Brain Stimulation

Repetitive transcranial magnetic stimulation is a popular method of non-invasive brain stimulation used to study the human brain and treat neurological disorders. However, despite over three decades of use, the cellular mechanisms underlying its effects remain unknown which has limited its use. Using spatial transcriptomics on excised human cortical tissue, we characterized and mapped changes to gene expression following stimulation with two common stimulation protocols. We find that repetitive magnetic stimulation alters the expression of genes related to neuronal and glial plasticity mechanisms that were mostly cortical layer, cell type, and protocol dependent. These findings show that repetitive transcranial magnetic stimulation acts on multiple neural plasticity mechanisms simultaneously in the human brain, which to some extent, can be biased by the stimulation frequency used.

Neural oscillations provide temporal frameworks for coordinating communication within and across distributed brain networks. In essential tremor (ET), pathological synchronization within the cerebello-thalamo-cortical circuit produces rhythmic activity that manifests as an involuntary action tremor. Although deep brain stimulation can effectively suppress tremor, its invasiveness and cost highlight the need for non-invasive interventions capable of selectively modulating pathological oscillations. Transcranial magnetic stimulation (TMS) offers a non-invasive means of engaging cortical circuits, yet conventional stimulation protocols are delivered independently of the ongoing neural dynamics. Such open-loop approaches ignore the temporal structure of tremor-related activity, potentially stimulating during both amplifying and suppressing phases of the oscillation. To address this, we compared two phase-targeted TMS paradigms: first-pulse phase-locked TMS (First-pulse-TMS), in which only the initial pulse of a stimulation train is aligned to the tremor phase, and cycle-by-cycle phase-locked TMS (Continuous-TMS), in which each pulse is continuously triggered based on real-time tremor phase. Ten patients with ET underwent stimulation guided by peripheral tremor recordings using an accelerometer, with tremor phase estimated in real time via the Oscilltrack algorithm. Sixty-four trains of TMS pulses were delivered at nine discrete phase bins of the tremor cycle, such that each phase bin was repeated approximately seven times. Continuous-TMS maintained accurate phase-locking across consecutive cycles (mean phase-locking value ~0.9), whereas First-pulse-TMS exhibited progressive drift over time and low phase consistency (mean phase-locking value <0.2). The circular concentration of stimulation phase was significantly greater for Continuous-TMS than First-pulse-TMS (Mann-Whitney U-test, p < 0.001), indicating a significant difference in overall phase-locking accuracy between the two protocols. Critically, Continuous-TMS, unlike First-pulse-TMS, induced bidirectional, phase-dependent modulation of tremor amplitude. Circular-linear modelling revealed a sinusoidal relationship between stimulation phase and changes in tremor amplitude, with tremor amplification and suppression occurring at opposite phases of the cycle. Covariates including baseline tremor amplitude and trial number were accounted for. In some people, tremor suppression outlasted the stimulation period, suggesting phase-locked TMS may be a potentially useful therapeutic tool. By enabling reliable, phase-specific stimulation of the tremor cycle, Continuous-TMS allows identification of the individual phase that produces maximal tremor suppression, supporting the development of personalized, phase-specific neuromodulation strategies. This proof-of-principle study demonstrates that temporally precise, closed-loop TMS can interact with pathological oscillations in real time, providing a mechanistic framework for probing oscillatory contributions to motor symptoms and a scalable therapeutic approach for ET and other oscillopathies.

Gamma oscillations are altered in several conditions such as schizophrenia, Alzheimers Disease, and Mild Cognitive Impairment. Both 40-Hz transcranial alternating current stimulation (tACS) and 40-Hz auditory steady-state stimulation can entrain gamma oscillations and improve cognitive outcomes, but their combined effects remain unclear. This study tested whether preconditioning gamma activity with tACS enhances the auditory steady-state response (ASSR) to 40-Hz auditory stimulation, reflecting a potential synergistic interaction. In a within-subject, sham-controlled design, EEG was recorded before and after 40-Hz tACS delivered over bilateral sensorimotor areas in 34 healthy participants. 40-Hz auditory stimulation was administered before and after tACS to evaluate potential changes in ASSR. Source-level gamma power was analyzed in temporal and sensorimotor regions using linear mixed-effects models. Compared to sham, real tACS increased ASSR-related gamma activity in the superior temporal gyrus, with no effects elsewhere or between hemispheres. These findings support the use of multimodal gamma entrainment to enhance neural oscillations. To conclude, combining 40-Hz tACS with auditory stimulation enhances gamma activity more than either intervention alone, supporting potential clinical applications for neuropsychiatric conditions with disrupted gamma oscillations.

