BACKGROUND:The presence of childhood adversity predicts poorer outcome to antidepressant medications and/or psychotherapy. However its impact on neuromodulation outcomes is unclear. We investigated whether adversity affects outcomes in patients receiving Deep Brain Stimulation (DBS) of the subcallosal cingulate area (SCC) for Treatment-Resistant Depression (TRD). METHODS:Longitudinal follow-up data on 56 TRD patients receiving SCC-DBS. The ACE (Adverse Childhood Experiences) questionnaire was used to quantify adversity and estimate its prevalence in these patients. The primary outcome was remission (Hamilton Depression Rating Scale, HAMD-17 ≤ 7). Pre-operative structural MRI metrics were probed for relationships with ACE score. RESULTS:93% of patients reported experiencing childhood adversity (ACE ≥ 1) and 45% reported ≥4 ACEs (score consistently associated with poor health outcomes). ACE score did not significantly impact rates of remission at 12 or 36 months. There was no differential effect of adversity type (e.g. abuse, neglect, or household dysfunction) on remission. In both high and low ACE score groups, average HAMD-17 scores dropped significantly from baseline to 12 months and remained stable to 36 months. In females, ACE score was negatively correlated with left anterior cingulate cortex surface area, bilateral angular gyrus surface area and left fornix volume, while it was positively correlated with right subiculum volume. CONCLUSIONS:TRD patients receiving SCC-DBS report a high degree of ACEs. There was no deleterious effect of ACEs on antidepressant outcomes with SCC-DBS in the short- or long-term. A history of childhood adversity should not preclude consideration of SCC-DBS for TRD.

Dysfunction of corticostriatal circuitry is related to the emergence of self-injurious behavior (SIB) in autism spectrum disorder (ASD). Despite mounting interest in circuit-based interventions for severe, refractory SIB, the lack of causal evidence linking modulation of corticostriatal networks to changes in SIB has limited the advancement of effective, targeted therapies. In this study, we demonstrate that electrical stimulation of the nucleus accumbens (NAcc) mitigates SIB and induces structural changes along corticostriatal circuits in a mouse model relevant for ASD and children with severe SIB undergoing NAcc-targeted deep brain stimulation. In BTBR T+ Itpr3tf/J mice, NAcc stimulation selectively reduced injurious self-grooming-a behavioral metric of SIB-and led to morphological changes in corticostriatal networks. In children with severe SIB, electric stimulation at a locus of optimal therapeutic response within the NAcc engaged widespread sensorimotor, limbic, and striatal networks and induced longitudinal structural changes in fronto-limbic-striatal brain regions. These findings highlight the role of the fronto-limbic-striatal network in SIB regulation and support corticostriatal neuromodulation as a mechanistic therapy for these extreme behaviors.

Causal modulation of autonomic outflow could yield new therapeutic targets for autonomic hyperactivation. We employed three natural experiments in which different brain regions were targeted using transcranial magnetic stimulation (TMS) (n=139 sites, n=14 individuals), deep brain stimulation (n=392 sites, n=58 individuals), or low-intensity focused ultrasound (n=46 sites, n=23 individuals) with subsequent autonomic measurements. Using a human connectome database (n=1000) as a wiring diagram, we identified a convergent brain circuit that, when focally modulated, transiently reduces autonomic arousal. This circuit significantly resembled previously reported causal circuits for posttraumatic stress disorder (PTSD) and anxiety. In independent datasets, TMS to the autonomic arousal circuit reduced laboratory startle in healthy volunteers (n=28), lesions to this circuit reduced exaggerated startle in PTSD (n=193), and TMS to this circuit reduced anxiety-related autonomic symptoms in patients with clinically significant anxiety (n=30). Thus, the convergent circuit may serve as a potential neuromodulation target for autonomic hyperactivation. ### Competing Interest Statement The authors have declared no competing interest.

