The Deep Brain Stimulation (DBS) Think Tank XIII was held September 2-4th, 2025, in Gainesville, Florida, at the Norman Fixel Institute for Neurological Diseases at the University of Florida. The theme was "The Evolving Landscape of DBS: New Indications, New Goals." This theme was a continuation of the DBS Think Tank XI and XII, which were focused on emerging technology and pushing the horizon of indications. Since its founding in 2012, the DBS Think Tank has provided a global forum for leading clinicians, engineers, and researchers in both in industry and academia to present, discuss, and debate the current state of DBS technologies as well as to consider important logistics and ethical challenges. Over the course of three days, members of each panel presented and facilitated discussions on the cutting edge of DBS research. The keynote speaker was Dr. Kamil Uğurbil of the University of Minnesota, who led the first group of researchers to demonstrate the feasibility of imaging the human brain using fMRI technology and who was a pioneer in the development of high-field human MRI scanning. Nobel laureate Dr. Stanley Prusiner, from the University of California, San Francisco, used the story of the discovery of prions to demonstrate the power of pursuing a finding even when the idea conflicted with the prevailing state of the field. The think tank was divided into sections, including: Next Generation Neuromodulation for Gait, Brain Networks and Neuromodulation, Neuroscience & Society, Interventional Psychiatry & Behavior, Devices for Closing the Loop, Physiology & Closing the Loop, and A Roadmap for Genetics & Neuromodulation.

BACKGROUND:Emotion processing is critical in the neuropathology of major depressive disorder (MDD), while its relationship with clinical treatment remains unclear. This study aims to indicate the associations between emotion processing and treatment effects following a sequential dual-site accelerated repetitive transcranial magnetic stimulation (rTMS) protocol. METHODS:MDD patients were recruited to receive rTMS treatment with four sessions per day for four consecutive days, with stimulation sequentially delivered to the left dorsolateral prefrontal cortex (dlPFC) and the dorsomedial prefrontal cortex (dmPFC). Symptoms were assessed at baseline, end of treatment, and week 4 using the Montgomery-Åsberg Depression Rating Scale (MADRS), Snaith-Hamilton Pleasure Scale (SHAPS), and Fatigue Severity Scale (FSS). Emotional valence and arousal were evaluated with the Affect Rating Task (ART). RESULTS:A total of 51 participants completed the clinical assessments and ART, with two excluded due to missing baseline data in the SHAPS and FSS. The linear mixed-effects models revealed significant improvement in depressive (p < 0.001, d = -0.343) and fatigue symptoms (p = 0.010, d = -0.572) following rTMS treatment. Neutral valence was correlated with MADRS scores at baseline (R2 = 0.096, p = 0.027). In addition, changes in arousal for positive images (p = 0.047, adjusted R2 = 0.097) and neutral images (p = 0.019, adjusted R2 = 0.160) at treatment end were significantly correlated with MADRS improvement at week 4. CONCLUSIONS:Our study highlights the association between changes in emotional arousal and improvement in MDD following accelerated dlPFC-dmPFC dual-site rTMS treatment.

Background: Obsessive-compulsive disorder (OCD) remains refractory to conventional pharmacological and psychotherapeutic treatments in a substantial proportion of patients. Neuromodulation has emerged as a promising intervention, but optimal neural circuit targets remain unclear. This systematic review and meta-analysis aimed to evaluate the efficacy of invasive and non-invasive neuromodulation for OCD using a circuit-based framework and to translate these findings into clinical practice. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials investigating neuromodulation for OCD. PubMed/MEDLINE, Web of Science, and the Cochrane Library were searched from database inception to December 2023. Eligible studies included adult patients with a primary diagnosis of OCD receiving invasive or non-invasive neuromodulation, with symptom outcomes assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Random-or fixed-effects meta-analyses were performed using mean differences or standardized mean differences, depending on heterogeneity. The review was registered in PROSPERO (CRD42024518326). Results: Twenty-seven randomized controlled trials involving 868 patients met inclusion criteria. Overall, neuromodulation significantly reduced OCD symptoms compared with control conditions. Circuit-based subgroup analyses indicated that modulation of the fronto-limbic circuit--primarily via invasive deep brain stimulation--was associated with the largest and most consistent Y-BOCS improvements, while sensorimotor, dorsal cognitive, and ventral affective circuits also demonstrated significant but more heterogeneous effects. Invasive neuromodulation showed greater efficacy than non-invasive approaches. These findings informed a translational multi-target deep brain stimulation case, demonstrating clinically meaningful symptom improvement (Y-BOCS decreased from 25 to 16 after 6 months). Limitations: Heterogeneity across non-invasive studies, short follow-up durations, and limited circuit-specific data constrain interpretation of long-term and symptom-domain-specific effects. Conclusions: This systematic review, meta-analysis, and case study suggest that circuit-based neuromodulation--particularly targeting the fronto-limbic circuit--may offer the most consistent benefit for treatment-refractory OCD. Larger, longer-term, and circuit-informed trials are needed to optimize individualized neuromodulation strategies.

