Brain Stimulation

BackgroundDeep brain ultrasound offers a novel means of modulating human cognition by noninvasively targeting subcortical structures that were previously accessible only through invasive procedures. While decades of research have mapped cortical circuits of attention, the causal roles of deep hubs such as the basal ganglia and thalamus remain poorly understood in the healthy human brain. Objectives/HypothesisTo test whether low intensity transcranial ultrasound stimulation (TUS) of two nodes in the basal ganglia-thalamic network, the globus pallidus internus (GPi) and the pulvinar, causally alters visual attention. We hypothesized that TUS-induced modulations in attentional performance would be site specific, reflecting distinct circuit functions. ResultsAcross sessions, focal TUS accelerated reaction time in a visual search task, indicating augmented attention. Reaction time improvements were observed after stimulation relative to baseline. A dissociation emerged across sites: both GPi and pulvinar enhanced reaction times, but pulvinar yielded more robust benefits for target present trials at peripheral eccentricities, and improved search efficiency in the same trials. ConclusionsThese findings provide causal evidence that human attentional control can be steered at deep subcortical sites. TUS offers a practical approach for dissecting circuit level contributions to cognition and a potential noninvasive avenue for enhancing attention and other cognitive or affective functions.

Brain-state-controlled transcranial magnetic stimulation (TMS) studies with real-time electroencephalography (EEG) show that the phase of ongoing oscillations modulates cortical susceptibility to TMS pulses. Translating this principle to repetitive clinical protocols, such as intermittent theta burst stimulation (iTBS), is an open challenge because within-train stimulation pulses corrupt real-time EEG. Moreover, the general difficulty of predicting EEG theta phase even to initiate an iTBS train applies. We present our solution for prefrontal EEG-phase-controlled iTBS, a personalized stimulation framework. We demonstrate the technical feasibility of aligning each trains initial bursts to the individual prefrontal theta phase and propose a "seed-and-sustain" hypothesis, whereby intra-train stimulation-induced entrainment at the individual theta rhythm carries the later bursts. Future human trials will be needed to evaluate the practical benefits of this approach. HighlightsO_LIIntermittent TBS synchronized to the prefrontal EEG theta rhythm is feasible C_LIO_LIPersonalized iTBS-EEG parameters are stable over the typical session time C_LIO_LIClinical evaluation of iTBS-EEG is a direction for future work C_LI

BackgroundDeep brain stimulation (DBS) reduces the motor symptoms of Parkinsons disease. The two most common targets are the subthalamic nucleus and the globus pallidus. Dual target deep brain stimulation may better reduce symptoms and minimize side effects, but the optimal parameters of dual target deep brain stimulation and their potential interactions are unknown. ObjectiveOur purpose was to quantify the frequency response of dual target DBS on bradykinesia and beta oscillations in participants with Parkinsons disease, and to explore intrahemispheric pulse delays as a means to reduce total energy delivered. MethodsWe applied dual target DBS using the Summit RC+S in six participants, varying deep brain stimulation frequency. ResultsDual target DBS at 50 Hz was effective at reducing bradykinesia, whereas increasing deep brain stimulation frequency up to 125 Hz also significantly reduced beta power. This frequency effect on beta power was replicated in a biophysical model. The model suggested that 22 Hz dual target deep brain stimulation, with an intrahemispheric delay of 40 ms, can reduce beta power by 87%. ConclusionWe conclude that dual target DBS at 125 Hz best reduced bradykinesia. However, low frequency DBS with an appropriate intrahemispheric delay could improve symptom relief.