Introduction: MRI-guided focused ultrasound (MRgFUS) ablation has become increasingly utilised for movement disorders since its approval by the US Food and Drug Administration (FDA) in the treatment of unilateral essential tremor (ET) in 2016. While most patients achieve significant improvement in their symptoms, a proportion of ET patients experience tremor recurrence. Deep brain stimulation (DBS) is a potential rescue therapy post-MRgFUS. However, the safety profile of such scenarios is currently unknown. Case Presentations: Here, we report 3 ET patients who previously underwent MRgFUS of the ventral intermediate nucleus of the thalamus (Vim) and subsequently had DBS insertion due to tremor recurrence. Three patients (ranging from 58 to 85 years of age; one female) presented with a history of refractory ET. Patient 1 had left Vim MRgFUS and then left Vim DBS. However, the tremor control was still inadequate, and he had a further revision DBS surgery where two electrodes were inserted into left Vim. Patient 2 had two MRgFUS procedures in left Vim and then underwent left Vim DBS insertion due to hand tremor recurrence. Patient 3 had left Vim MRgFUS and then bilateral Vim DBS due to midline tremor. Patients 2 and 3 experienced substantial improvement in symptoms after DBS, but patient 1 only had minimal improvement. There were no surgical complications and no readmission within 30 days. Conclusions: This case series demonstrates that insertion of DBS electrodes in the vicinity of prior MRgFUS site can be safe. These findings have important implications for pre-operative counselling of patients with ET with high surgical risks, as well as supporting MRgFUS as a first-line therapy in selected patients. Further studies with larger population will delineate the optimal timeline where DBS may be safely performed in this population, as well as the long-term therapeutic effect of such rescue intervention.

BACKGROUND:Transcranial ultrasound stimulation (TUS) enables non-invasive neuromodulation of cortical and subcortical brain regions. Technological advances have facilitated rapid expansion of the field in recent years. However, the overall scope, methodological trends, and reporting practices of human TUS research remain unclear. OBJECTIVE:To characterize the global landscape of registered clinical trials using TUS for neuromodulation, including their design features, indications, targets, device platforms, and dissemination. METHODS:A systematic search of major international registries (ClinicalTrials.gov, WHO ICTRP, EUCTR, ChiCTR, CRiS, ANZCTR, JPRN, ISRCTN, and CTRI) was performed through September 2025. Interventional studies using low-intensity ultrasound for brain neuromodulation were included. Data were extracted on indication, target, device, design, enrollment, sponsorship, and publication linkage. RESULTS:A total of 177 unique clinical trials were identified. Registrations have increased sharply over time, with 27 trials registered between 2014 and 2019, and 150 trials registered in the last 5 years. The United States (52%) and China (18%) lead activity. Psychiatric disorders were the most common indication (32%), followed by healthy volunteer studies (16%), pain (11%), cognitive (11%), and movement disorder (9%) studies. Among trials specifying a target, over half (51%) targeted subcortical regions. A considerable proportion of studies were randomized, multi-arm, and double-blinded (40%). Device information was reported in 32% of trials, identifying 11 distinct commercial and prototype systems. Of completed trials, 37% were linked to a peer-reviewed publication. CONCLUSIONS:TUS clinical research is expanding rapidly but remains heterogeneous in design, targets, and device reporting. Enhanced transparency in trial registration and parameter documentation will facilitate the development of stronger study designs and encourage the field to direct its efforts toward understudied areas.

Implantable neurotechnologies are increasingly used to reduce seizure burden in pediatric epilepsy. Vagus nerve stimulation (VNS), the most common option, is effective for only half of patients, with no means to predict outcome prior to surgery. As a result, many children undergo invasive and costly procedures without benefit. Although T1-weighted magnetic resonance imaging (T1w) is routinely acquired presurgically and may capture structural brain differences relevant to treatment outcome, its high dimensionality relative to sample sizes has limited its utility in predictive modelling. To address this challenge, we present VQ-VNS, a deep representation learning model to predict VNS outcome based on preoperative T1w (n = 263). First, we present data from the largest paediatric VNS cohort (n = 1046), wherein presurgical clinical data could not predict response (AUC 0.54,p > 0.99). Next, VQ-VNS was pretrained on 7433 T1w images to learn compact anatomical representations enabling its classifier to predict VNS response (AUC = 0.73,p = 0.007). Model predictions localized to serotonin-rich brain regions and inferred large-scale disruptions in network connectivity among non-responders. This biologically interpretable predictor based on routine structural imaging improves upon current clinical decision-making.

