The functional organization of human cortex has been mapped in considerable detail1-5, yet the axonal connections linking these areas remain largely unknown. This gap precludes inferring either the computational pathways through cortical networks or the principles governing why each area connects to its particular target regions. Here, in patients undergoing intracranial monitoring for epilepsy, we used concurrent electrical stimulation and functional magnetic resonance imaging (es-fMRI), validated previously against tracer studies in nonhuman primates6, to map anatomical connectivity of cortical sites across the whole brain, and combined these maps with task and resting-state fMRI in the same individuals. Es-fMRI revealed four main findings. First, connectivity followed an asymmetric functional-similarity principle: connected sites tended to share similar functional profiles, but, because connectivity is sparse, most pairs of functionally similar sites were not connected. Second, although connectivity also declines with distance7, the functional profile explained three times as much variance in connectivity as distance did, and long-range connections were the most functionally specific. Third, es-fMRI revealed direct monosynaptic links between established functional regions, including between the fusiform face area (FFA)2 and the temporoparietal junction (TPJ)3 for social cognition. Fourth, resting-state functional connectivity (rsFC) of a stimulation site was only weakly correlated with that site's es-fMRI connectivity. Together, these results provide a first principled link between anatomical connectivity and functional organization in the human cortex, and establish es-fMRI as a scalable approach to building a tracer-grade connectome of the human brain.

BACKGROUND:Olfactory dysfunction is highly prevalent worldwide and linked to major neurologic and psychiatric disorders. Electrical stimulation of the olfactory bulb (OB) and olfactory tract (OT) has emerged as a potential therapeutic approach to restore olfactory percepts and possibly improve associated conditions. OBJECTIVE:This study aimed to systematically review preclinical and clinical electrical stimulation studies of the OB and OT, evaluate their relevance for olfactory prosthesis development, and identify key technical and translational requirements for clinical implementation. MATERIALS AND METHODS:Following Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidelines, PubMed, EMBASE, and Web of Science were searched until December 31, 2025. Eligible studies reported in vivo electrical stimulation of the OB or OT in mammals. A narrative synthesis of the data was undertaken. RESULTS:Overall, 42 studies were included (38 animal, four human). Critically for prosthesis development, all four human studies successfully elicited olfactory perceptions through OB/OT stimulation. In rodent anosmia models, electrical stimulation evoked spatially selective neural responses, with animals indicating discrimination between stimulation sites spaced as close as 250 μm-establishing proof of principle for encoding distinct odor percepts. Stimulation parameters significantly influenced outcomes: Spatially targeted, patterned stimulation produced odor-like responses and supported associative learning, whereas diffuse, high-frequency stimulation modulated mood and memory circuits. The OB/OT's extensive connectivity to limbic structures offers potential therapeutic benefits beyond smell restoration, although this requires careful parameter optimization. CONCLUSION:OB and OT stimulation are accessible neuromodulation targets with promising but context-dependent effects. Translation requires standardized protocols, large-mammal validation, and early-phase adult human studies.

Patients with drug-resistant epilepsy can be treated with the Responsive Neurostimulation (RNS) system. This system has the ability to sense the electrical activity of the brain and provide stimulation when epileptiform patterns are detected. Patients implanted with the RNS system in the thalamus experience longer periods of stimulation. Since the implanted electrodes have a dual function of sensing and stimulating, patients with RNS in the thalamus show recordings with significant data information loss. Consequently, deep learning algorithms developed to analyze the presence of epileptogenic patterns in RNS recordings have shown decreased performance when evaluated in thalamic patients. This study aims to enhance the detection capability of epileptogenic patterns in a deep neural network (iESPnet) for thalamic patients by integrating a spatial attention mechanism called Dynamic Spatial Filtering (DSF) into the learning process. Various experiments were conducted to determine if the combined use of DSF and iESPnet has the potential to improve the detection capacity of epileptogenic patterns. A database of 30 patients implanted with RNS was utilized. The results demonstrate that the integration of the attention mechanism has the potential to enhance the network’s detection capabilities, achieving relative improvements of up to 30

