Brain Stimulation

Non-invasive deep-brain stimulation (DBS) using transcranial alternating current stimulation (tACS) with temporal interference (TI) has emerged as a promising approach for therapeutic applications in motor and neuropsychiatric disorders. Here, we present a preclinical TI tACS protocol for adult rats that follows a systems approach: an anatomically realistic finite-element digital twin of the rat head is used to optimize electrode placement and injected currents for a deep target, and the model predictions are then tested in vivo. We combine, minimal invasive TI tACS with functional MRI (fMRI) to characterize stimulation-related brain-wide neural responses, alterations in functional connectivity, and changes in neurotransmitter levels. The optimized montage targeted in particular the ventral (motor-related) thalamus. Stimulation-evoked fMRI revealed robust bilateral activation across both subcortical and cortical regions, such as the thalamus, hippocampus, amygdala, retrosplenial and anterior cingulate cortex, which, in turn, reflects direct and indirect activations of brain circuitries by TI tACS. Changes in the connectivity patterns during resting-state fMRI were limited (e.g., fimbria of the hippocampus), but partially overlapped with regional stimulation-evoked fMRI. Therefore, we assume only a short-term influence of TI on neural networks following a single stimulation. MR spectroscopy indicated a trend towards an increased glutamate/GABA ratio in the thalamus. Overall, we demonstrate that TI is a feasible and effective approach for non-invasive DBS in rodents, and that digital twin-based optimization combined with in vivo validation provides a workflow towards individualized stimulation and a foundation for future mechanistic and translational studies in disease models.

Closed-loop brain stimulation offers a promising approach for modulating neural oscillations, but the mechanisms of phase-dependent neuromodulation remain poorly understood. We developed a real-time MEG-based closed-loop system delivering median nerve stimulation using a phase-modulated Poisson process. Sixteen healthy participants (11 female, 5 male) underwent open-loop characterization followed by closed-loop testing of eight phase-offset conditions (0 degrees-315 degrees), each paired with a statistically matched replay control. Closed-loop stimulation induced robust phase-dependent modulation (14.21 +/- 8.24%) versus replay (7.03 +/- 2.95%; p = 0.0003), with consistent phase specificity across participants (circular mean: 70.2 degrees, referenced to each individual's dominant frequency). At the group level, alpha oscillations (8-12 Hz) showed bidirectional modulation (mean boost: +21.0 +/- 19.9% at 0 degrees-135 degrees; mean suppression: -13.3 +/- 10.8% at 180 degrees-315 degrees), while beta oscillations (13-30 Hz) showed predominantly unidirectional suppression (-9.3 +/- 9.6%). Successful fixed-frequency targeting required alignment with each individual's natural peak. Misalignment led to different phase shifts producing power at different frequencies, a phenomenon we term phase-frequency coupling. Dynamic frequency tracking (8-30 Hz) automatically identified and targeted each individual's natural peak, achieving robust bidirectional modulation without prior knowledge of peak location. These findings demonstrate that real-time phase-locked peripheral nerve stimulation selectively modulates sensorimotor oscillations beyond statistically matched open-loop stimulation. The distinct phase-excitability relationships of alpha and beta oscillations, together with the importance of aligning stimulation with individual natural peaks, establish principled guidelines for personalized closed-loop neuromodulation.

Deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) has been explored to treat gait disturbances. However, clinical outcomes of MLR-DBS have been disappointing overall, with only modest benefits in some individuals and unwanted effects, including anxiety, reported in others. Preclinical studies in several species, by contrast, show that MLR-DBS can improve locomotor and gait deficits, although defensive behaviours in response to stimulation have also been reported in some species. To investigate this discrepancy, we examined frequency- and amplitude-dependent effects of MLR-DBS in healthy rats, combining semi-supervised and unsupervised behavioural analyses. High-frequency, high-amplitude DBS (80-130 Hz), but not low-frequency stimulation (20-60 Hz), elicited hyperlocomotion intermixed with acute defensive-like behaviours. Low-frequency stimulation instead promoted phases of immobility. Consistently, only high-frequency DBS induced region-specific c-Fos expression in the MLR. Complex behaviours, including hyperlocomotion, rearing, tail rattling, and periods of immobility, were most pronounced in animals with the DBS electrode tip localized to the cuneiform nucleus (CnF) of the MLR. Using AAV tracer constructs for bright labelling of CaMKII-positive neurons and their axons, we identified prominent ascending projections from the CnF to the thalamus, substantia nigra pars compacta, zona incerta, hypothalamus, subthalamic nucleus, and central amygdala (CeA). Retrograde tracing confirmed the CnF-to-CeA projection independently. These findings show that the MLR is anatomically connected to higher-order centres linking motor and defensive networks, with DBS frequency and amplitude critically shaping behavioural outcomes that extend beyond locomotion.