Introduction: Peripheral nerve field stimulation (PNFS) for facial pain delivers subcutaneous electrical stimulation to reduce pain. Blood oxygenation level-dependent (BOLD) functional MRI (fMRI) can be used to characterize central effects of neuromodulation techniques such as deep brain stimulation and spinal cord stimulation (SCS). However, the safety and utility of MRI in patients with PNFS have not been established, limiting both clinical MRI use and the application of fMRI in this population. This study evaluated the MRI safety and feasibility of imaging an active SCS implant used for PNFS in patients with facial pain; and defined sequence parameters for concurrent BOLD fMRI acquisition. Methods: An anthropomorphic 3D-printed phantom filled with tissue-mimicking gel and fitted with an SCS implant replicating a patient with PNFS was used for in vitro safety testing. Two phantom experiments evaluated the relationship between (i) head-averaged specific absorption rate (SAR), (ii) time-averaged positive radiofrequency magnetic field component (B1rms+) and maximal temperature rises at critical locations (i.e., distal lead electrodes, cranial coiling, and implantable pulse generator) across clinical and research-based structural and fMRI sequences. For validation, a PNFS patient was scanned using localizer, T1-weighted magnetization-prepared rapid gradient echo, T2-weighted sampling perfection with application-optimized contrasts using different flip angle evolutions, and BOLD fMRI sequences informed by phantom experiments. Results: FMRI during active PNFS is safe under specific conditions, with temperature increases remaining below the 2°C threshold at all monitored locations. Heating had a stronger relationship with head SAR (higher adjusted coefficient of determination [R2] value) than B1rms+, particularly at distal lead electrodes. These in vitro findings informed selection of safe fMRI protocols for in vivo scanning. A patient (n = 1) underwent MRI with no device- or patient-related adverse events. Successful fMRI acquisition was achieved, demonstrating engagement of pain-related regions in the patient. Conclusion: Phantom testing confirmed the safety and feasibility of MRI with an active SCS device configured for facial PNFS. These findings, specific to the tested conditions, underscore the need for context-specific safety evaluations to enable safe MRI in such implantable medical devices.

BACKGROUND:Though deep brain stimulation (DBS) has emerged as a promising treatment for idiopathic cranio-cervical dystonia (iCCD), the best location at which to stimulate remains unclear at a granular level. This study aimed to identify optimal sites and related white matter pathways of globus pallidus internus (GPi) and subthalamic nucleus (STN) for DBS therapy. METHODS:We analyzed a total of 70 iCCD patients treated with bilateral DBS, targeting the STN (n = 40) or GPi (n = 30). A retrospective cohort (n = 48) was utilized for training, while a prospective cohort (n = 22) was used for out-of-sample validation. We identified optimal stimulation sites, validating their spatial specificity and reproducibility. Target-specific and convergent "sweet tracts" for STN and GPi-DBS were identified based on a human axonal pathway model (the Basal Ganglia Pathway Atlas). RESULTS:Optimal stimulation in both GPi and STN targeted distinct subregions mapped to cranio-cervical motor control-specifically, the posterior ventrolateral GPi and dorsolateral STN. Therapeutic "sweet tracts" engaged craniocervical- and dystonia-specific fiber pathways within the basal ganglia-thalamo-cortical loop, including the GPi-specific lenticular fasciculus, the STN-specific hyperdirect pathway and corticospinal tract, and the convergent posterior subthalamo-pallidal connections pathway. This convergent pathway was independently validated using a streamline-level analysis. CONCLUSION:Our work provides a network-based explanation for the comparable efficacy of GPi and STN stimulation, suggesting that therapeutic benefit is driven by modulating specific pathways rather than the nucleus alone. This provides a new framework for refining and personalizing therapy.