Repetitive transcranial magnetic stimulation (rTMS) is used widely in neuroscience to study and alter neural plasticity. The cellular mechanisms underlying the effect of rTMS on the brain remain unclear but is primarily thought to act via activity-dependent synaptic plasticity mechanisms. Here we investigated whether chronic repetitive magnetic stimulation in vitro and in vivo can induce another form of activity-dependent neural plasticity, axon initial segment (AIS) plasticity. Cortical neurons isolated from postnatal wild-type mice were stimulated with 6 hours of sham, repetitive magnetic stimulation in the form of intermittent theta-burst stimulation (iTBS), or 15 mM potassium chloride, with changes to AIS location and length measured +0 hours and +24 hours post-stimulation. In addition, adult transgenic mice expressing green fluorescent protein at the AIS received daily sham or iTBS over the primary motor cortices for 7 consecutive days and processed for microscopy 3 hours after the last stimulation. Analysis of neurons stimulated in vitro showed that chronic iTBS caused bidirectional and time-dependent shifts to the AIS position relative to the soma and a delayed shortening of the AIS length at +24 hours. In the adult mice, 7 consecutive days of daily iTBS decreased AIS lengths in layers 2/3 and 5 pyramidal neurons. Our findings provide in vitro and in vivo evidence that rTMS induces neuronal plasticity outside of the synapse, which may contribute to the long-lasting effect of rTMS on the brain with repeated stimulation protocols.

Although transcranial magnetic stimulation (TMS) is widely used for brain stimulation, fundamental issues about its underlying mechanisms remain unresolved. We investigated some of these issues experimentally using an intact isolated turtle cerebellum in vitro, employing a novel chamber designed to deliver precisely calibrated induced electric fields along cortical depth. Our results show that single-pulse TMS can directly activate Purkinje cells and climbing fibers, and synaptically activate Purkinje cells via climbing fibers - all within the first 1.2 ms. Specifically, current source density analysis showed that TMS directly (non-synaptically) activated (1) climbing fibers near the bend with intracellular current directed toward the axonal terminals and (2) Purkinje cells directly near the axon initial segment with intracellular current directed toward the distal dendrites. The thresholds for direct activation of climbing fibers and Purkinje cells were found to be very similar, 25 {+/-} 1 V/m. The climbing fibers synaptically activated Purkinje cells, as expected, with intracellular current originating in the proximal dendritic trunk and directed toward the distal dendrites. At higher electric fields (> 58 {+/-} 17 V/m), TMS synaptically activated dendritic currents in Purkinje cells. These results provide new insight into how TMS may activate afferent fibers and cell bodies of cortical neurons.

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.

BackgroundElectroencephalography (EEG) can be combined with transcranial magnetic stimulation (TMS) to perform brain-state-dependent stimulation. EEG-TMS studies have shown that corticospinal excitability, as measured via motor evoked potentials (MEPs), is modulated by pre-stimulus periodic EEG features, such as sensorimotor mu-rhythm phase and power. However, the influence of aperiodic brain activity on corticospinal excitability is largely unexplored. ObjectivesWe evaluated the relationship between aperiodic and periodic mu-power, aperiodic exponent, and mu-phase on MEP amplitudes using EEG-TMS. MethodsWe applied 800 single TMS pulses to the left primary motor cortex in 78 healthy adults. We calculated aperiodic/periodic mu-power, aperiodic exponent, and mu-phase for each trial from the pre-stimulus C3-Hjorth transformed EEG. MEP amplitudes were extracted from the right first dorsal interosseous muscle. A linear mixed-effects model assessed relationships between MEP amplitudes and EEG features, with interactions between mu-phase and all other EEG features. ResultsAperiodic and periodic mu-power, aperiodic exponent, and mu-phase significantly modulated MEP amplitudes. Higher aperiodic/periodic mu-power was associated with larger MEP amplitudes, while higher aperiodic exponent was associated with smaller MEP amplitudes. We found a significant interaction effect of aperiodic exponent and mu-phase on MEP amplitude. Aperiodic exponent was negatively associated with MEPs for trough, rising, falling phases, but positively associated with MEPs for peak phase. ConclusionsAperiodic and periodic features of brain activity are reflective of dissociable corticospinal excitability states. Future brain-state-dependent TMS interventions may include aperiodic EEG features, such as aperiodic mu-power and exponent, in addition to the well-established periodic features.