Deep brain stimulation (DBS) is a well-established therapy for various neurological disorders. Clinical outcomes of DBS depend on electrode placement and stimulation programming, with growing evidence suggesting that targeting specific sites and networks can improve therapeutic efficacy. This targeting can be facilitated using high-accuracy, multi-modal biophysical models. In this article, we present the open-source platform OSS-DBS v2 that enables researchers and clinicians to build such biophys- ical models. Building upon previous work, the new version combines automated volume conductor generation, accurate and efficient electric field modelling and stimulation-driven neural simulations. OSS-DBS v2 provides an extensive library of intracranial electrodes, which can be modelled simul- taneously to test complex stimulation paradigms. Its application programming interface facilitates integration of external data workflows, such as impedance measurements. Furthermore, an integration with the Lead-DBS toolbox offered a straightforward graphical user interface for stimulation volume and pathway activation modelling, further complemented by an optimization framework. OSS-DBS v2 relies entirely on open-source software, supports all major operating systems and is designed for efficient execution on consumer-grade hardware.

Transcranial ultrasound stimulation (TUS) can noninvasively modulate deep brain structures, but the relationship between delivered dose and neuromodulatory response remains poorly characterized in humans. Here, we show that ultrasound-induced tissue displacement measured in vivo predicts local and downstream functional neuromodulation. In 24 healthy adults, we combined magnetic resonance acoustic radiation force imaging (MR-ARFI) with concurrent TUS-fMRI in a double-blind, counterbalanced, within-subject design. Relative to active control stimulation, targeting the lateral geniculate nucleus (LGN) increased visually evoked BOLD responses in the LGN and ipsilateral primary visual cortex, localized to the retinotopic projection zone of the stimulated LGN site. Displacement predicted effect magnitude in both regions across participants and covaried with voxelwise responses within participants. Simulated in situ intensity showed no significant association with displacement or neuromodulatory response. These findings link in vivo mechanical displacement to functional modulation of a human thalamocortical circuit, providing an empirical basis for individualized dosing in causal neuroscience and clinical intervention.

Background: Response to Comprehensive Behavioral Intervention for Tics (CBIT), the first-line treatment for tic disorders, is suboptimal. We conducted Phase 1 of a two-phase, milestone-driven trial to determine if augmenting CBIT with repetitive transcranial magnetic stimulation (TMS) to supplementary motor area (SMA) could safely engage targeted sensorimotor circuitry and improve tic controllability. Methods: In a 3-arm, double-blind, sham-controlled randomized trial (NCT04578912), 50 youth (ages 12-21) with moderate-to-severe tics received 10 sessions of either 1Hz rTMS, continuous theta burst stimulation (cTBS), or sham stimulation to the SMA, immediately followed by CBIT. Primary outcomes were safety, feasibility, and neural target engagement (fMRI SMA activation and resting-state functional connectivity [RSFC]). Secondary outcomes included change in tic controllability, tic frequency at rest, and urges. Results: The CBIT+TMS intervention was safe and feasible (96% completion). Treatment-related adverse events were mild-to-moderate and occurred more frequently in the 1Hz rTMS group (27% of sessions) vs. cTBS (14.7%) and sham (11.3%). While task-based SMA activation remained unchanged, cTBS demonstrated robust neural target engagement, reducing SMA-primary motor cortex (M1) RSFC and putamen-M1 RSFC. Conversely, 1Hz rTMS blunted the cortico-striatal connectivity reductions observed in the sham group. All groups exhibited significant reductions in tic frequency and improved controllability. Premonitory urges increased in the 1Hz rTMS group but decreased in sham and cTBS. Conclusions: SMA-directed cTBS is a safe, feasible augmentation that may amplify the neural effects of CBIT on sensorimotor circuitry. Findings identify cTBS as the preferred stimulation regimen for future efficacy testing. Clinical Trial Registration: ClinicalTrials.gov; Identifier: NCT04578912.