BackgroundTranscranial ultrasonic stimulation (TUS) is an emerging non-invasive neuromodulation technique with the potential to target both cortical and subcortical brain regions. This study investigates the effects of theta-burst TUS (tb-TUS), a neuromodulatory pattern characterized by bursts of pulses repeated at a theta frequency, on cerebral blood flow, functional connectivity, and metabolite concentrations in the primary motor cortex (M1). The aim of this study is to take a first step towards the mechanistic and methodological feasibility of tb-TUS at the M1 using multimodal neuroimaging. MethodsSeventeen healthy participants underwent a double-blind, sham-controlled crossover design, receiving both active and sham tb-TUS to the left M1 over three days. Multimodal MRI, including pseudo-continuous arterial spin labeling (PCASL), resting-state functional MRI (rs-fMRI), and magnetic resonance spectroscopy (MRS), was conducted at baseline, pre-, and post-stimulation. Acoustic simulations and finger-tapping BOLD-peak signal guided individualized TUS targeting. ResultsActive tb-TUS significantly reduced cerebral blood flow (p < .001) and within-region functional connectivity (p < .001) in the M1 compared to sham stimulation. A non-significant trend towards decreased GABA was observed, with no significant session x condition interaction found for GABA, Glutamate, or Glx concentrations. ConclusionThis pilot study demonstrates that tb-TUS of the M1 induces reductions in cerebral blood flow and functional connectivity in healthy participants. Our findings indicate that tb-TUS may be mitigating neural hyperactivity patterns, but preliminary studies so far arrive at differing results, highlighting the need for further research to replicate our findings, elucidate the underlying mechanisms, and optimize stimulation protocols.

BackgroundThe hippocampus and medial temporal lobe are crucial for spatial memory, and their dysfunction is linked to Alzheimers disease (AD), with changes detectable even in preclinical stages. Recently, neuromodulation has gained interest as a potential treatment due to its beneficial effects on AD pathology and cognitive performance. However, outcomes vary significantly based on stimulation parameters and study conditions, and evidence from large animal models remains limited. ObjectiveTo assess whether epicranial current stimulation (ECS) at 40 Hz can improve non-navigational spatial memory and hippocampal activations. MethodsThree rhesus macaques were implanted with spiral platinum electrodes bilaterally on the skull and were trained in a non-navigational spatial memory task. ECS was applied at 40 Hz or at 10 Hz and performance across multiple sessions was evaluated. We further performed ECS during fMRI to examine the spread of activations caused by ECS across the brain in a block-design experiment. ResultsECS at 40 Hz improved performance in a non-navigational spatial memory task, while 10 Hz ECS had minimal or negative effects. Concurrent ECS-fMRI showed extensive brain activations at 40 Hz, including significant hippocampal activations, which was not observed at 10 Hz. ConclusionsOur results show that ECS could be a minimally-invasive and effective approach to improve memory performance and activate the hippocampus. ECS could represent a potential treatment for patients suffering from memory impairment.

Background: Theta burst stimulation (TBS) is an efficient form of repetitive transcranial magnetic stimulation, but tolerability may depend on target and stimulation pattern, limiting translation to accelerated protocols. Objective: To estimate tolerable intensities for intermittent TBS (iTBS) over F3, approximating left dorsolateral prefrontal cortex, and continuous TBS (cTBS) over Fp1, intended to engage more anterior ventral/frontopolar circuitry, in non-treatment-seeking adults with obesity or tobacco use disorder. Methods: In an open-label randomized crossover titration study, 64 adults completed two TBS visits 7 days apart. Each visit included 3 sessions of 600 pulses, beginning at 80% resting motor threshold (RMT) with protocol-permitted escalation or de-escalation. The primary endpoint was participant-level maximum final maintained intensity. Bayesian grouped-binomial logistic regression estimated the intensity tolerated by 70% of participants (ED70), and a prespecified rule selected the highest dose with at least 80% posterior probability of meeting 70% tolerability. Results: Observed tolerability at 80% RMT was 86.4% for iTBS and 51.6% for cTBS. Primary-model ED70 was 105.5% RMT (95% credible interval [CrI], 99.0%-113.9%) for iTBS and 69.2% RMT (95% CrI, 65.0%- 73.4%) for cTBS. The recommended intensity was 100% RMT for iTBS and 60% RMT for cTBS; no cTBS dose at or above 80% RMT met criterion. cTBS produced greater immediate symptom burden, whereas 24-hour symptoms were uncommon. Conclusion: iTBS over F3 supported a future-trial design window of 90%-100% RMT, whereas cTBS over Fp1 showed a tolerability ceiling below 80% RMT. Future cTBS protocols targeting ventral prefrontal circuitry may need to move dorsally to improve tolerability.