Causal modulation of sympathetic arousal could yield new therapeutic targets for sympathetic hyperactivation. We employed a natural experiment in which different brain regions were incidentally targeted using transcranial magnetic stimulation (TMS) (n=139 sites, n=14 individuals), deep brain stimulation (n=392 sites, n=58 individuals), or low-intensity focused ultrasound (n=46 sites, n=23 individuals). Using the human connectome (n=1000) as a wiring diagram, we identified a convergent brain circuit connecting focal neuromodulation sites that preferentially modified sympathetic arousal across all three modalities. In independent datasets, TMS to the sympathetic circuit reduced anxiety-related sympathetic arousal on a laboratory task (n=28) and clinical questionnaire (n=30). The sympathetic circuit aligned with lesion-derived circuits previously linked to sympathetic hyperactivation (i.e., aggression, anxiety, PTSD), but not other eight other lesion circuits. It was also more similar to a map of norepinephrine transporter distribution versus 20 other neurotransmitters. This sympathetic circuit may be a promising treatment target for sympathetic hyperactivation.

Spontaneous fluctuations in attention can impede adaptation to changing goals and environments. Endogenous control over attentional shifts, referred to as attentional flexibility, is prone to disruption in children with attention deficit disorders. Here we studied in vivo intracranial recordings in children with epilepsy to identify a reproducible neural signature of attentional control that could predict and prevent impending lapses in real time. Machine learning classifiers were trained on intracranial signals while each child performed an attentional set-shifting task and predicted delays in attention shifting over multiple days and across several pediatric populations. Intracranial electrical stimulation in response to impending delays rescued attention shifts indexed by eye tracking, reaction time and accuracy. Simultaneous electroencephalography identified corresponding scalp signatures that enabled noninvasive modulation of attention shifting in healthy participants. These findings provide insight into the neural basis of attentional shifts with implications for targeted neuromodulation and exogenous attentional control.

This paper presents DBS-ElecNet, a deep learning framework for automated segmentation of electrodes and artifact regions in post-operative DBS MRI. To overcome reliance on manual annotations, we introduce a hybrid approach where a traditional image processing pipeline generates initial segmentations for the 3D U-Net model, which uses these as ground truth, and achieves robust segmentation performance. DBS-ElecNet performs inference in $\sim 3$ seconds, a 60-100x speedup over manual segmentations. This efficient and accurate approach enables scalable analysis for surgical verification and paves the way for advanced clinical applications like artifact inpainting.

Accurate registration of regions of interest (ROIs) from standard atlases to participants' native spaces is a critical step in fMRI studies, as it directly affects the reliability of sampled BOLD signals. While T1-weighted (T1w) image-based ROI registration is well validated and widely adopted in cortical fMRI, its performance degrades in brainstem studies due to the small size, dense packing, and poor visibility of brainstem nuclei on T1w contrast. We hypothesized that incorporating diffusion MR images, containing more information about internal brainstem architecture, should improve ROI registration accuracy. To test this, we developed four registration pipelines that either included or excluded diffusion-based alignment components and evaluated their performance using data from n = 20 healthy participants. Registration accuracy was assessed using Dice coefficient for the red nucleus (RN) and the substantia nigra (SN), and mis-registration fraction-a metric developed for nuclei that cannot be manually delineated-for the dorsal raphe nucleus (DRN). The results showed that diffusion-based pipelines, using fractional anisotropy (FA) images, non-diffusion-weighted (b0) images, and multivariate combination, outperformed the T1w-only baseline. Probabilistic maps derived from inverse-transformed native ROIs further supported improved sensitivity to inter-individual anatomical variability in the diffusion-augmented pipelines. In addition, analysis of gradient magnitude maps from the Jacobian determinants revealed associations between localized deformation and image modality-specific landmarks. These findings demonstrate the potential of diffusion-augmented pipelines for improving brainstem ROI registration, which could enhance the robustness of fMRI studies on brainstem disorders characterized by functional dysregulation.