Recurrent brain-computer interfaces (rBCIs) deliver targeted stimulation to one brain region based on neural activity recorded and processed in real-time at another. In a volitionally controlled rBCI, the user must also learn to intentionally produce the triggering neural activity, a process typically facilitated by an external reward. However, reliance on an external reward introduces a delay between the triggering event and reinforcement that can slow association between the two and, ultimately, control of the rBCI (particularly for neural activity not directly related to an observable behavior such as a goal-directed movement). The constraint to an external reward also limits studies of neural dynamics during natural, free behavior. In contrast, delivering activity-dependent stimulation directly to the brain's own reward centers - i.e., covert reinforcement - would bypass the need for external feedback, enabling precise temporal coupling between triggering events and reward and allowing for unrestrained rBCI use. Here, we show that rats can gain volitional control of an rBCI using activity-dependent electrical stimulation of the medial forebrain bundle as a sole reinforcer. Animals successfully learned to modulate motor unit discharge rates as well as specific electrocorticographic frequency bands (beta and gamma) to self-trigger stimulation. Furthermore, rats demonstrated flexible control by independently modulating distinct spectral features from the same cortical site. These findings suggest that covert reinforcement of endogenous reward networks can drive operant conditioning of specific neural signals during unrestrained behavior, opening new avenues for adaptive BCIs and closed-loop psychiatric therapies.

Over 30% of patients with epilepsy are refractory to medication and may require surgical or neuromodulation-based intervention. Accurate localization of seizure-onset zones (SOZ) and assessment of treatment-associated brain responses remain major clinical challenges. Current workflows may involve invasive intracranial monitoring, prolonged hospitalization, adjustment of anti-seizure medications, and seizure capture to localize the SOZ, while opportunities for complementary intraoperative functional assessment remain limited. We used intraoperative functional ultrasound imaging (fUSI) to characterize interictal (i.e., non-seizure) cortical activity in nine patients with drug-resistant focal epilepsy and to assess treatment-associated brain responses following SOZ resection and responsive neurostimulation (RNS). fUSI signals were acquired directly from the exposed cortex during standard-of-care surgery. We developed six ultrafast power Doppler-based interictal activity markers (IaMs) to distinguish SOZ from peri-resection zone (PRZ) cortex and to quantify treatment-associated changes. The IaMs revealed distinct interictal hemodynamic dynamics between SOZ and PRZ cortex. Following SOZ resection, all six markers changed significantly within the surrounding PRZ. RNS also induced robust, stimulation paradigm-dependent modulation of cortical hemodynamic dynamics. Notably, RNS and surgical resection produced concordant directional changes across five of the six IaMs, despite representing fundamentally different therapeutic interventions. Together, these findings demonstrate the feasibility of intraoperative fUSI for characterizing and distinguishing interictal dynamics within SOZ and PRZ cortex and assessing treatment-associated cortical responses during human epilepsy surgery. Furthermore, fUSI could provide a complementary high-resolution functional imaging approach alongside established clinical methods for SOZ localization and intraoperative functional assessment.

Background: Working memory, the cognitive ability to maintain and manipulate a finite amount of information, is fundamental in reasoning, learning, and decision-making. Working memory erodes in conditions from Alzheimer's disease to stroke to healthy aging. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising neuromodulation method for improving working memory. By stimulating the auricular branch of the vagus nerve, taVNS is thought to engage ascending arousal systems such as the locus coeruleus-norepinephrine (LC-NE) system. However, the physiological link between LC-NE system modulation via taVNS and improved working memory remains largely unknown. This mechanistic gap limits the rational optimization of the stimulation protocol and the identification of the cognitive functions and patient populations that are likely to benefit. Objective: We test two competing hypotheses for how taVNS may improve working memory: sensory amplification or enhancement of cortical efficiency. The sensory-amplification hypothesis predicts increased cortical responses to stimuli, whereas the cortical-efficiency hypothesis predicts reduced cortical responses. Methods: Twenty healthy adults completed N-back working memory tasks during three counterbalanced sessions: baseline, active vibrotactile taVNS (vtaVNS), and sham stimulation, while we simultaneously recorded electroencephalography, electrocardiography, eye-tracking, and behavioral responses. To study the effect of vtaVNS on neuronal activity, we also recruited 20 patients with epilepsy undergoing invasive monitoring. Of these, 19 fully completed the spatial working-memory task. We quantified cortical responses to visual stimuli using event-related potentials (ERPs) in scalp EEG and high-gamma activity in intracranial local field potentials. To examine prediction of the cortical-efficiency hypothesis, we further explored the effect of vtaVNS on distance to criticality and heartbeat-evoked potentials. Results: Active vtaVNS reduced both scalp-recorded visual ERP and high-gamma response in temporal cortices, relative to sham stimulation. Moreover, smaller visual event-related potentials were associated with successful encoding during the most demanding working-memory condition (i.e., 4-back task). Exploratory analyses showed that vtaVNS shifted cortical dynamics closer to criticality. Conclusion: Our results converge on the conclusion that vtaVNS does not uniformly amplify cortical responses to external stimuli. Instead, vtaVNS enhances cortical efficiency, supporting more effective allocation of cognitive resources between exteroceptive and mnemonic processes. These findings provide a framework for predicting when taVNS will be most beneficial and for optimizing stimulation protocols across cognitive and clinical applications.