Transcranial electrical stimulation (TES) holds promise to treat neurological disorders, but its efficacy is limited by poor spatial focality and depth of penetration. Here, we examined the potential utility of Intersectional Short-Pulse (ISP) stimulation of deeper brain penetration. Using computational modeling and in vivo patch-clamp recordings in rats, we demonstrate that neurons integrate ISP-induced electric fields in a non-vectorial manner. This mechanism allows ISP to overcome some limits of conventional TES, achieving spatially limited stimulation across cortical and subcortical structures. In a rat model of temporal lobe epilepsy, closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 49% and 41% compared to sham stimulation and conventional TES and significantly reduced motor seizure severity. Our findings demonstrate that ISP stimulation can rapidly terminate hippocampal seizures, offering a potential new approach for non-invasive neuromodulation with applications across diverse neurologic and psychiatric disorders.

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.

BackgroundIdentifying effective deep brain stimulation (DBS) parameters for psychiatric disorders has historically been a time-consuming and error prone process due to a lack of an objective and rapid readout of target circuit engagement. Cognitive control may have use as a biomarker of treatment efficacy but it has yet to be shown that DBS parameters can be reliably optimized to produce cognitive control improvements in individual subjects. ObjectiveWe sought to leverage a rat model of DBS-driven cognitive control improvements to determine whether state of the art optimization algorithms could consistently identify effective stimulation amplitudes to enhance cognition. MethodsWe delivered periods of active and inactive DBS-like stimulation at variable parameters while rats performed a Set-Shifting task that we previously showed to be stimulation-sensitive. We tested both predefined settings of interest and settings that were personalized to individual animals using Bayesian Optimization. Measurements of task performance including reaction time and accuracy were compared between acute, optimized, and traditional settings to evaluate effects on cognitive control. ResultsAcute stimulation reduced reaction times without hindering accuracy (N=15), replicating the effects previously observed with chronic stimulation. In a second cohort (N=6), optimization of stimulation amplitude successfully reduced reaction times in all animals with comparable effect size to historically best settings. ConclusionThese findings confirm that optimization techniques can be effective for improving symptomatically-relevant cognitive markers supporting the feasibility of personalized, quantitatively-informed approaches to neuromodulation and target engagement for psychiatric and/or cognitive disorders. HighlightsProving target engagement is a substantial challenge across brain stimulation modalities, and objective, rapid behavioral read-outs may be a solution to that challenge. Reaction times in cognitive control tasks are an example of a behavioral measure that changes rapidly in response to changes in stimulation parameters, and that also may predict clinical outcomes. Individually optimal stimulation amplitudes for reducing reaction time by stimulating corticofugal fibers passing through the striatum can be determined using Bayesian Optimization. Individually optimized settings discovered in an acute preparation demonstrate consistent effects when applied chronically.

Transcranial Magnetic Stimulation (TMS) evokes electroencephalographic (EEG) responses that can persist for hundreds of milliseconds. While the first 80 ms after the pulse are widely accepted to reflect genuine cortical responses to TMS, later components have mainly been attributed to the effects of sensory co-stimulations. Here we reappraise this view by investigating the target-specificity of the spatiotemporal evolution of TMS-evoked potentials (TEPs). To this end, we compared TEPs elicited by targeting the premotor and primary motor cortices in 16 healthy subjects, under conditions designed to optimize TMS effectiveness on the cortex while minimizing peripheral confounds. As a counterfactual, we conducted the same comparison on the EEG responses evoked by realistic sham TMS and high-intensity somatosensory scalp stimulation. We found that EEG responses to motor and premotor TMS can exhibit distinct spatiotemporal evolutions, lasting up to 300 ms, both at the group and single-subject levels. These differences were absent or marginally detectable in both realistic sham TMS and high-intensity somatosensory scalp stimulation. Our findings suggest that, when effectiveness is optimized and peripheral confounds are controlled, TMS elicits specific long-lasting genuine EEG responses that reflect the initial engagement of specific cortical targets. These results challenge previous assumptions and highlight how TMS-EEG can be reliably used to assess large-scale properties within corticothalamic networks.