Psychiatric symptoms in Parkinson's disease (PD) are highly prevalent and challenging to treat. This study maps oscillatory neural activity to diverse psychiatric symptoms in PD, using resting-state subthalamic nucleus (STN) local field potentials (LFPs) and frontal EEG in 55 PD patients undergoing deep brain stimulation (DBS). We tested whether 1) distinct psychiatric symptoms are associated with frequency-specific neural signatures using power spectral analyses and machine learning, across both eyes-open and eyes-closed sensory-attentional states. 2) symptom encoding is spatially segregated within the STN, with electrophysiological (defined by peak spectral power) and anatomical (defined by STN boundaries) mappings providing complementary information. 3) these regions exhibit distinct structural connectivity profiles, assessed using STN-seeded tractography from the UK Biobank normative connectome. Our analysis revealed spectral, spatial, and connectivity segregation. Depression was associated with increased alpha power, primarily detected by anatomical mapping, whereas apathy (increased high beta) and trait impulsivity (reduced low gamma) were detected with both anatomical and electrophysiological STN mapping. UK Biobank analyses further showed that STN-based alpha clusters (depression-related) preferentially connected with prefrontal, orbitofrontal, and cingulate cortices, while peak low-beta clusters (motor-related) connected with SMA and premotor areas. High-beta and low-gamma bands showed convergent connectivity across peak and STN-based clusters despite ventral-dorsal differences. These findings disentangle neurophysiological substrates of PD psychiatry, identifying symptom-specific biomarkers and informing targeted neuromodulation strategies.

Background Relapse after inpatient treatment for alcohol dependence is frequent, particularly within the first three months post-discharge. Cognitive Bias Modification (CBM), and specifically alcohol Approach Bias Modification (ABM), has demonstrated benefits in inpatient care, but its efficacy for aftercare remains uncertain. Methods A two-phase research program was conducted. The pilot study tested the feasibility of a desktop-based, home-delivered ABM. A total of 308 patients were randomized into two intervention groups, differing in reminder intensity, or a control group without any intervention. The main study built on these findings by developing a smartphone-based, gamified ABM using an active control design. A total of 273 active app users were randomized to training or control, and participants were instructed to use the app as often as they liked over a three month period. Gamification features included team competitions, rewards, and peer interaction to enhance engagement. Results In the pilot study, adherence proved low (mean 7.7 sessions out of 25 instructed sessions), and reminders did not improve participation. No group-level differences in abstinence were observed. In the main study, engagement was markedly higher: participants completed on average 57 sessions, and nearly half reached the adherence threshold of ≥25 sessions. Among those meeting this threshold, the ABM group achieved significantly higher abstinence rates at one-year follow-up compared to active controls. Feedback indicated general satisfaction, willingness to continue use, and offered suggestions for further app refinement. Conclusions Gamification and mobile delivery improved adherence, and sufficient engagement with ABM produced specific and clinically meaningful aftercare benefits at one-year follow-up.