Intraoperative intracranial electrophysiological recordings provide unique access to human cortical dynamics but remain difficult to translate across patients due to inconsistent localization of transient surface electrodes. Unlike chronic implantations, intraoperative electrodes are placed transiently, rarely visible on imaging, and often inconsistently documented. We present an open-source imaging pipeline, ALIGNER (Advanced Localization and Imaging Guidance for Neurosurgical Electrode Recording), designed to reconstruct intraoperative surface electrode array placements and quantitatively map neural activity to individualized anatomical and pathological substrates. By enabling anatomical localization of these electrodes, this framework supports systematic analysis of spatial gradients in neural activity relative to pathological tissue. We developed a multimodal reconstruction framework integrating pre- and postoperative MRI and CT, cortical surface modeling, semi-automated pathology segmentation, intraoperative photographs or videos when available, and physics-based electrode modeling. To improve robustness in cases with distorted anatomy, artificial intelligence tools such as SynthSR were used to enable reliable cortical surface reconstruction prior to FreeSurfer processing. A monocular depth-estimation network was incorporated to constrain electrode placement in conjunction with Blender cloth-physics simulation when photographic images were available, while atlas- and note-guided inference supported reconstruction otherwise. The pipeline was applied to 38 neurosurgical patients across drug-resistant epilepsy resection (n = 24), malformation (n = 1), brain tumor (n = 11), and deep brain stimulation (n = 2) cases, achieving some type of reconstruction and electrode localization in all participants. By exporting electrode coordinates for quantitative spatial analyses, including distance-based mapping relative to lesions and resection cavities, ALIGNER enables anatomically grounded and reproducible analysis of intraoperative electrophysiology. This open-source framework provides foundational infrastructure for cancer neuroscience studies of tumor–neuron interactions and establishes a scalable platform for future neurostimulation, implantable neurodevice, and brain–computer interface applications requiring precise anatomical localization.

Working memory (WM), the human brain's system for maintaining and manipulating information over short timescales, is critical for goal-directed behavior. Classic neurophysiological models, which emphasize persistent delay activity, are being challenged by an idea that WM is maintained through dynamic and activity-silent mechanisms, where the memory trace is preserved by transient changes in the connections between neurons. To date, human evidence for this alternative model has been limited to non-invasive studies. Here, leveraging high-resolution intracranial stereo-EEG with advanced machine learning decoding techniques, we investigate neuronal mechanisms of human auditory WM. Neuronal activity is quantified as broadband high frequency activity (70-190 Hz), a correlate of neuronal firing activity. Our multivariate pattern analyses, validated via robust non-parametric permutation testing, show that WM content is represented in multiple brain regions, exhibiting dynamic rather than persistent delay activity. Crucially, by using task-irrelevant sounds to probe latent mnemonic states, we provide the first human intracranial evidence of activity silent WM maintenance in a local sensory network.