BackgroundTranscutaneous auricular vagus nerve stimulation (taVNS) is a promising brain stimulation method for the treatment of pharmaco-resistant epilepsy and depression. Its clinical efficacy is thought to depend on taVNS-induced activation of the locus coeruleus. However, unlike for invasive VNS, there is little evidence for an effect of taVNS on noradrenergic activity. ObjectiveWe attempted to replicate recently published findings by Sharon et al. (2021), showing that short bursts of taVNS transiently increased pupil size and decreased EEG alpha power, two correlates of central noradrenergic activity. MethodsFollowing the original study, we used a single-blind, sham-controlled, randomized cross-over design. We applied short-term (3.4 s) taVNS in healthy human volunteers (n=29), while collecting resting-state pupil-size and EEG data. To analyze the data, we used scripts provided by Sharon and colleagues. ResultsConsistent with Sharon et al. (2021), pupil dilation was significantly larger during taVNS than during sham stimulation (p = .009; Bayes factor supporting the difference = 7.45). However, we failed to replicate the effect of taVNS on EEG alpha power (p = .37); the data were four times more likely under the null hypothesis (BF10 = 0.28). ConclusionOur findings support the effectiveness of short-term taVNS in inducing transient pupil dilation, a correlate of phasic noradrenergic activity. However, we failed to replicate the recent finding by Sharon et al. (2021) that taVNS attenuates EEG alpha activity. Overall, this study highlights the need for continued research on the neural mechanisms underlying taVNS efficacy and its potential as a treatment option for pharmaco-resistant conditions. It also highlights the need for direct replications of influential taVNS studies.

BackgroundElectrical cortical stimulation is often used in patients with neurological disorders but it is unclear how it modulates different types of brain cells. ObjectiveThe aim of this study was to determine the effect of sinusoidal electrical brain stimulation (SEBS) on different types of brain cells and to identify the exact types of brain cells that are stimulated. MethodsThe study subjects were 40 male Sprague Dawley rats (weight 300-350 g; age 9 weeks). SEBS was delivered continuously at frequencies of 20, 40, 60, or 100 Hz to the sensory parietal cortex using epidurally placed electrodes for 1 week. Transverse rat brain tissue sections were immunolabeled with calmodulin-dependent protein kinase II and parvalbumin (PV) antibodies and with c-Fos for counting of activated excitatory and inhibitory neurons. Computer simulation was performed to cross-validate the frequency-specific cell stimulation results. ResultsInhibitory neurons were more excited than excitatory neurons after epidural EBS. Most excitatory neural activity was evoked at 40 Hz (p<0.05) and most inhibitory neuronal activity was evoked at 20 Hz (p<0.01). The contralateral sensory cortex was activated significantly more at 40 Hz (p<0.05) and the corticothalamic circuit at 20 Hz (p<0.001). Stimulation-induced excitatory and inhibitory neuronal activation was widest at 20 Hz. ConclusionsEpidural electrical stimulation targets both excitatory and inhibitory neurons and the related neural circuits. Further exploration is needed to identify circuits that promote the plasticity needed for recovery in patients with specific neurological diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/855395v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@3fbad8org.highwire.dtl.DTLVardef@3dad5org.highwire.dtl.DTLVardef@113fbe9org.highwire.dtl.DTLVardef@ffa066_HPS_FORMAT_FIGEXP M_FIG C_FIG

Although stimulation with ultrasound has been shown to modulate brain activity at multiple scales, it remains unclear whether transcranial focused ultrasound stimulation (tFUS) exerts its influence on specific cell types. Here we propose a novel form of tFUS where a continuous waveform is amplitude modulated (AM) at a slow rate (i.e., 40 Hz) targeting the temporal range of electrophysiological activity: AM-tFUS. We stimulated the rat hippocampus while recording multi-unit activity (MUA) followed by classification of spike waveforms into putative excitatory pyramidal cells and inhibitory interneurons. At low acoustic intensity, AM-tFUS selectively reduced firing rates of inhibitory interneurons. On the other hand, higher intensity AM-tFUS increased firing of putative excitatory neurons with no effect on inhibitory firing. Interestingly, firing rate was unchanged during AM-tFUS at intermediate intensity. Consistent with the observed changes in firing rate, power in the theta band (3-10 Hz) of the local field potential (LFP) decreased at low-intensity, was unchanged at intermediate intensity, and increased at higher intensity. Temperature increases at the AM-tFUS target were limited to 0.2{degrees}C. Our findings indicate that inhibitory interneurons exhibit greater sensitivity to ultrasound, and that cell-type specific neuromodulation may be achieved by calibrating the intensity of AM-tFUS.