Magnetic Resonance guided High Intensity Focused Ultrasound (MRgHIFU) has been demonstrated to be a safe and effective minimally invasive therapy for essential tremor (ET). However, it is not clear whether older adults ([&ge;]70 years old) or individuals with comorbidities exhibit similar safety and efficacy. This IRB approved project collected EPIC EMR data on patients that underwent MRgHIFU at Parkview Regional Medical Center from January 2023 to November 2025. 68 patients were assessed for tremor severity using Clinical Rating Scale for Tremor (CRST), quality of life using Quality of life in ET Questionnaire (QUEST), and safety profile via reported post-procedure side effects. CRST and QUEST scores improved up to 1 year from baseline in our patient cohort and efficacies in older ([&ge;]70 years of age) and younger (<70 years of age) patients up to 3 months post MRgHIFU were not statistically different. Effects of comorbidities on CRST or QUEST scores improvements were all transient or did not affect endpoints. Older patients showed fewer total side effects at 3 months (1.17 (95% CI: 0.47-1.87) vs 0.21 (95% CI: -0.09-0.51), p=0.017) as did patients with pulmonary disease at 1 month (1.9 (95% CI: 1.6-2.2) vs 1.1 (95% CI: 0.9-1.3), p=0.036) while patients with family history of tremor showed more side effects at day 1 (1.5 (95% CI: 0.8-2.2) vs 2.5 (95% CI: 2.1-2.9), p=0.025). Age and comorbidities were not detected to adversely affect safety or efficacy following MRgHIFU in ET patients.

Visual prostheses have targeted early structures in the visual pathway, including the retina, optic nerve, lateral geniculate nucleus, and visual cortex, to generate visual percepts. Stimulation of higher-order visual regions, which may better encode complex visual features, remains relatively unexplored. We tested whether electrical stimulation of the medial and inferior pulvinar elicits visual percepts in a patient with medically refractory epilepsy undergoing invasive seizure monitoring with intracranial electroencephalography. Bipolar stimulation (30 biphasic pulses, 0.5 ms per phase, 3 mA, 1 Hz) was delivered between adjacent pulvinar contacts while eye movements were tracked. Stimulation of different electrode pairs elicited visual percepts at distinct retinotopic locations (p = 0.010). Stimulation also altered cortical activity, producing an early power increase followed by gamma desynchronization in occipital and parietal regions (p < 0.001) and beta desynchronization in the lateral temporal region (p < 0.01). These findings suggest that pulvinar stimulation can generate visual percepts and modulate distributed cortical networks, supporting further investigation of the pulvinar as a target for vision restoration.