Closed-loop neuromodulation via responsive neurostimulation (RNS) of the thalamus has emerged as a promising therapy for drug-resistant epilepsy (DRE), particularly in patients with broad or multifocal onset. However, response to thalamic RNS is inconsistent, and there is a crucial need to identify factors that distinguish responders from non-responders. Given the heterogeneous composition of the thalamus, the specific contributions of individual thalamic nuclei during seizures may explain the variability in outcomes between patients and could potentially serve as biomarkers for guiding target selection. We analyzed 129 seizures from 28 patients with DRE who underwent stereo-EEG monitoring with recordings of the centromedian (CM: n = 15) or pulvinar (PLV: n = 13) thalamic nuclei and were subsequently treated with RNS targeting the corresponding nucleus (CM: 11/15 [73%] responders; PLV: 7/13 [54%] responders). Patients were classified as responders (Engel class I-III) or non-responders (Engel class IV) based on reduction in seizure frequency. For each seizure, we constructed functional connectivity networks spanning seizure onset to termination and quantified the role of the thalamic nucleus by computing its total node strength. We also used an automated detection algorithm to measure the time of seizure spread to each thalamic nucleus relative to seizure onset. Connectivity and spread timing were then compared between responders and non-responders within each nucleus group. The timing of thalamic recruitment following seizure onset did not differ significantly between responders and non-responders in either nucleus, although CM responders showed a non-significant trend toward earlier recruitment. Analysis of functional connectivity revealed nucleus-specific patterns. CM responders exhibited significantly higher thalamic node strength than non-responders during the late-seizure phase, with no significant difference at early- or middle-seizure phases. PLV responders showed significantly higher thalamic node strength during the middle-seizure phase, but there was no significant difference at early- or late-seizure phases. These findings suggest that the degree and timing of thalamic involvement during seizures may serve as biomarkers for predicting response to thalamic RNS in DRE. CM involvement in responders was characterized by stronger connectivity that persisted through seizure termination, whereas PLV involvement in responders was reflected primarily in connectivity during seizure propagation and progression. Incorporating these nucleus-specific ictal network features into pre-surgical evaluation could improve patient selection and guide nucleus-specific targeting for thalamic RNS.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare and often devastating neurometabolic disorder characterized by impaired synthesis of dopamine, serotonin, and norepinephrine. Affected children present with severe developmental delays, motor dysfunction, autonomic instability, and behavioral symptoms, and current treatments remain largely supportive. Current gene therapy trials for AADC deficiency have demonstrated the safety and tolerability of bilateral AAV2-hAADC infusion into the putamen or midbrain. These approaches have restored dopamine synthesis in the basal ganglia and the limbic systems. However, they have not affected serotonin levels, likely due to the lack of transduction of serotonergic neurons by inadequate coverage of relevant brainstem nuclei. Restoring serotonergic signaling may be critical for improving cognitive and behavioral outcomes, which are still not fully addressed by current dopamine-focused therapies. To address this limitation, we evaluated the safety of a multi-target, magnetic resonance (MR)-guided convection-enhanced delivery strategy in nonhuman primates, administering AAV2-AADC into serotonergic and noradrenergic nuclei in addition to current dopaminergic targets. This broader targeting approach aims to enhance serotonin modulation and restore neuromodulatory balance, with potential benefits for cognitive and behavioral function in children with AADC deficiency undergoing gene therapy.

OBJECTIVE The field of neuromodulation for idiopathic generalized epilepsy is rapidly evolving. The recently completed NAUTILUS trial, an industry-sponsored multicenter, randomized, sham-controlled study evaluating centromedian nucleus (CM) stimulation, represents a landmark effort to rigorously assess this approach. Although trial results are not yet available, the need to understand and standardize the anatomical targeting of the CM remains critical. The precision of electrode placement fundamentally determines whether stimulation engages the intended thalamocortical circuits, shaping both efficacy and reproducibility across centers. METHODS The authors present a comprehensive review of the evolution of CM targeting in epilepsy, tracing its development from early stereotactic approaches to current imaging-based strategies. The authors detail the surgical targeting workflow used across NAUTILUS trial sites, which incorporates advanced MRI sequences and atlas-informed refinements. This review also offers practical resources and tools enabling clinicians to implement the described methodology in clinical and research settings. RESULTS Modern CM targeting strategies reflect a transition from indirect, coordinate-based techniques to individualized, image-guided planning. These methods have been successfully implemented across centers participating in the NAUTILUS trial, enabling accurate electrode placement even in patients with complex anatomy. The workflow accommodates both direct visualization and atlas-based alternatives when imaging quality is suboptimal. CONCLUSIONS This review outlines the evolution of CM neuromodulation—from Velasco’s early targeting approaches to modern image-guided surgery—and provides a reproducible framework for clinicians. As neuromodulation moves toward broader clinical adoption, anatomically precise targeting will be key to optimizing outcomes. The surgical approach recommended in the NAUTILUS trial offers an implantation framework intended to support future location-based outcome analysis.