Background Gambling disorder (GD) involves persistent risky choices despite losses, suggesting impaired impulse control. While static paradigms reveal inhibition deficits in GD, they cannot model dynamic risk-reward escalations during real gambling. This study aims to investigate whether GD involves impaired dynamic impulse control during escalating stakes and to dissociate contributions of subjective risk evaluation and trait impulsivity to this deficit.Methods Using a sequential gambling task with 83 male patients with GD and 62 matched healthy controls (HCs), this study investigated dynamic impulse control deficits under escalating stakes. We quantified dynamic impulse control via the reward-reaction time (RT) coupling for 'continue' choices (dynamic impulse control index [DICI]) using Bayesian modeling. Risk sensitivity and risk preference were derived from stop/continue decisions. Trait impulsivity was assessed with the Barratt Impulsiveness Scale (BIS-11). Regression analyses examined the modulation of DICI by risk sensitivity and trait impulsivity.Results Patients with GD exhibited significantly attenuated DICI versus HCs, reflecting failure to increase deliberation with escalating stakes. Computational modeling revealed markedly reduced risk sensitivity in GD despite comparable risk preference. Critically, trait impulsivity positively modulated DICI in HCs but not in GD, indicating pathological decoupling. Risk sensitivity positively predicted DICI in both groups, though significantly weaker in GD.Conclusions These findings establish a triadic impairment in GD: (1) attenuated adaptive impulse control during escalation (impaired DICI), (2) deficient subjective risk weighting (reduced sensitivity), and (3) breakdown of impulsivity-based modulation of control. This reveals a dynamic, mechanism-focused pathology beyond static trait models.

Abstract Adaptive behaviour relies on the flexible encoding and suppression of aversive associations often underpinned by amygdala-hippocampal interactions. Yet the spectral and directional dynamics underlying these interactions in humans remain poorly understood. Using intracranial EEG recordings from the amygdala and the hippocampus acquired during a two-day aversive learning and extinction task, we identified frequency-specific shifts: amygdala theta (3–8 Hz) and gamma (30–45 Hz) power increased during conditioning and decreased during extinction, while hippocampal alpha and gamma activity gave way to theta and gamma during extinction. Directional phase connectivity, results showed frequency-specific reversals: amygdala-to-hippocampus dominance at 3-5 Hz and hippocampus-to-amygdala predominance at 6-8 Hz, a reconfiguration validated by computational modelling. These findings uncover distinct theta sub-bands coordinating dynamic, bidirectional communication in the human amygdala–hippocampal circuit, elucidating a neural mechanism for the flexible regulation of emotional memory.

Although deep brain stimulation (DBS) shows potential in treatment-resistant depression (TRD), the efficacy remains controversial. To assess the efficacy of DBS of the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAc) for TRD, we conduct a randomized, double-blind, crossover trial after an open-label optimization stage. Stimulation leads to a mean decrease in the Hamilton Depression Scale-17 (HAMD) scores of 10.1 points (p < 0.001) with a 50% response rate at the end of the open-label stage. Anxiety, quality of life, and disability are also improved. The HAMD scores are significantly lower in patients during active DBS than during sham DBS (p < 0.001). Serious adverse events include suicide (1 patient) and seizure (1 patients). With individual stimulation analysis, we identify optimal stimulation sites, fiber tracts, and functional networks (false discovery rate [FDR] p < 0.05). This study demonstrates the efficacy and safety of BNST-NAc DBS for TRD and reveals optimal brain targets for stimulation. This study was registered at ClinicalTrials.gov (NCT04530942).