Transcranial direct current stimulation (tDCS) is a promising non-invasive therapy for drug-resistant epilepsy, but the montage optimization pipelines used to personalize it often rely on biophysical head models that capture only the induced electric field and ignore the network dynamics through which stimulation influences epileptogenic activity. We aimed to develop and evaluate a montage optimization framework that incorporates individualized network dynamics. We introduce a framework based on a digital twin, or neurotwin, a personalized replica of a patient's brain that couples a biophysical head model of the stimulation-induced field with a personalized whole-brain model (WBM) of seizure dynamics constrained by structural connectivity and intracranial recordings. We applied it to produce optimal montages in 12 patients with drug-resistant epilepsy, compared them with conventional biophysics-based optimization, and assessed the framework retrospectively against the clinical outcomes of six treated patients. Because the neurotwin optimization suppresses simulated spread by construction, the informative result is the divergence between pipelines: the network-informed and field-based optimizations produced substantially different montages despite delivering comparable inhibitory fields at the epileptogenic zone, and montages with nearly identical field distributions could yield markedly different network outcomes within the model. A minimum-replacement-set analysis traced these differences to field changes at a few propagation-zone and off-target parcels rather than to the overall field. The parcels whose inhibition most reduced spread tended to occupy highly connected (hub) positions in the structural connectome, a robust but partial association indicating that network structure shapes, but does not fully determine, where stimulation is most effective. In the retrospective analysis, model-predicted spread reduction tracked clinical seizure-frequency change in the expected direction, though not significantly (n=6). We hypothesize that accounting for individualized network dynamics may improve seizure control, a hypothesis now being tested prospectively (NCT06334952).

Background: High-definition transcranial alternating current stimulation (HD-tACS) is favored by the neurostimulation community for its precision and ability to influence neuronal dynamics. Yet, the exact mechanism by which the underlying brain structures are being affected remains unclear. We believe that the investigation of the aperiodic nature of the electroencephalograph (EEG) could shed light on the modulatory effects of HD-tACS. Methods: We analyzed the EEG of 9 participants during a compensatory tracking task (CTT) in two sessions, each with different HD-tACS protocols. Every session consisted of an initial period of no stimulation, followed by 30 Hz HD-tACS in the left motor (M30) or frontal (F30) cortex. We then isolated the aperiodic component of the EEG and calculated its spectral slope {beta}. Results and Discussion: {beta} decreased during F30 mainly in the right frontal cortex, indicating a shift towards higher frequencies and an increase of the excitatory/inhibitory balance. Additionally, we found that despite the long monotonus task the accuracy of the participants did not decrease, which might be attributed to the ability of both M30 and F30 to sustain attention for prolonged time. Finally, the change of CTT accuracy during the stimulation correlated with the {beta} of specific channels before the stimulation. This indicates the potential of {beta} to be used as a screening biomarker in future studies. In conclusion, we showed the ability of HD-tACS to alter EEG aperiodic dynamics and paved the way for future exploration of such dynamics in the field.

Electrical stimulation of brain activity has emerged as a key therapeutic intervention for neurological diseases. The success of these approaches relies on precisely tuned stimulation parameters. A major challenge is that these parameters should ideally be adjusted in real-time based on changes in brain activity. Closed-loop controllers address this challenge by monitoring brain activity and adapting stimulation according to ongoing changes in neural dynamics. While machine learning has been helpful in this context, closed-loop controllers typically do not adapt in real-time to fluctuations in brain activity. Here, we propose a novel framework based on reservoir computing to train a closed-loop, real-time neural controller. This approach, termed CLEAR-FORCE, trains the output weights of a recurrent network based on a combination of target signals and feedback from brain activity. Two series of simulations were performed, where the controller was successful at (1) inducing neural oscillations in a population of spiking neurons and (2) suppressing pathological oscillations. This framework provides a promising avenue for the implementation of neural controllers in low-powered, real-time, and adaptive hardware that harnesses machine learning for the personalized treatment of brain disorders.

Although functional neuroimaging studies using caloric and galvanic vestibular stimulation have identified a distributed cortical network involved in human vestibular processing, including the posterior insula, parietal operculum, temporo-parietal junction, cingulate and frontal areas, the causal contribution of specific brain regions to vestibular self-motion perception remains poorly understood. Invasive electrical brain stimulation (EBS) during stereoelectroencephalography (SEEG) offers a unique opportunity to causally map the cortical networks underlying vestibular self-motion perception in humans. Here, we retrospectively analyzed EBS-induced vestibular percepts in 354 patients with drug-resistant epilepsy undergoing SEEG. A total of 19,708 stimulations (11,004 at 50 Hz and 8,704 at 1 Hz) yielded 3,015 clinical responses. Vestibular self-motion illusions were defined as sensations of vertigo, dizziness, whole-body rotation, or translation occurring without corresponding physical movement. Stimulation sites were assigned to the seven large-scale functional networks of the Schaefer-Yeo atlas to characterize the network organization of vestibular self-motion perception. Vestibular self-motion sensations were elicited in 46 patients during 86 EBS delivered outside epileptogenic and lesional regions. Percepts ranged from nonspecific vertigo and dizziness (54.7%) to more explicit rotational (30.2%) and translational (15.1%) self-motion illusions. Vestibular responses were most commonly evoked by stimulation of the insula, medial temporal regions, cingulate cortex, inferior frontal gyrus, and premotor cortices. Network-level mapping using the Schaefer-Yeo atlas revealed a non-uniform distribution of vestibular sites across large-scale functional networks, with the highest representation within the salience/ventral attention, visual, and dorsal attention networks. Together, these findings provide causal evidence that vestibular self-motion perception emerges from activity within a distributed cortical network involved in attentional control and multisensory processing. Beyond advancing our understanding of human vestibular processing, these findings may have clinical relevance for disorders involving altered self-motion perception, including vestibular epilepsy and functional neurological disorders.