AbstractsSensorimotor mu-alpha rhythm reflects the state of cortical excitability. Repetitive transcranial magnetic stimulation (rTMS) can modulate neural synchrony by inducing periodic electric fields (E-fields) in the cortical networks. We hypothesized that the increased synchronization of mu-alpha rhythm would inhibit the corticospinal excitability reflected by decreased motor evoked potentials (MEP). In seventeen healthy participants, we applied rhythmic, arrhythmic, and sham rTMS over the left M1. The stimulation intensity was individually adapted to 35 mV/mm using prospective E-field estimation. This intensity corresponded to ca. 40% of the resting motor threshold. We found that rhythmic rTMS increased the synchronization of mu-alpha rhythm, increased mu-alpha/beta power, and reduced MEPs. On the other hand, arrhythmic rTMS did not change the ongoing mu-alpha synchronization or MEPs, though it increased the alpha/beta power. We concluded that low intensity, rhythmic rTMS can synchronize mu-alpha rhythm and modulate the corticospinal excitability in M1. HighlightsO_LIWe studied the effect of rhythmic rTMS induced E-field at 35 mV/mm in the M1 C_LIO_LIProspective electric field modeling guided the individualized rTMS intensities C_LIO_LIRhyhtmic rTMS entrained mu-alpha rhythm and modulated mu-alpha/beta power C_LIO_LIArrhythmic rTMS did not synchronize ongoing activity though increased mu-alpha/beta power. C_LIO_LIRhythmic but not arrhythmic or sham rTMS inhibited the cortical excitability in M1 C_LI

Slice electrophysiological studies have experimentally demonstrated that theta burst stimulation, consisting of electrical pulses delivered at 10 ms (100 Hz) inter-pulse intervals, optimally induces long-term potentiation in the hippocampus. Inspired by this observation, a novel transcranial magnetic stimulation (TMS) paradigm, 100 Hz high-density theta burst stimulation (100 Hz hdTBS), is presented. This paradigm delivers 6 pulses per burst with an inter-pulse interval of 10 ms - doubling the pulse frequency and total pulse count of the conventional intermittent TBS (iTBS). The effect of this new paradigm was studied in the motor cortex of awake rats using a rat-specific focal TMS coil and a hdTBS stimulator developed in house. Results reveal that 100 Hz hdTBS triples the after-effects of conventional iTBS. In a separate group of animals that received two consecutive iTBS session back-to-back (prolonged iTBS), we observed an inhibitory effect. Since that prolonged iTBS matches the total pulse count of 100 Hz hdTBS but produced opposite after-effects, our results underscore the critical roles of the temporal structure of TMS pulses--not merely the total number of pulses--in driving neuroplasticity. This new paradigm has the potential to significantly enhance therapeutic efficacy if confirmed to be safe and effective in humans.

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.

The progress of therapeutic neuromodulation greatly depends on improving stimulation parameters to most efficiently induce neuroplasticity effects. Intermittent Theta Burst stimulation (iTBS), a form of electrical stimulation that mimics the natural brain activity patterns, has shown efficacy in inducing such effects in animal studies and rhythmic Transcranial Magnetic Stimulation (rTMS) studies in humans. However, little is known about the potential neuroplasticity effects of iTBS applied through intracranial electrodes in humans which could have implications for deep brain stimulation therapies. This study characterizes the physiological effects of cortical iTBS in the human cortex and compare them with single pulse alpha stimulation, another frequently used paradigm in rTMS research. We applied these stimulation paradigms to well-defined regions in the sensorimotor cortex which elicited contralateral hand or arm muscle contractions during electrical stimulation mapping in epilepsy patients implanted with intracranial electrodes. Treatment effects were evaluated using effective connectivity and beta oscillations coherence measures in areas connected to the treatment site as defined with cortico-cortical evoked potentials. Our results show that iTBS increases beta band synchronization within the sensorimotor network indicating a potential neuroplasticity effect. The effect is specific to the sensorimotor system, the beta frequency band and the stimulation pattern (no effect was found with single-pulse alpha stimulation). The effects outlasted the stimulation by three minutes. By characterizing the neurophysiological effects of iTBS within well-defined cortical networks, we hope to provide an electrophysiological framework that allows clinicians and researchers to optimize brain stimulation protocols which may have translational value.