Obsessive-compulsive disorder (OCD) is characterized by widespread executive function impairments linked to disrupted fronto-striatal circuits. Ablative therapies such as capsulotomy show promise efficacy in treatment-refractory OCD, yet their effects on executive neural substrates remain poorly understood. This study explores how OCD and capsulotomy influence executive prefrontal function. Twenty-three post-capsulotomy OCD patients, thirty OCD controls, and thirty-two health controls (HC) were recruited in the study. Post-capsulotomy patients were recruited at least 6 months following surgery to allow for post-operative stabilization. Participants completed three executive function tasks assessing distinct cognitive domains: the Extra-Dimensional Intra-Dimensional (EDID) task testing set-shifting, the N-back task testing working memory and flanker task measuring conflict processing. The EDID and N-back tasks were administered during concurrent task-based fMRI, while the flanker task provided only behavioral measures. In the EDID task, OCD capsulotomy patients demonstrated greater post-error flexibility towards ID versus ED shifting relative to both OCD controls and healthy controls, despite exhibiting more ED errors. OCD controls showed less shifts after errors compared to HC, which was not revealed in the capsulotomy group. OCD patients showed less neural differentiation between ED versus ID in lateral and mesial prefrontal regions relative to HC. Capsulotomy was associated with decreased pre-supplementary motor area activity to ED shifts compared to HC, indicating impairments in neural reactivity to ED shifting. No evidence supported the influence of capsulotomy in the n-back or the flanker task. Specifically, both OCD groups showed impaired working memory performance at high memory load along with dysfunction in the whole frontoparietal network. In the flanker task, impairment in dissociating congruent and incongruent conditions were found in both OCD groups but not in the HC group. These findings suggest capsulotomy specifically remediates error-monitoring and behavioral flexibility through mesial prefrontal remodeling, while leaving working memory and conflict processing deficits intact. This dissociation implies that cognitive flexibility may represent a state-dependent process amenable to intervention, whereas working memory and conflict processing impairments may reflect trait markers of OCD vulnerability. These results have clinical implications on relative safety profile of capsulotomy and patient selection for precision neuromodulation.

Identifying novel neuromodulatory targets for deep brain stimulation (DBS) in psychiatric disorders is an urgent clinical need. Equally critical is the discovery of simple oscillatory biomarkers that bridge behaviour and clinical symptoms, enabling personalized treatment strategies. The bed nucleus of the stria terminalis (BNST), a pivotal output structure of the amygdala, is a potential candidate for DBS due to its key role in regulating fear, emotional valence, and prosocial behaviour. However, owing to the small size, its neural dynamics and functional contributions are poorly understood, precluding behavioural-clinical relevance. In a cross-sectional design, we acquired BNST neural recordings from 23 patients with depression undergoing DBS during two tasks: pain perception with painful/non-painful scenarios and an affect task with emotionally valenced images. We first localized the electrode contacts in the BNST and using their neural recordings for further analysis. We subjected the preprocessed data to time frequency decompositions to find condition differences. The significant clusters were then used to link to the behavioural ratings and clinical symptom severity. Furthermore, cross-frequency interactions were also undertaken. Pain perception elicited late theta and alpha activity (∼1s), with theta activity linked to subjective pain ratings and alpha correlating with anxiety/depression scores and anxiety symptoms post-DBS. Negative imagery induced early theta (∼250 ms), resembling previously reported amygdalar responses, and which link to valence ratings, depression and anxiety symptom severity. These results reveal distinct BNST dynamics in depression: early theta for rapid threat processing and late theta/alpha for complex socio-cognitive responses. Task-dependent theta and alpha activity linked behavioural profiles and symptom severity, highlighting BNST's role in behaviourally and clinically relevant oscillatory patterns, contributing novel insights for advancing precision neuromodulation strategies.

Methamphetamine use disorder (MUD) involves persistent cue reactivity and impaired inhibitory control, posing major treatment challenges. Closed-loop noninvasive neuromodulation can tailor stimulation to dynamic brain states, but its application in MUD remains largely unexplored. This study developed a cue reactivity biomarker-guided closed-loop transcranial alternating current stimulation (tACS) system, examined its optimal stimulation frequency, and preliminarily evaluated its efficacy in improving inhibitory control and reducing cue reactivity. Three cohorts of individuals with severe MUD were enrolled. Drug-cue exposure increased parietal-occipital theta power in Cohort 1. Based on this biomarker, a closed-loop tACS system targeting the left dorsolateral prefrontal cortex was developed. In Cohort 2, a within-subject crossover design examined closed-loop tACS at 6, 10, and 40 Hz. Random-time and open-loop continuous stimulation at the identified optimal frequency served as controls. In Cohort 3, an open-label, single-arm study of five consecutive daily closed-loop stimulation sessions assessed preliminary clinical efficacy. The results showed that closed-loop tACS at 40 Hz was the only condition that simultaneously reduced cue-related electroencephalographic (EEG) activity (P = 0.007) and improved inhibitory control (P = 0.031). Random-time stimulation reduced cue-related activity but did not improve inhibitory control, whereas open-loop continuous stimulation showed no significant effects. Repeated 40 Hz closed-loop tACS over five days in severe MUD significantly reduced craving and improved inhibitory control. These findings suggest that biomarker-guided 40 Hz closed-loop tACS can modulate neural and behavioral dysfunction in MUD and support the feasibility, safety, and preliminary efficacy of this neuromodulation strategy.

