junction). We measured pupil dilation, brain activation (BOLD signal), and functional connectivity between the ventral striatum and dorsal anterior cingulate cortex (VS-dACC). ResultsVLPFC stimulation increased pupil size during reward and punishment outcomes, indicating greater physiological arousal. At the neural level, -tACS enhanced VLPFC activation during reward and suppressed its responses during punishment. Stimulation also changed VS-dACC connectivity in a context-dependent manner. Importantly, stimulation-driven increases in pupil size during reward correlated positively with stimulation-induced changes in VS-dACC connectivity. Exploratory moderated mediation analyses suggested that stimulation influenced the degree to which striatal responses mediated the relationship between task outcomes and pupil size changes. ConclusionsTargeting VLPFC with -tACS modulates local cortical activity and corticostriatal networks during reward processing, providing a promising noninvasive approach to influence reward circuitry. HighlightsO_LI-tACS over VLPFC increases pupil responses to reward and punishment. C_LIO_LIStimulation alters reward-related VLPFC activity without enhancing striatal BOLD. C_LIO_LI-tACS modulates ventral striatum-dACC connectivity in a task-dependent manner. C_LIO_LIConnectivity changes predict pupil dilation, linking brain and autonomic responses. C_LI

BackgroundOscillations underpin a large spectrum of brain function. Brain oscillations are altered by neuromodulation approaches including deep brain stimulation (DBS), but a mechanistic understanding of the brain oscillation - DBS interaction is missing. DBS is predominantly used in the treatment of Parkinsons disease. DBS can induce or alter pre-existing narrow frequency band gamma oscillations at half the stimulation frequency. Such half-harmonic responses have been interpreted as entrainment of endogenous oscillations by an exogenous oscillator with an associated Arnold tongue structure. However, half-harmonic responses are not exhibited by all patients. MethodsHere, a Wilson-Cowan model of subcortical neuronal populations is used to set out a broad theoretical framework explaining the heterogeneity of observed responses. ResultsIn the absence of stimulation, the model exhibited either damped oscillations or self-sustained oscillations, depending on parameter values. Off-stimulation behaviour determined observed stimulation response. When oscillations were strongly damped, the only observed response was a driven oscillation at the stimulation frequency. When off-stimulation oscillations were weakly damped, additional half-harmonic responses occurred for sufficiently large amplitude stimulation. When self-sustained oscillations were present they were entrained by the stimulation frequency leading to harmonic, half-harmonic and many other subharmonic responses. Varying stimulation amplitude highlighted hysteresis with the onset and offset of half-harmonic responses appearing at different thresholds. Such two-threshold systems present challenges for adaptive control systems. ConclusionsThis framework captures observed heterogeneity and will help guide future therapeutic practices and the development of adaptive neuromodulation techniques for more effective promotion of physiological rhythms and suppression of abnormal rhythms.

This study extends our previous research on neurological adaptations associated with learning to use chopsticks, in which we observed increased functional activity and connectivity changes in the anterior supramarginal gyrus (aSMG), a brain region previously implicated in novel tool use. In the present study, we investigated the effects of high-definition transcranial direct current stimulation (HD-tDCS) on motor learning by applying anodal stimulation to the aSMG in a double-blind, sham-controlled design with 24 participants (12 active, 12 sham). Participants in the active condition received [~]3 mA of HD-tDCS focused over the aSMG while watching a 20-minute video of the task - picking up a marble with chopsticks and dropping it into a cylindrical container. In comparison, participants in the sham condition watched the same video while receiving sham stimulation consisting of a 30-s ramp-up and ramp-down at the start and end of the 20-minute video. Immediately after the video task, all participants completed 15 one-minute trials in which they performed the task while electroencephalography (EEG) was recorded. Performance was assessed by the average number of successful marble drops per minute (MDPM) across trials. Additionally, video-based motion was analyzed using DeepLabCut to compare key kinematic metrics, providing insights into subtle variations in movement patterns during the marble task. Results showed a significant increase in MDPM in the active stimulation group compared to the sham group (17. 3 vs. 14. 1 MDPM; p < .05). Kinematic data showed increased movement jerk in the active stimulation group compared to sham (21719 vs 16926; p < .05), and EEG revealed differences in task-related gamma-band power over Cz (.0227 vs -.0758; p < .05). These findings suggest that HD-tDCS enhances the rate of motor learning in novel tool use and underscore the potential of aSMG-targeted stimulation in facilitating complex motor tasks. Further studies are warranted to explore the broader applicability of HD-tDCS in skill acquisition and rehabilitation. New and NoteworthyThe presented study shows the role that the left anterior supramarginal gyrus plays in experience-independent tool learning. Anodal HD-tDCS applied during action observation increased performance in a subsequent chopstick skill acquisition task. This increase in performance was accompanied by enhanced task-related gamma-band activity and altered movement kinematics. By linking neuromodulation of the parietal tool-use hub to behavioral, kinematics, and electrophysiological changes, these findings significantly advance our understanding of how higher-order sensorimotor networks support tool-use learning.