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 extended 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). se-iTBS more than doubled the MEP effect (55% vs. 26% MEP enhancement) and persisted for at least 30 minutes. Notably, more than 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.

Background: Low-intensity focused ultrasound (LIFU) is an emerging noninvasive neuromodulation technique capable of targeting deep cortical and subcortical structures with high spatial precision. In healthy human volunteers, LIFU has demonstrated a favorable safety and tolerability profile across multiple studies. However, its safety and tolerability in clinical populations remains poorly characterized, representing a critical barrier to clinical translation. Here, we prospectively evaluate the safety and tolerability of LIFU targeting the left dorsal anterior insula (dAI) in patients with fibromyalgia (FM). Methods: In a single-blind, sham-controlled, within-subjects crossover design, 13 individuals with FM (43.1 +/- 13.2 years; 12 female) received 10 minutes of active LIFU (500 kHz, 1 kHz PRF, 36% duty cycle, 4.2 W/cm2 Isppa; 100 x 1-second pulse trains with a 5-second inter-train interval) targeting the left dorsal anterior insula (dAI) or sham on separate visits. Safety was evaluated through neuroradiological review of post vs. pre LIFU FLAIR MRI, quantitative voxel-wise FLAIR analysis, and patient report of symptoms (ROS). Tolerability was assessed using an experience assessment. Efficacy of the LIFU intervention was assessed using quantitative sensory testing (QST) including temporal summation of pain (TSP) and conditioned pain modulation (CPM). Results: Neuroradiological review identified no new evidence of edema, microhemorrhage, acute ischemia, or white matter injury on post-LIFU structural imaging. Quantitative FLAIR analysis using contralateral-mirror-referenced relative FLAIR (rFLAIR) showed no significant within-subject change in the stimulated beam volume (delta rFLAIR = 0.002 +/- 0.025, t(12) = 0.30, P = 0.769, Cohen's dz = 0.08). No serious adverse events were documented and ROS indicated no change due to LIFU sonication. Participants rated the procedure as comfortable and could not distinguish active from sham LIFU. LIFU did not result in statistically significant changes for TSP (p = 0.797) or CPM (p = 0.465). Conclusions: Ten minutes of LIFU targeting the left dAI was safe and well tolerated in individuals with FM, with no neuroradiological or quantitative MRI evidence of tissue effects and no serious adverse events. Blinding was preserved, and participants rated the procedure as comfortable. Although no significant changes were observed in experimental pain measures, these findings support the feasibility of targeting deep salience and pain amplification circuitry with LIFU in patients with FM and provide a foundation for adequately powered efficacy trials.

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.

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.

We employed a noninvasive high-density surface electromyography (HDsEMG) framework to track spinal motor neuron responses during repetitive transcranial magnetic stimulation (rTMS) and characterize corticospinal transmission of different stimulation frequencies and intensities to the alpha motor neuron pool. Eleven healthy individuals performed isometric thumb flexion at 10% of maximal voluntary contraction while rTMS was delivered over the motor cortex at five frequencies (5, 10, 20, 30, and 50 Hz) and three subthreshold intensities (50%, 60%, and 70% of resting motor threshold). Motor units were decomposed from HDsEMG signals before stimulation and tracked during rTMS. Input-output coupling was quantified using coherence between the rTMS train and individual motor unit spike trains or the cumulative spike train (CST), with shuffled spike trains used as surrogate controls. rTMS inputs were robustly transmitted to spinal motor neurons for all frequencies except 5 Hz, indicating widespread corticospinal coupling. Transmission behaved linearly, with CST output spectra reproducing input frequencies and scaling proportionally with stimulation intensity. The estimated transfer function revealed a bandpass-like profile, with maximal transmission between 10 and 60 Hz. Transmitted inputs also induced oscillatory components in the common synaptic input to motor neurons at stimulation frequency. Simulations indicated that this frequency selectivity emerges from balanced excitatory and inhibitory inputs to the motor neuron pool, with specific synaptic dynamics. These findings demonstrate that corticospinal transmission during rTMS acts as a frequency-selective linear system and provide a framework for assessing and modulating corticospinal pathways, with potential application as tool for tracking disease progression and neurorehabilitation. Highlights- HDsEMG decomposition tracks spinal motor neuron activity during rTMS. - Corticospinal transmission scales with rTMS stimulation intensity. - Corticospinal pathways act as a frequency-selective system. - rTMS transfer function shows maximal transmission at 10-60 Hz. - EPSP-IPSP interactions explain bandpass corticospinal transmission during rTMS.