Although deep brain stimulation (DBS) shows potential in treatment-resistant depression (TRD), the efficacy remains controversial. To assess the efficacy of DBS of the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAc) for TRD, we conduct a randomized, double-blind, crossover trial after an open-label optimization stage. Stimulation leads to a mean decrease in the Hamilton Depression Scale-17 (HAMD) scores of 10.1 points (p < 0.001) with a 50% response rate at the end of the open-label stage. Anxiety, quality of life, and disability are also improved. The HAMD scores are significantly lower in patients during active DBS than during sham DBS (p < 0.001). Serious adverse events include suicide (1 patient) and seizure (1 patient). With individual stimulation analysis, we identify optimal stimulation sites, fiber tracts, and functional networks (false discovery rate [FDR] p < 0.05). This study demonstrates the efficacy and safety of BNST-NAc DBS for TRD and reveals optimal brain targets for stimulation. This study was registered at ClinicalTrials.gov (NCT04530942).

Deep brain stimulation (DBS) for treatment-resistant depression (TRD) is challenged by significant individual variability in efficacy and unclear neural circuit mechanisms. To address this, a cross-species, multi-level electrophysiological study was conducted to elucidate the core underlying pathophysiology and reveal the precise therapeutic mechanisms of DBS. Based on the clinical trial (NCT04530942), this study focuses on the bed nucleus of the stria terminalis-nucleus accumbens (BNST-NAc) circuit, and it is hypothesized that the fundamental pathology of the depressive state lies in the persistent hyperactivity of BNST neurons, which disrupts the high-fidelity signal communication capacity of this circuit. In a mouse model, a key communication pattern, inhibitory period isolated spikes (IPIS), was first identified within the excitation/inhibition (E/I) cycle. This pattern involves slow-wave oscillations creating a high signal-to-noise ratio window for the firing of single or few action potentials, thereby enabling efficient inter-regional communication. Subsequently, it was found that chronic stress-induced pathological hyperactivity of BNST neurons in stress-susceptible animals specifically disrupts the inhibitory periods of network activity, thereby dismantling IPIS-mediated cross-regional neural synchrony and leading to circuit dysfunction. The therapeutic mechanism of DBS was verified to involve precisely suppressing the pathological hyperactivity of the BNST, thereby restoring the network's inhibitory periods and re-establishing the efficient signal transmission pathway mediated by IPIS. In a closed-loop DBS paradigm, only continuous stimulation and stimulation precisely locked to the inhibitory periods produced antidepressant effects and most effectively restored cross-regional communication. Furthermore, in a cohort of human TRD patients, local field potential (LFP) data were recorded during BNST-NAc DBS treatment, and LFP biomarkers corresponding to the restoration of circuit function were identified. To more directly validate changes in E/I cycles in the human brain, an innovative cross-species algorithm was developed to decode functional excitatory and inhibitory periods from macroscopic human LFP signals. It was confirmed that the therapeutic response to DBS is associated with an increased proportion of inhibitory periods and the functional recovery of the BNST-NAc circuit, providing direct quantitative evidence for the theory that DBS restores E/I balance in the human brain. Finally, a double-blind, crossover randomized controlled trial (RCT) involving 18 participants confirmed that active DBS clinically alleviated depressive symptoms (an average of 9.4 reduction). Open-label data were used for model development, while RCT data served as an independent validation set. Model ablation study within a deep learning framework confirmed that E/I cycle features provide significantly higher informative value than spectral models, establishing these dynamics as the primary electrophysiological determinants of the clinical state. This study integrates mechanistic research with clinical validation, providing evidence for precision and personalized closed-loop DBS therapy.