Drug-resistant epilepsy affects roughly one-third of people with epilepsy, and options remain limited for patients whose seizures arise from eloquent cortex, involve multiple foci, or persist after prior surgery. For these patients, closed-loop neurostimulation offers a nondestructive and adjustable alternative that detects pathological activity and delivers stimulation only when and where it is needed. The NeuroPace responsive neurostimulation (RNS) System, approved in 2013, remains the most established clinical example: it senses at the therapeutic target, drives stimulation from biomarkers recorded there, and stores raw neural signals for iterative programming. These same principles increasingly define a newer generation of adaptive deep brain stimulation (DBS) platforms developed largely for movement disorders, motivating a direct, device-level comparison of contemporary implantable closed-loop systems for epilepsy. We compare four clinically approved systems in depth (the NeuroPace RNS, Medtronic Percept PC, Newronika AlphaDBS, and PINS G106RS) together with three investigational platforms (the Picostim-DyNeuMo, CorTec Brain Interchange, and Cadence Neuroscience system), examining sensing architecture, artifact management, bandwidth, onboard data handling, stimulation-source design, and degree of autonomous control, and summarizing their relative capabilities across a common set of scored dimensions. Across platforms, the most consequential differences arise less from stimulation parameter ranges than from sensing design: which contacts can record, whether sensing can continue during stimulation, what frequency range is accessible, how stimulation artifact is suppressed, and whether raw waveforms or only derived features are retained. Because much of the sensing and adaptive-control evidence for the DBS platforms derives from movement-disorder rather than epilepsy applications, we interpret their epilepsy relevance conservatively and highlight where epilepsy-specific validation is still needed.

Abstract Objective Expanded indications, diagnostic tools, and treatment options have transformed the landscape of modern pediatric epilepsy surgery. Published real‐world experiences from large surgical cohorts are still needed. To close this gap, we evaluated access, indications, treatment, and outcomes in a contemporary pediatric epilepsy surgery program. Methods We evaluated data from 100 consecutive diagnostic and therapeutic procedures in 62 pediatric and young adult patients. Data collected included demographics, diagnostics, procedures, 12‐month seizure and medication outcomes, and adverse events. Primary outcome for patients who underwent treatment with the goal of cure or resection, along with the intent of palliation, was 12‐month postoperative Engel/ILAE scores. For those who underwent RNS‐implant (alone or in combination with a second procedure) with the goal of seizure reduction, the primary outcome was proportion seizure reduction in the prior 28 days at 12 months postoperatively. Results Patients largely matched state and regional demographics. Epilepsy types included unifocal (n = 33, 53.2%), multifocal (n = 15, 24.2%), generalized (n = 12, 19.4%), and combined (n = 2, 3.2%). Of the 100 procedures, 36.0% were diagnostic SEEG (n = 35) and 64.0% were treatment procedures (n = 58; note: n = 4 pending). Among patients who underwent surgical treatment with the goal of cure (n = 33), a 12‐month Engel I/ILAE I or III outcome was achieved in 81.8% (n = 27). Among patients who underwent RNS implantation, 79.0% were responders (>50% reduction) and 38.0% were super‐responders (>90% reduction), with a median seizure reduction of 78% at 12 months. Three treatment procedures (4.7%, n = 3 patients) had a surgical complication, none permanent. Significance Contemporary pediatric epilepsy surgery, utilizing modern diagnostic and surgical techniques, including off‐label use of RNS, provides safe, effective, accessible, and equitable treatment to children across a broad range of indications, many of whom, historically, have not been considered viable surgical candidates. Plain Language Summary “In this article by McLaren et al, 100 consecutive procedures were examined from a modern pediatric epilepsy surgery program. By utilizing advanced diagnostic and surgical techniques, they've shown that pediatric epilepsy surgery can be safe, effective, and accessible across diverse conditions and demographics. Notably, 82% of patients who underwent surgery aimed at curing their condition achieved seizure‐freedom in 12 months and 79% of patients with Responsive Neurostimulation (RNS) implants experienced significant seizure reduction.”

Opioid use disorder (OUD) is a significant public health concern, with over 30% of the affected population not responding to available treatments. Severe OUD is characterized by drug-cue reactivity that has been reported to predict treatment failure. We leveraged this pathophysiological feature to optimize deep brain stimulation (DBS) of the nucleus accumbens region (NAc) in a male patient with OUD. A personalized drug-cue-reactivity task was administered while recording NAc electrophysiology from a lead externalized for clinical purposes. We identified a drug-cue-evoked electrophysiological signal in the ventral NAc that was associated with an elevated craving state and attenuated with stimulation delivered to the same area. This electrophysiological biomarker, along with behavioral assessments, informed the re-programming of DBS to a more focal and effective stimulation site. This resulted in sustained suppression of drug-related cravings. This study represents a proof-of-principle for a personalized, biomarker-informed neuromodulation strategy in OUD.