BackgroundGamma 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. MethodWe 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 Hedges 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. ResultFifty-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). ConclusionGamma neuromodulation showed moderate therapeutic benefits in SZ and MDD. Substantial heterogeneity likely reflects protocol differences, highlighting the need for well-powered future trials.

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.

BackgroundElectrophysiological recordings from chronically implanted Deep Brain Stimulation (DBS) electrodes can greatly advance understanding of disease and treatment mechanisms of motor and psychiatric disorders. The Medtronic Percept system allows for chronic recordings of local field potentials (LFP) from DBS target regions. However, these systems lack an inbuilt synchronization option to align LFP recordings to other recording modalities and consequently events in computerized tasks. ObjectiveWe propose and evaluate a synchronization method based on Transcutaneous Electrical Stimulation (TES) with low amplitudes to precisely align recorded LFP signals from the DBS electrodes to EEG recordings. MethodsThe TES-based synchronization approach was implemented and tested in 11 participants implanted with the Medtronic Percept for treatment of Parkinsons disease. ResultsThe proposed method provides high reliability, precise alignment and usability across all Medtronic Percept recording modes. Notably, the method enables recordings during adaptive DBS and with stimulation turned off. In this recording mode, LFP signals can be acquired from all recording contact pairs simultaneously, with a high signal-to-noise ratio. We provide detailed setup plans and share Python and Matlab scripts for signal alignment to enable easy application of our approach. ConclusionBy enabling reliable, well-aligned LFP recordings from all DBS contacts, our method provides a robust tool for studying neural dynamics and refining therapeutic interventions in diverse neurological conditions.

IntroductionNociceptive processing in the human spinal cord remains difficult to study directly, and its oscillatory dynamics are poorly understood. Oscillatory activity in the beta band (13-35 Hz) is of particular interest, as beta rhythms are widely associated with sensorimotor network state and transient desynchronisation following salient input. ObjectivesIdentify the effects of nociceptive laser thermal stimuli on beta-band oscillatory activity in epidural spinal field potentials. MethodsWe recorded epidural spinal field potentials during noxious thermal laser stimulation of the unaffected foot using externalised thoracic spinal cord stimulation electrodes in two subjects with neuropathic pain (persistent spinal pain syndrome type 2). ResultsTime-frequency analysis combined with cluster-based permutation testing revealed reproducible suppression of spinal beta oscillations (13-35 Hz) following nociceptive stimulation. Beta suppression was spatially organised along contiguous rostro-caudal bipolar channels and most prominent within the first 0-200 ms after stimulation. Both low- (13-20 Hz) and high-beta (20-35 Hz) sub-bands contributed to early effects, with low-beta suppression predominating rostrally and while high-beta suppression was more ubiquitous. Inter-trial coherence increases were modest and not consistently aligned with early suppression, suggesting induced desynchronisation rather than a dominant phase-reset response. ConclusionNociceptive input produces early, spatially organised modulation of spinal beta oscillation dynamics in awake subjects.

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.

BackgroundCognitive impairment poses a significant challenge to healthcare systems worldwide, impacting patient autonomy, social participation, and quality of life, while placing a considerable burden on caregivers. Non-pharmacological interventions, particularly cognitive training and non-invasive brain stimulation, have emerged as promising therapeutic strategies. ObjectiveThis study aims to quantify the synergistic effects of transcranial direct current stimulation (tDCS) with cognitive training on cognitive function across a spectrum of pathologies that induce cognitive impairment. MethodsWe conducted a systematic review and meta-analysis following PRISMA guidelines. We searched PubMed for randomized controlled trials that investigated the effect of combined tDCS and cognitive training compared with cognitive training alone. The analysis was based on the GRADE framework for systematic reviews and meta-analyses. ResultsAcross 27 studies including 1,012 participants, tDCS combined with cognitive training showed a small effect compared with cognitive training alone (SMD = 0.36, 95% CI: 0.15-0.56). The effect was found only immediately after the intervention and declined during follow-up. ConclusiontDCS combined with cognitive training may provide a small, short-term benefit for cognitive function, but high heterogeneity across studies and loss of effect at follow-up underscore the need for larger, better-standardized trials to clarify its clinical value. Highlights- Combined tDCS and cognitive training produce a small but statistically significant short-term improvement in global cognitive performance. - Effects attenuate over time, highlighting limited durability without sustained or maintenance interventions. - High methodological heterogeneity and very low certainty of evidence limit broad clinical generalization.