Full abstractO_ST_ABSBackgroundC_ST_ABSPrevious studies in people with substance use disorders (SUDs) have implicated both the frontopolar cortex and amygdala in drug cue reactivity and craving, and amygdala-frontopolar coupling is considered a marker of early relapse risk. Accumulating data highlight that the frontopolar cortex can be considered a promising therapeutic target for transcranial magnetic stimulation (TMS) in SUDs. However, one-size-fits-all approaches to TMS targets resulted in substantial variation in both physiological and behavioral outcomes. Individualized TMS approaches to target cortico-subcortical circuits like amygdala-frontopolar have not yet been investigated in SUDs. ObjectiveHere, we (1) defined individualized TMS target location based on functional connectivity of the amygdala-frontopolar circuit while people were exposed to drug-related cues, (2) optimized coil orientation based on maximizing electric field (EF) perpendicular to the individualized target, and (3) harmonized EF strength in targeted brain regions across a population. MethodMRI data including structural, resting-state, and task-based fMRI data were collected from 60 participants with methamphetamine use disorders (MUDs). Craving scores based on a visual analog scale were collected immediately before and after the MRI session. We analyzed inter-subject variability in the location of TMS targets based on the maximum task-based connectivity between the left medial amygdala (with the highest functional activity among subcortical areas during drug cue exposure) and frontopolar cortex using psychophysiological interaction (PPI) analysis. Computational head models were generated for all participants and EF simulations were calculated for fixed vs. optimized coil location (Fp1/Fp2 vs. individualized maximal PPI location), orientation (AF7/AF8 vs. orientation optimization algorithm), and stimulation intensity (constant vs. adjusted intensity across the population). ResultsLeft medial amygdala with the highest (mean {+/-} SD: 0.31{+/-}0.29) functional activity during drug cue exposure was selected as the subcortical seed region. Amygdala-to-whole brain PPI analysis showed a significant cluster in the prefrontal cortex (cluster size: 2462 voxels, cluster peak in MNI space: [25 39 35]) that confirms cortico-subcortical connections. The location of the voxel with the most positive amygdala-frontopolar PPI connectivity in each participant was considered as the individualized TMS target (mean {+/-} SD of the MNI coordinates: [12.6 64.23 -0.8] {+/-} [13.64 3.50 11.01]). Individual amygdala-frontopolar PPI connectivity in each participant showed a significant correlation with VAS scores after cue exposure (R=0.27, p=0.03). Averaged EF strength in a sphere with r = 5mm around the individualized target location was significantly higher in the optimized (mean {+/-} SD: 0.99 {+/-} 0.21) compared to the fixed approach (Fp1: 0.56 {+/-} 0.22, Fp2: 0.78 {+/-} 0.25) with large effect sizes (Fp1: p = 1.1e-13, Hedgesg = 1.5, Fp2: p = 1.7e-5, Hedgesg = 1.26). Adjustment factor to have identical 1 V/m EF strength in a 5mm sphere around the individualized targets ranged from 0.72 to 2.3 (mean {+/-} SD: 1.07 {+/-} 0.29). ConclusionOur results show that optimizing coil orientation and stimulation intensity based on individualized TMS targets led to stronger electric fields in the targeted brain regions compared to a one-size-fits-all approach. These findings provide valuable insights for refining TMS therapy for SUDs by optimizing the modulation of cortico-subcortical circuits. Short AbstractO_ST_ABSBackgroundC_ST_ABSPrior research on drug addiction has linked the frontopolar cortex and amygdala coupling to drug cue reactivity/craving. However, one-size-fits-all approaches for transcranial magnetic stimulation (TMS) over frontopolar-amygdala have led to inconsistent results. ObjectiveHere, we (1) defined individualized TMS target location based on functional connectivity of the amygdala-frontopolar circuit while people were exposed to drug-related cues, (2) optimized coil orientation for maximum electric field (EF) perpendicular to the individualized target, and (3) harmonized EF strength in targeted brain regions across a population. MethodMRI data were collected from 60 participants with methamphetamine use disorders (MUDs). and examined the variability in TMS target location based on task-based connectivity between the frontopolar cortex and amygdala. using psychophysiological interaction (PPI) analysis. EF simulations were calculated for fixed vs. optimized coil location (Fp1/Fp2 vs. individualized maximal PPI), orientation (AF7/AF8 vs. optimization algorithm), and stimulation intensity (constant vs. adjusted intensity across the population). ResultsLeft medial amygdala with the highest (0.31{+/-}0.29) fMRI drug cue reactivity was selected as the subcortical seed region. The location of the voxel with the most positive amygdala-frontopolar PPI connectivity in each participant was considered as the individualized TMS target (MNI coordinates: [12.6,64.23,-0.8]{+/-}[13.64,3.50,11.01]). Individualized frontopolar-amygdala connectivity showed a significant correlation with VAS craving scores after cue exposure (R=0.27, p=0.03). Averaged EF strength in a sphere with r=5mm around the individualized target location was significantly higher in the optimized (0.99{+/-}0.21V/m) compared to the fixed approach (Fp1:0.56{+/-}0.22V/m, Fp2:0.78{+/-}0.25V/m) with large effect sizes (Fp1:p=1.1e-13,Hedgesg=1.5, Fp2:p=1.7e-5,Hedgesg=1.26). Adjustment factor to have identical 1V/m EF strength in a 5mm sphere around the individualized targets ranged from 0.72-to-2.3 (1.07{+/-}0.29). ConclusionOur results show that optimizing coil orientation and stimulation intensity based on individualized TMS targets led to stronger harmonized electric fields in the targeted brain regions compared to a one-size-fits-all method that hopefully helps to refine future TMS therapy for MUDs.