BACKGROUND:Clinically used magnetic resonance imaging (MRI) modalities field strengths (1.5T and 3T) are not optimal for minimizing either geometric distortion nor maximizing image quality, respectively, when imaging patients with DBS. Lower and higher field strengths can be used to overcome these limitations by improving imaging resolution and reducing geometric distortion. PURPOSE:Our aim is to assess the safety and feasibility of DBS at non-conventional (not 1.5T, 3T) MRI to explore more effective options for scanning patients with DBS. DATA SOURCES:We performed a search of preclinical and human studies investigating the safety of non-conventionally used MRI field strengths (i.e., not 1.5T or 3T) for deep brain stimulation (DBS). Relevant articles were retrieved from OVID, PubMed, and Web of Science from database inception to August 25, 2025. STUDY SELECTION:Twelve studies were included. Seven studies assessed safety of DBS at ultra-high-field (UHF) MRI. Five studies assessed safety of DBS at low-field MRI. No human studies were found. DATA ANALYSIS:For in-silico and in-vitro studies, measures of radiofrequency energy deposition and heating of the hardware were recorded whereas for in-vivo studies, clinical and histological assessments were retrieved. DATA SYNTHESIS:For in-vitro and in-silico studies, heating of DBS systems were within clinically acceptable parameters for realistic configurations and intended use sequences of DBS placements in non-conventional UHF (> 3 T) and low-field MRI (< 1.5T). For in-vivo studies, no significant histological damages were observed at UHF MRI compared to 3T and 1.5T. LIMITATIONS:Our systematic review is limited by the lack of human studies and variations in scanning sequences across studies. CONCLUSIONS:Our findings comprising of pre-clinical studies provide early data on the safety of UHF and low-field MRI for DBS. At this stage, studies do not support scanning DBS patients at these field strengths, but provide a framework for developing human studies examining the safety of DBS in non-conventional MRI.

The network changes elicited by deep brain stimulation (DBS) in Parkinson's disease (PD) remain incompletely understood. We used functional MRI (fMRI) during active stimulation of the subthalamic nucleus (STN) to identify brain networks associated with clinical improvement. Forty PD patients (61 y ±8, 40% female) underwent 3-Tesla fMRI during active stimulation. Stimulation-induced changes in brain activity were correlated with outcomes (tremor, rigidity, bradykinesia, and axial instability). Symptom-specific fMRI response maps revealed distributed networks associated with long-term motor improvement, but ROI-based models showed poor out-of-sample performance and limited spatial stability. In contrast, somatomotor network modulation demonstrated symptom-specific coupling preferentially in rigidity improvement (ΔR² = 0.24, pFDR = 0.01) and bradykinesia (ΔR² = 0.13, pFDR = 0.07). Normative connectivity explained variance less consistently. These findings support the use of patient-specific fMRI as a tool for studying the neural mechanisms of DBS and highlight the importance of distributed network engagement in mediating therapeutic benefit.

Neuromodulatory treatments for obsessive-compulsive disorder (OCD) target diverse anatomical regions yet yield comparable clinical benefit. Integrating 142 studies with normative functional connectomics, we identified a convergent, outcome-weighted brain network whose engagement predicted symptom improvement across modalities. This network, localized to low-myelinated association cortex, was enriched for mu-opioid, mGluR5, and histamine H3 receptors, providing a multiscale framework linking circuit modulation, molecular systems, and clinical response in refractory OCD.