Mesial (a.k.a., medial) temporal lobe epilepsy (MTLE) is the most common focal epilepsy1,2 and, in drug-resistant cases, is treated by surgical removal of the anterior temporal lobe, which often shows neuronal loss and gliosis consistent with hippocampal sclerosis (HS)2. MTLE with HS has minimal contribution from germline genetic variation3, and is associated with prior precipitating insults such as prolonged childhood seizures and head trauma4-6. Somatic variants in Ras-MAPK pathway genes were recently reported in a few MTLE surgical specimens7,8, but their prevalence, clinical relevance, and underlying biological mechanisms remain unknown. Targeted duplex sequencing of hippocampal DNA from 462 surgical resections revealed significant enrichment of deleterious somatic variants in MTLE versus controls, with >40% of MTLE specimens harboring activating Ras-MAPK variants in PTPN11, NF1, BRAF, KRAS, and twelve genes not previously associated with focal epilepsy. Eight Ras-MAPK genes showed positive clonal selection in MTLE. Increased somatic variant burden predicted worse surgical outcome. Somatic Ras-MAPK variants at ultra-low (<0.5%) variant allele fractions were associated with older seizure onset and HS pathology, supporting a late prenatal or postnatal origin. Ras-MAPK variants in MTLE were enriched in cells derived from hippocampal progenitors-neurons, astrocytes, oligodendrocytes-in line with the known neuronal hyperexcitability and seizures induced by Ras-MAPK overactivation9,10; in contrast, Alzheimer disease hippocampi exhibited microglial enrichment of Ras-MAPK variants, consistent with prior reports11. Single-nucleus RNA sequencing showed increased expression of Ras-MAPK genes in neurons and upregulation of pathways mediating neurogenesis and neural development in MTLE. Functional validation of novel, recurrent PTPN11 variants confirmed gain-of-function, while cellular modeling in induced pluripotent stem cells demonstrated proliferative/survival advantages for mutant cells in mosaic culture. Overall, our data suggest that somatic Ras-MAPK variants and acquired risk factors may converge on clonal competition in the hippocampus to modulate epilepsy risk.

Abstract Objective The NeuroPace responsive neurostimulation (RNS) System effectively treats focal drug‐resistant epilepsy (DRE) in adults but lacks pediatric regulatory approval. Despite effective off‐label pediatric use, systemic device‐trial challenges have impeded label expansion. The prospective RESPONSE Study (NCT04839601), evaluating RNS in children with focal DRE, terminated prematurely after enrolling nine of 200 planned participants. We aimed to identify barriers to pediatric device‐trial participation and evaluate whether anticipated ethical concerns about insurance‐based access disparities materialized in practice. Methods We conducted a mixed‐methods study: a multi‐site cross‐sectional survey of barriers to RESPONSE participation, and a retrospective single‐site case study at Massachusetts General Hospital (MGH) analyzing insurance distribution against state benchmarks in 96 RNS patients (73 adults and 23 pediatric), with denial rates and time to first reimbursement in a 62‐patient subset (2020–2025). Results Survey respondents comprised 8 of 9 RESPONSE sites plus MGH (which declined): 2 active, 6 withdrawn, and 1 declined. Study‐design and enrolment feasibility were the dominant barriers (89%), followed by financial (44%), resource (33%), ethical (22%), and regulatory concerns (11%). The narrow eligible population reflected a mismatch between regulatory‐aligned criteria (≤ 2 seizure‐onset zones; exclusion of generalized or multifocal epilepsy; ages 12–17) and the heterogeneous presentations of real‐world pediatric DRE, limiting recruitment. Insurance distributions did not differ from statewide benchmarks ( p = .13) or between pre‐ and post‐evaluation periods ( p = .15). Denial occurred in 2/26 off‐label pediatric (7.7%) and 1/36 focal adult (2.8%) RNS indications, all upheld on appeal and resolved by institutional subsidy; time to reimbursement did not differ ( p = .31). Significance The RESPONSE Study's premature termination reflected systemic barriers to pediatric device trials rather than isolated site failures. Anticipated insurance‐based access disparities did not materialize locally. Advancing pediatric neuromodulation will require practice‐aligned protocol design, alternative evidence pathways including registry‐based real‐world evidence, and leadership from well‐resourced centers in collaborative evidence generation.