Sensory gating -- the brains ability to filter out repetitive sensory input -- is essential for preventing sensory overload. Impaired gating is frequently observed in nociplastic and other chronic overlapping pain conditions, yet the specific brain regions supporting this inhibitory process in humans remains unclear. Neuroimaging studies examining pain processing implicate the anterior insula (AI), posterior insula (PI), and anterior mid-cingulate cortex (aMCC), but their deeper locations limit direct mechanistic testing using conventional non-invasive techniques. Here, we leveraged low-intensity focused ultrasound (LIFU), a novel non-invasive neuromodulation method with high depth-penetration and millimeter resolution, to examine the contributions of the AI, PI, and aMCC to sensory gating of nociceptive stimuli. Twelve healthy adults completed four counterbalanced visits of a paired-pulse contact heat evoked potential (CHEP) paradigm while receiving LIFU targeted to each region or an active sham. Using surface electroencephalography (EEG), placed at site Cz, we quantified the peak-to-peak (P2P) amplitude of the cortical response to the first stimulus (S1), the second stimulus (S2), and used the ratio of the response to each stimulus (S2/S1 ratio) as an index of sensory gating. Subjective ratings of pain intensity to the second stimulus were also recorded. Results demonstrated that all subjects displayed sensory gating at baseline and thatLIFU produced region-specific effects. Both PI and aMCC neuromodulation reduced subjective pain ratings and significantly decreased S2 amplitude relative to sham, whereas LIFU to AI had no effect. Critically, only PI neuromodulation enhanced sensory gating by reducing the S2/S1 ratio. These findings identify the PI as a key contributor to gating of repetitive nociceptive input and a promising neuromodulation target for remediating sensory gating deficits in nociplastic pain.

Deep brain stimulation (DBS) is increasingly viewed as a network-level intervention, yet clinical practice typically targets a single brain structure per hemisphere. Coordinated multi-site stimulation may help probe and modulate distributed circuits, but additional invasive implantation is limited by safety and ethical constraints. Here, we present an approach to couple DBS with non-invasive transcranial alternating current stimulation (tACS) via precise phase synchronization. We introduce DeepPLL, an open-source interface device enabling real-time phase locking between DBS pulse trains and external stimulation like tACS. The system extracts DBS EEG artefacts using an isolated analogue front-end and stabilizes timing via a phase-locked loop (PLL) implemented in hardware or software. A digital phase-delay module with 1 degree resolution allows controlled adjustment of DBS phase, and low-jitter TTL outputs drive the external device. In two individuals with Parkinson's disease treated with subthalamic DBS, DeepPLL achieved reliable phase locking between DBS and motor-cortex tACS with sub-millisecond jitter in both PLL modes. This demonstrates feasibility of precise invasive-non-invasive stimulation synchronization in vivo and provides a platform for investigating phase-dependent network dynamics and plasticity.