BACKGROUND AND OBJECTIVES:Motivated by growing literature suggesting that skull density ratio (SDR) has limitations in patient selection and outcome prediction for magnetic resonance‑guided focused ultrasound treatments, this study sought to systematically review imaging-based alternatives to SDR that have been explored in relation to clinical and technical outcomes. METHODS:This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines and was registered in the International Prospective Register of Systematic Reviews (CRD420251081059). We searched MEDLINE, Embase, and Scopus from inception to February 2025 for studies evaluating imaging-derived alternatives to SDR in human magnetic resonance‑guided focused ultrasound procedures. Data were extracted independently by 2 reviewers and studies were grouped into 4 categories: skull geometric factors, histogram-based SDR analysis, patient-specific multivariate modeling, and advanced imaging processing. Each category was also assessed for clinical implementation feasibility based on imaging processing complexity, required expertise, and scalability. RESULTS:Of 1684 screened studies, 23 met the inclusion criteria. Skull geometric factors (n = 9), particularly skull thickness and volume, were the most commonly studied and showed consistent associations with both thermal and clinical outcomes. Histogram-based SDR metrics (eg, skewness) occasionally had stronger correlations with outcomes than mean SDR. Multivariate models and advanced imaging showed strong technical correlations but comparatively lower clinical feasibility due to complexity and computing demands. CONCLUSION:Although SDR remains the approved screening metric, our review suggests potential imaging-based alternatives to SDR. Specifically, readily available and implementable metrics such as skull geometric features show promising correlations with clinical and technical outcomes. Other methods, such as multivariate modeling, show promise but will need more time to become validated, accessible, and widely implemented.

BACKGROUND:Intracranially extending temporomandibular joint (TMJ) lesions may be radiologically misinterpreted as primary intracranial or skull base pathologies, leading to diagnostic delays or inappropriate management. PURPOSE:This systematic review aimed to characterize the clinical and imaging features of such TMJ lesions and evaluate the impact of radiologic misclassification. We also aimed to develop a diagnostic framework for when to consider an intracranially extending TMJ lesion, based on clinical and radiologic features. DATA SOURCES:A comprehensive search of MEDLINE, Scopus, and EMBASE, conducted in accordance with PRISMA guidelines, yielded 2255 records. STUDY SELECTION:After screening with predetermined inclusion and exclusion criteria, 128 studies involving 152 patients were included in the final analysis. DATA ANALYSIS:Statistical analyses were performed using STATA software. We also identified 3 patient cases through our institutional neuroradiology practice who were clinically and radiologically assessed for intracranially extending TMJ lesions. DATA SYNTHESIS:Patients had symptoms for an average of 34 months before diagnosis (47% women, mean age 50 years). The most common pathologies were pigmented villonodular synovitis/tenosynovial giant-cell tumor (43%) and synovial chondromatosis (24%). Neurologic symptoms were reported in 48% of cases, most frequently hearing loss (70%). Nearly one-third (33%) of cases with an imaging differential did not list a TMJ pathology (18/55). In cases with accurate imaging diagnosis, 90% had both CT and MRI performed. Most lesions were nonenhancing (CT 83%, MRI 75%) and demonstrated no adjacent brain edema (96%). In 2 cases, a TMJ ganglion cyst and pseudogout were misdiagnosed as intracranial tumors, resulting in unnecessary intervention, including repeat craniotomy and radiotherapy. LIMITATIONS:There were inherent biases of case report literature, including variability in the reporting of the imaging and clinical features, management, and follow-up. CONCLUSIONS:TMJ lesions with intracranial extension often present with nonspecific symptoms and can mimic extra-axial tumors, leading to misdiagnosis on imaging. Recognition of hallmark imaging features, including lack of parenchymal invasion and distinct imaging patterns, may help improve radiologic accuracy and prevent overtreatment. We propose a diagnostic framework outlining when to suspect intracranially extending TMJ lesions based on clinical and imaging features, and how to avoid common diagnostic pitfalls.

Deep brain stimulation (DBS) is a well-established therapy for adult neurological disorders, most commonly Parkinson’s disease, and is increasingly being explored for medically refractory conditions in the pediatric population. Magnetic Resonance Imaging (MRI) is essential for DBS safety and efficacy through precise surgical targeting and trajectory planning, yet MRI protocols and reporting vary substantially and are constrained by pediatric-specific considerations. We aimed to systematically characterize MRI use and reporting practices in pediatric DBS studies and clinical trial registries. We systematically reviewed the published literature and the clinical trials registry to characterize MRI use in pediatric patients undergoing DBS, identify common imaging practices, and evaluate reporting of MRI sequence parameters (e.g., TR, TE). Preoperative MRI was primarily used for anatomical targeting and surgical planning. Most studies used 1.5T scanners (86