BackgroundThe frontoparietal network (FPN) has been strongly implicated in both the development of and recovery from major depressive disorder (MDD), making it a promising target for transcranial magnetic stimulation (TMS) therapy of MDD. However, commonly used TMS targeting approaches often co-stimulate multiple neighboring functional brain networks to varying degrees across individuals. We therefore aimed to develop a clinically feasible, standardized TMS coil placement that enables stronger and more selective stimulation of the FPN without requiring individual neuroimaging or neuronavigation. MethodsWe optimized the placement of a prototypical figure-of-eight coil in a population-based brain template by maximizing simulated electric field (E-field) strength within a representative FPN cluster. Based on this optimized placement, we derived a practical heuristic using EEG electrode positions and simple scalp measurements. The FPN-optimized placement and its heuristic were validated by comparing E-field hotspot coverage of the FPN and other functional networks against a clinically established, standard coil placement (Beam F3 method) in precisely mapped brains of 20 healthy individuals (15 female) and 20 patients with MDD (7 female). We further assessed robustness of FPN stimulation to coil tilt inaccuracies and the role of coil orientation. ResultsThe optimized heuristic places the center of the coil over the F5 electrode and orients its handle along the F5-AF7 axis. This placement yielded significantly stronger and more selective FPN coverage than the established clinical approach. Targeting was largely robust to tilt inaccuracies but sensitive to rotational deviations. DiscussionThis scalp-based F5-AF7 TMS coil placement enables selective and reliable targeting of the frontoparietal depression network in routine clinical settings. Whether it improves antidepressant efficacy compared to established targeting strategies should be evaluated in future clinical trials.

BACKGROUNDTheta-gamma phase-amplitude coupled ({theta}{gamma}-PAC) oscillations in primary motor cortex (M1) have been shown to support motor skill acquisition. Past research has shown that driving gamma activity at the theta peak (TGP), but not the theta trough (TGT) using transcranial alternating current stimulation (tACS) enhances motor learning (Akkad et al., 2021). However, the neurophysiological mechanisms underlying this phase-specific effect remain unclear. METHODSIn a double-blind, sham-controlled, cross-over study, twenty-two healthy participants received 20 minutes of 75Hz/6Hz TGP-tACS, TGT-tACS, or sham stimulation over M1. We used paired-pulse transcranial magnetic stimulation (TMS) to assess GABAergic and NMDAR-mediated activity before, during, and after tACS. Outcome measures included short-interval intracortical inhibition at 1ms (SICI1ms; extrasynaptic GABAergic tone) and 2.5ms (SICI2.5ms; synaptic GABAA activity), intracortical facilitation at 12ms (ICF12ms; NMDAR activity), and motor evoked potential (MEP) amplitude (corticospinal excitability). RESULTSTGP-tACS selectively decreased SICI1ms, a putative marker of extrasynaptic GABAergic tone (main effect of Stimulation: p=.021), with significant differences between TGP and TGT during late stimulation (p=.047). No significant effects were observed on corticospinal excitability, synaptic GABAergic activity (SICI2.5ms), or NMDAR signalling (ICF12ms). CONCLUSIONSDriving theta-gamma oscillations at the theta peak using tACS specifically modulates extrasynaptic GABAergic tone in M1 without affecting corticospinal excitability or synaptic inhibition. Given that reductions in GABAergic signalling supports motor learning, these findings provide a neurophysiological mechanism for the phase-specific behavioural effects of {theta}{gamma}-PAC tACS and suggest a potential therapeutic approach for facilitating motor recovery after stroke. HighlightsO_LITheta-gamma peak tACS selectively reduces extrasynaptic GABA in human motor cortex C_LIO_LIOnly gamma at the peak, not trough, of theta stimulation modulates GABA C_LIO_LINo effects on corticospinal excitability, synaptic GABA, or NMDAR signalling C_LIO_LItACS-TMS reveals mechanism for phase-dependent motor learning effects C_LI