Importance: Upper extremity impairment is a leading cause of post-stroke disability, yet clinically approved neuromodulation therapies are currently limited by the risks and costs of surgical implantation. There is an unmet need for non-invasive brain stimulation. Objective: To evaluate the feasibility, safety, and preliminary clinical efficacy of a novel form of non-invasive brain stimulation, kilohertz transcranial magnetic perturbation (kTMP), for upper limb motor recovery after stroke. Design: A single-center, open-label trial was conducted between September 2025 and April 2026 and comprised a 4-week standard-of-care baseline period, 4 weeks of active treatment with kTMP combined with motor training, and a 4-week follow-up. Setting: Academic research center. Participants: Seven individuals with chronic stroke and upper extremity motor deficits. Intervention: Four weeks of kTMP (3 sessions/week), a brain stimulation approach using magnetic induction to generate subthreshold electric fields, paired with motor tasks. Main Outcomes: Change in Fugl-Meyer Assessment for Upper Extremity (FMA-UE) scores across study periods (standard-of-care baseline, active treatment, follow up). Secondary outcomes included measures of movement smoothness (Spectral Arc Length, SPARC) and fragmentation (mean velocity peak count), and intervention tolerability ratings. Results: Across 7 participants (mean [SD] age, 57.4 [8.7] years; 4 males; mean [SD] time poststroke, 3.5 [2.1] years). No device-related adverse events occurred, and the intervention was well-tolerated (participants rated sensation intensity at an average of less than 0.5 on a 0-10 scale). FMA-UE scores remained stable during the baseline period (mean change, +0.14 points; 95% CI, -1.21 to 1.50; adjusted P = .98), increased significantly following the kTMP-intervention (mean change, +7.00 points; 95% CI, 5.31 to 8.69; adjusted P = .047), and were sustained at the 4-week follow-up (mean change, -1.33 points; 95% CI, -2.42 to -.25 points; adjusted P = .13). Movement smoothness improved significantly within 1 week of kTMP onset (mean change, 1.48 points; 95% CI, .49 to 2.47; adjusted P = .03); movement fragmentation showed a similar but nonsignificant trend. Conclusions and Relevance: This pilot trial provides preliminary evidence that kTMP combined with motor tasks is safe, feasible, and may support upper extremity recovery. These pilot data warrant large, randomized controlled trials to evaluate efficacy in support of poststroke motor recovery. Trial Registration: ClinicalTrials.gov Identifier: NCT06317194

Severe hearing impairment affects approximately 5% of the global population, with a prevalence projected to increase over the coming decades. Cochlear implant devices pose a neuroprosthetic treatment option to allow sound perception and speech comprehension. However, users are limited in the spectrum of auditory information they can regain because electrical stimulation of the auditory nerve generates a broad spread of current and limits the transmission of sound frequency information. Recently, optogenetic stimulation of the cochlear nerve has emerged as a promising alternative for hearing restoration. Because light can be precisely confined in space, optogenetic stimulation of the cochlea permits to activate auditory neurons within smaller tonotopic regions, thereby improving the encoding of sound frequencies compared to electrical stimulation. However, this approach is limited in terms of dynamic range and ability to follow rapidly varying inputs, thus preventing faithful transmission of auditory information. Here, we developed an alternative approach targeting directly sensory inner hair cells with optogenetics. We demonstrate that this approach decreases the amount of light energy necessary to evoke auditory responses. Direct stimulation of hair cells increases the dynamic range of intensities encoded by neurons in subcortical auditory areas and improves the temporal fidelity of optogenetic responses. Finally, a biophysical model of the auditory system suggests that preserving the synapses between inner hair cells and auditory neurons greatly improves the encoding performance of an optical cochlear implant. Together, our results suggest that targeting sensory inner hair cells is a promising approach for hearing restoration through an optical implant.