OBJECTIVE:Responsive neuromodulation with the Responsive Neurostimulation (RNS) System is an important treatment option for pediatric patients with drug-resistant epilepsy. Early reports on seizure reduction and safety have been encouraging, but there is a need for greater understanding of evolving indications, treatment approaches, and outcomes in this population. The authors report patient characteristics, adverse events, seizure outcoames, quality-of-life outcomes, and programming details for young patients treated at their institution, focusing on pediatric outcomes. METHODS:A retrospective review of all patients treated in the Massachusetts General Hospital Pediatric RNS Clinic between August 2020 and January 2025 was conducted. Clinical characteristics, seizure frequency, and programming parameters were collected for each patient. Primary outcome was seizure response at 12 months after implantation. Secondary outcomes included seizure response at last follow-up, change in antiseizure medications at last follow-up, responses to a questionnaire focused on quality of life at last follow-up, and adverse surgical or stimulation-related events. RESULTS:Thirty-two patients underwent RNS implantation (63% female, mean [range] age 15 [6-28] years) with a median follow-up of 24 months, including 27 children ≤ 18 years (47% female) with median follow-up 22 months. RNS targets were bilateral thalamic (n = 24), cortical (n = 3), hippocampal (n = 2), and corticothalamic (n = 3). No surgical complications occurred. Stimulation-related adverse effects occurred in 44% of patients (36% pediatric). Among patients with at least 1 year of follow-up (n = 24 [19 pediatric]), the responder rate at 12 months was 79% (74% pediatric), with median 78% seizure reduction (p = 0.0003) (pediatric 73%, p = 0.0097). At last follow-up, the responder rate was 92% (89% pediatric), with 91% median seizure reduction (p = 0.0002) (pediatric 90%, p = 9.9 × 10-8); 54% of patients were super responders (53% pediatric). No clinical characteristics evaluated were significantly different between responders and nonresponders. Patients reported significant improvements in quality of life across categories related to physical activities and activities of daily living (p = 0.003, pediatric p = 0.009), cognition and school (p = 0.0006, pediatric p = 0.001), social and mood (p = 0.03, pediatric p = 0.05), and seizures (p = 1.8 × 10-6, pediatric p = 1.3 × 10-5). CONCLUSIONS:The authors' cohort of young patients with severe drug-resistant epilepsy from a variety of etiologies experienced comparable improvements in seizure control at 12 months to that reported in adults at 9 years. Patients also reported improvements in quality of life. These robust outcomes may be due to empirical targeting of patient-specific seizure networks and rapid escalation of therapy to higher treatment parameters.

The cross-regional interplay of slow oscillations, spindles, and ripples during sleep is believed to support systems memory consolidation but remains understudied in humans. Using a validated behavioral task and simultaneous intracranial neural recordings from the orbitofrontal cortex, thalamus, and hippocampus in 19 patients with epilepsy, we examined the cross-regional interplay of sleep oscillations (slow oscillations, spindles, and ripples), alongside epileptic spikes, and their role in motor memory consolidation. Orbitofrontal slow oscillations robustly modulate spindle and ripple oscillations within and across regions during sleep. Although most combinations of oscillation rates positively predicted overnight performance change in a motor task, hippocampal ripple rate and coupled hippocampal-orbitofrontal ripple rates were the most reliable predictors across subjects. In contrast, rates of most sleep oscillations coupled to epileptic spikes were negative predictors of overnight motor performance change, with the rate of slow oscillations co-occurring with epileptic spikes the most reliable predictors of negative change across subjects. These findings provide direct evidence of a hierarchical cascade of sleep oscillations in human motor memory processing and reveal that epileptic spikes coupled to sleep oscillations interfere with this process in patients with epilepsy.