Background: Transcranial temporal interference stimulation (tTIS) is an emerging noninvasive neuromodulation approach that enables focal, frequency-specific modulation of deep brain regions, offering a novel method for investigating therapeutic mechanisms underlying brain and mental health disorders. Pain is a key target because it is a feature of multiple disorders and is increasingly understood to depend on brain circuits. Here, we tested the effects of tTIS on bilateral evoked pain, capitalizing on converging evidence from human and animal studies indicating that the primary motor cortex (M1) contains body-wide inter-effector regions and has descending projections to regions implicated in nociceptive, motivational, and autonomic processing, making it a key cortical target for pain modulation. Methods: We conducted a pre-registered, triple-blind, randomized crossover study (N = 32, 160 study sessions), investigating frequency-dependent effects of tTIS applied to the left M1 on experimentally evoked thermal pain in healthy adults. We tested four stimulation frequencies (10 Hz, 20 Hz, 70 Hz, and sham) on separate days (>10,000 pain trials total). Noxious heat was applied to both the right and left forearms using individually calibrated temperatures both pre- and post-stimulation. Results: Active tTIS produced significant analgesia at all stimulation frequencies (10 Hz, 20 Hz, and 70 Hz) relative to sham (Cohens d = 0.46-0.82, all p < 0.05). 10 Hz produced the greatest reduction (d = 0.82), and both 10 Hz and 20 Hz produced more analgesia than 70 Hz (d = 0.44 and 0.38, respectively; p < 0.05). Stimulation-related sensations were equivalent across frequencies, and participants were blind to condition. Pain reductions remained stable over a [~]40-min post-stimulation period and were bilateral, consistent with stimulation of body-wide inter-effector regions. Conclusions: These results provide the first evidence that tTIS can reliably reduce experimental pain perception in humans in a frequency-dependent manner, providing a foundation for noninvasive pain modulation with tTIS.

BackgroundPatients with Parkinsons disease (PD) almost inevitably experience cognitive impairments. These deficits have been linked to low frequency "theta" cortical activity [~]4 Hz, previously associated with cognitive control. ObjectiveOur study investigated effects of 4 Hz subthalamic nucleus (STN) deep brain stimulation (DBS) on cognitive performance in PD patients with cognitive impairments. MethodsWe recruited 17 PD participants with (n=10) and without (n=7) cognitive impairment. In these patients, we compared motor and cognitive performance during 4 Hz STN DBS, typical DBS for motor symptoms of PD ([~]130Hz) and DBS OFF. Motor performance was tested by Part III of the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS-III). Cognitive performance was tested during performance of the Multi-Source Interference Task (MSIT), which requires conflict resolution to respond accurately. ResultsMotor function improved with 4 Hz STN DBS and further improved with [~]130 Hz STN DBS. Compared to DBS OFF, reaction times were decreased during 4 Hz STN DBS and were further decreased at [~]130 Hz. Strikingly, 4 Hz DBS alone improved accuracy compared to both DBS OFF and compared to [~]130 Hz STN DBS. ConclusionsThese data suggest that theta-frequency 4 Hz STN stimulation is effective in PD patients with cognitive impairments. Our findings will help guide new therapies targeted at improving cognitive dysfunction in PD and could broaden applications for low-frequency brain stimulation.

Background: Gamma oscillation dysfunction has been implicated in neuropsychiatric disorders. Restoring gamma oscillations via brain stimulation represents an emerging therapeutic approach. However, the strength of its clinical effects and treatment moderators remain unclear. Method: We conducted a systematic review and meta-analysis to examine the clinical effects of gamma neuromodulation in neuropsychiatric disorders. A literature search for controlled trials using gamma stimulation was performed across five databases up until April 2025. Effect sizes were calculated using Hedge's g. Separate analyses using the random-effects model examined the clinical effects in schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder, and autism spectrum disorder. For SZ and MDD, subgroup analyses evaluated the effects of stimulation modality, stimulation frequency, treatment duration, and pulses per session. Result: Fifty-six studies met the inclusion criteria (NSZ = 943, NMDD = 916, NBD = 175, NASD = 232). In SZ, gamma stimulation was associated with improvements in positive (k = 10, g = -0.60, p < 0.001), negative (k = 12, g = -0.37, p = 0.03), depressive (k = 8, g = -0.39, p < 0.001), anxious symptoms (k = 5, g = -0.59, p < 0.001), and overall cognitive function (k = 7, g = 0.55, p < 0.001). Stimulation frequency and treatment duration moderated therapeutic effects. In MDD, reductions in depressive symptoms were observed (k = 23, g = -0.34, p = 0.007). Conclusion: Gamma neuromodulation showed moderate therapeutic benefits in SZ and MDD. Substantial heterogeneity likely reflects protocol differences, highlighting the need for well-powered future trials.