Functional ultrasound (fUS) imaging provides deep, wide-field access to brain function, but instrument cost and complex acquisition and analysis workflows restrict its wider adoption. Here we introduce @fUS, an agentic transcranial imaging platform with an open architecture that integrates purpose-built hardware with executable experimental skills and persistent structured memory. The system combines 128-channel, 16-bit acquisition at 125 MHz with GPU-based processing and enables functional imaging through the intact scalp and skull of mice, with approximately 100-m spatial resolution and 10-Hz temporal sampling, providing a basis for longitudinal studies without cranial-window surgery. Its agent connects scientific objectives to experimental design, direct instrument control and data analysis, retaining context across interactions and supporting inspectable workflows through text and hands-free voice control. Neuroscience trainees with limited engineering experience independently configured the system within 30 min. Agent-assisted exploration of whisker-stimulation datasets revealed low-frequency vascular changes beyond conventional response mapping, supported by complementary two-photon measurements of single-vessel diameter. By combining transcranial imaging with accessible instrument control and analysis, @fUS provides a foundation for wider adoption and larger, more diverse neuroscience datasets. More broadly, it offers a framework for scientific instruments in which measurement, computation and experimental reasoning are developed as parts of the same system.

Objective. Intermittent theta burst stimulation (iTBS) is a repetitive transcranial magnetic stimulation (rTMS) protocol used in clinical settings to alleviate symptoms of psychiatric disorders. Although the pulse parameters currently used in iTBS have remained unchanged since the first treatments, recent controllable TMS devices allow for the personalization of pulse shape and duration, opening the possibility of testing the efficacy of other pulse parameters in modulating corticospinal excitability (CSE). Methods. In a repeated-measures design, changes in CSE were induced by the administration of iTBS over the left primary motor cortex under three different conditions: long bidirectional pulse (L-Bi), long quasi-unidirectional pulse (L-QU), and a control short quasi-unidirectional pulse (S-QU). We assessed TMS-induced motor evoked potentials before and up to 70 minutes after iTBS. We hypothesized that L-QU pulses would induce greater facilitation than other conditions. Results. A mixed linear model showed that all conditions induced increased MEPs compared to baseline. However, the L-Bi pulse led to a larger and more sustained MEP increase than both unidirectional pulses, while the S-QU pulse appeared less effective in modulating CSE. We observed large within- and between-subject variability in responsiveness to the iTBS protocols. Conclusion. These results suggest that L-Bi pulses in iTBS protocols are more potent than unidirectional pulses in inducing CSE changes in the cortex of healthy adults. The individual variability in response to iTBS and the potential clinical relevance of these findings are discussed.

Rhythmic visual stimulation offers a non-invasive means of modulating oscillatory brain activity, but conventional flicker may induce considerable visual discomfort. We developed an individualized Gabor flicker stimulation designed to balance neural entrainment and tolerability. In Experiment 1, thirty-four participants passively viewed Plain and Gabor flickers presented at their individual alpha frequency (IAF), IAF - 2 Hz, or IAF + 2 Hz, and at threshold-adjusted or full intensity. Steady-state visual evoked potential signal-to-noise ratio (SNR) was highest at IAF and increased with intensity. Plain and Gabor flickers produced comparable overall SNR, but Gabor flicker was rated as substantially more comfortable and less mentally fatiguing, with stimulation at IAF providing the most favorable balance between neural entrainment and tolerability. In Experiment 2, the optimized stimulation parameters were applied during a retro-cue working memory task using individualized theta and alpha frequency flickers. Stimulation increased SNR and inter-trial phase coherence relative to a non rhythmic Natural condition. No behavioral benefit was observed in the full sample. However, an exploratory subgroup analysis indicated higher accuracy with theta stimulation of cued representations and alpha stimulation of uncued representations than in the Natural condition among participants who showed limited baseline retro-cue benefits. These findings show that individualized Gabor flicker can provide robust and well-tolerated neural entrainment during passive viewing and working memory retention, although its behavioral effects may vary across individuals according to their cognitive performance.