OBJECTIVE:Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can modulate brain circuits, and certain stimulation targets may relieve or exacerbate anxiety. The objective of this study was to localize circuit-based stimulation targets that modify anxiety by integrating causal sources of information, including lesion, TMS, and DBS datasets. METHODS:The authors leveraged a series of natural experiments across multiple datasets (N=936). First, patients with incidental brain lesions (N=451) and TMS-treated individuals with incidental variability in stimulation location for depression (N=111) were analyzed. Functional connectivity of these sites was estimated using a normative connectome. Next, a TMS dataset (N=300) with a common set of stimulation coordinates but individual variability in brain connectivity was analyzed. Finally, the authors examined subthalamic DBS locations in patients with Parkinson's disease (N=74). RESULTS:Similar brain circuits were derived from lesions associated with greater anxiety and TMS sites that decreased anxiety (spatial r=0.68). In an independent TMS dataset (N=300), individualized TMS site connectivity to this circuit was significantly correlated with treatment-induced anxiety change. In Parkinson's disease, overlap of subthalamic DBS (N=74) sites with the anxiety circuit significantly predicted greater anxiety increases, confirming network involvement despite the circuit being derived independently of DBS. The circuit was associated significantly with trait anxiety versus state anxiety in two datasets that measured both. The peak proposed TMS target for anxiety was in the right superior frontal gyrus. CONCLUSIONS:This study identified a convergent anxiety circuit across lesions, TMS, and DBS. This provides a potential therapeutic target for brain stimulation and represents a generalizable approach for identifying stimulation targets across neuropsychiatric conditions.

Critical real-world neurocognitive processes, such as settling into a conversation and neurophysiological fluctuations, vary over minutes-to-days in real-world environments. We harnessed simultaneous multi-electrode intracranial and video recordings in twenty people during a week of unconstrained, spontaneous behavior. Using dynamical deep learning algorithms, we found neurodynamics linked to circadian rhythm, heart rate, and multiple aspects of behavior (socializing, watching a screen, sleep depth, etc.). Transitioning between behaviors was associated with bursts of rapid, chaotic neural exploration that stabilized into new states. Despite this chaos, large-scale dynamics anchored to a stabilizing center manifold associated with neurophysiological and conscious states, with a central attractor involving default mode network activation. When perturbed by sleep deprivation, neural transitions were more chaotic and dynamics around the central attractor were suppressed, suggesting diminished neurodynamic control due to lack of sleep. These findings highlight how the brain chaotically transitions around a stabilizing equilibrium to balance dynamic exploration and stable equilibria during real-world behavior.

Patients who participate in intracranial neuroscience research make invaluable contributions to our understanding of the brain, accelerating the development of neurotechnological interventions. Engagement of patients as part of this research presents unique challenges, where study goals can be distant from immediate clinical applications and require specialized domain knowledge. Yet methods for meaningfully integrating patient communities as part of these research efforts is essential, as intracranial neuroscience guides the application of artificial intelligence for understanding and enhancing human cognition. In order to identify what patients consider meaningful research engagement we interviewed individuals who participated in a study during their Deep Brain Stimulation (DBS) surgery and attended a group event where they interacted with our research team. Analysis of semi-structured interviews identified four main themes: interest in science and the future of clinical care, contributing to science to improve lives, connecting with others, and accessibility considerations. Based on these insights, we propose strategies for transformational participation of patient communities in intracranial neuroscience research with respect to engagement objectives, communication and scope. This approach offers a foundation for sustaining relationships between scientists and communities rooted in trust and transparency, to ensure that impacts of neurotechnology on human health and cognition are aligned with patient needs as well as desired public values.

Substance use disorder (SUD) is a significant public health concern, with over 30% of the affected population not responding to available treatments. Severe SUD is characterized by drug-cue reactivity that has been reported to predict treatment-failure. We leveraged this pathophysiological feature to optimize deep brain stimulation (DBS) of the nucleus accumbens region (NAc) in an adult with SUD. A personalized drug cue-reactivity task was administered while recording NAc region electrophysiology from a lead externalized for clinical purposes. We identified a drug cue-evoked signal in the ventral NAc associated with intensification of opioid-related cravings, which attenuated subsequent to stimulation delivered to the same area. DBS was then programmed to engage this focal region, which resulted in sustained suppression of drug-related cravings. This finding heralds the potential for personalized strategies to optimize DBS for SUD.