BackgroundDeep brain stimulation has emerged as an effective investigational treatment for select cases of severe Gilles de la Tourette Syndrome. Defining the optimal stimulation sites within different targets and the specific tic improvement network across targets will be important to guide neuromodulation therapies. MethodsThis retrospective multi-center cohort study analyzed stimulation locations in patients who received bilateral deep brain stimulation for Gilles de la Tourette Syndrome across 12 centers world-wide. The brain targets included the thalamus (n=43), pallidum (n=56) and subthalamic nucleus (n=16). The median follow-up period was 6 months. Imaging data were processed using a dedicated pipeline and a recently introduced voxel-wise sweetspot mapping technique. Since tic response landscapes visually resembled streamline tract connections, we carried out extensive anatomical delineations of pallidothalamic and thalamostriatal fibers. This anatomical information was used to interpret sweetspot landscapes across the three target regions. ResultsTic response maps revealed three tic-response peaks in both thalamus and pallidum. Based on thalamic and pallidal response maps, outcomes in the subthalamic DBS cohort, stimulated between the two other targets, could be explained (R=0.58, p=0.019). Across the three targets, response maps followed the anatomical course of three bundles. Namely, specific subregions of the ansa lenticularis, the fasciculus lenticularis, and projections from the posterior intralaminar thalamic nuclei to the lentiform nucleus. Stimulation overlaps with these bundles explained 19% of the variance in tic improvement across the three targets. Response maps could explain variance in an independent test cohort (n=8, R=0.70, p=0.026). Response maps were also calculated for obsessive compulsive behavior, which revealed similarities to the tic response sites in pallidum but clearly distinct results and generally less efficacy in the thalamus. ConclusionOur analyses identified tic response targets that followed the course of known structural projections interconnecting pallidum and thalamus.

The striatum, a critical hub for motor skill learning, is located deep within the subcortical region, making noninvasive stimulation particularly challenging. Nevertheless, recent studies suggest that transcranial magnetic stimulation (TMS) can modulate subcortical activity indirectly by targeting functionally connected cortical areas. In this study, we applied TMS to the dorsolateral prefrontal cortex (DLPFC) immediately before the fMRI session measuring task-related activity in the striatum during motor learning. We examined whether continuous theta-burst stimulation (cTBS) and high-frequency stimulation (20 Hz) could modulate motor learning and associated striatal responses with opposing effects. There was no significant effect of either stimulation condition on the overall motor learning performance. However, cTBS significantly reduced performance-related striatal activity, while 20 Hz stimulation did not show any modulatory effect. These findings demonstrate that cTBS targeting the corticostriatal network can suppress striatal activity and suggest its potential use in clinical trials for treating disorders such as addiction associated with hyperactive striatal responses.

ObjectivesTranscutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that has shown potential to enhance cognitive function, including working memory. This study investigated the acute effects of both electrical (E-taVNS) and ultrasound (U-taVNS) modalities on working memory using a 3-back task in healthy young adults. We hypothesized that active taVNS would enhance working memory performance relative to sham, and that both stimulation modalities would engage similar neuromodulatory mechanisms. Materials and MethodsFifty-nine participants underwent a single-blind, sham-controlled, within-subject design study, with working memory performance assessed using a 3-back task before and after stimulation. Primary performance measures included correct rejection rate, error false alarm, and sensitivity (d'). Statistical analyses compared pre- and post-stimulation performance across modalities. ResultsE-taVNS significantly enhanced working memory performance through an increase in correct rejection rate and sensitivity (measured by d), alongside a reduction in error of false alarm. U-taVNS showed a similar directional trend across performance measures, although these effects did not reach statistical significance. Baseline anxiety levels significantly predicted individual responsiveness to taVNS. In terms of tolerability, a higher proportion of participants receiving E-taVNS reported skin irritation compared to those receiving U-taVNS. ConclusionsE-taVNS can acutely enhance working memory performance, while U-taVNS may offer a comparable, better tolerated alternative. Our findings highlight the potential of taVNS to support memory function, while showing the importance of further research to clarify modality-specific effects and optimize stimulation parameters.