Risk-taking underpins everyday decision making and is often dysregulated in neuropsychiatric disorders. Theta oscillations in the subthalamic nucleus (STN) have been implicated in conflict, risk evaluation, reward processing and impulsivity, but their causal role in risky choice remains unclear. We aimed to determine whether targeted modulation of STN theta dynamics can influence decision-making under risk and uncertainty. In a randomized, double blind study of 20 patients with Parkinson s disease (PD), we applied bilateral subacute STN stimulation at 5 Hz, 130 Hz, or sham during a risk-taking card task. In a separate cohort of 9 perioperative patients, we implemented a closed loop brain machine interface to deliver state dependent theta stimulation. Bilateral subacute STN stimulation at either frequency did not alter risky choice behaviors although 5 Hz stimulation hastened drift rates and 130 Hz stimulation slowed drift rates thus decreasing and increasing caution respectively. Critically, theta state adaptive high frequency acute STN stimulation reduced risky and uncertain betting without affecting reaction times and was associated with decreased theta power, shorter bursts, and attenuated outcome-related responses. These findings demonstrate that theta state adaptive STN stimulation causally shapes decision-making under risk and uncertainty, supporting oscillatory closed-loop DBS as a promising neuromodulation strategy for impulsivity and psychiatric disorders. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study is funded by the STI 2030-Major Projects (No. 2021ZD0200407 [to VV]), the National Natural Science Foundation of China (Grant No. 82271515 [to BS], 81971294 [to DL] and T2250710686 [to VV]), the Science and Technology Commission of Shanghai Municipality (Grant No. 20410712000 [to DL]), Medical Research Council Senior Clinical Fellowship (Grant No. MR/W020408/1 [to VV]), the SJTU Trans-med Awards Research (Grant No. 2019015 [to BS]), the Scientific and technological innovation action plan of Shanghai (Grant No. KY20211478 [to BS]), the Shanghai Municipal Science and Technology Major Project (Grant No. 2021SHZDZX [to BS]), and the Nursing Development Program of Shanghai Jiao Tong University School of Medicine (Grant No. SJTUHLXK2022 [to XQ]). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The studies were approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and all participants provided written informed consent according to the Declaration of Helsinki. Gender and ethics were self-reported by patients. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting the results of this study are available upon reasonable request from the corresponding authors.

Major depressive disorder (MDD) represents a major global health challenge, with a significant proportion of patients being resistant to drug treatment (TRD). Repetitive transcranial magnetic stimulation (rTMS) has shown promise in the treatment of MDD/TRD, with a single stimulation session per day for five days per week over several weeks (the "standard" protocol). The two main paradigms used are high-frequency rTMS and intermittent theta burst stimulation (iTBS) delivered to the left dorsolateral prefrontal cortex (DLPFC). Accelerated TMS (aTMS) protocols aim to make the treatment more effective, or at least more rapidly effective, by delivering more stimulations in a shorter time, which could also facilitate the implementation of the protocols for a larger number of patients. In this systematic literature review, articles comparing in the same study an aTMS protocol to a standard or sham rTMS protocol were retained for analysis. Thus, 23 articles were retained and the analysis focused on the efficacy of aTMS protocols used for the treatment of depression (MDD/TRD) as well as on the impact of various stimulation parameters, such as stimulation pattern, intersession interval, dosage, and methods of cortical targeting. Although some studies did not report significant differences between aTMS and standard or sham protocols, others suggested potential advantages of aTMS, such as twice-daily HF-rTMS of the left DLPFC or more intensive iTBS protocols with a long interval between two sessions and personalized cortical targeting. Our results highlight the influence of the number of sessions or pulses per session (dosage), the duration of the interval between sessions, and the precision of target localization (using image-guided neuronavigation) on therapeutic efficacy. However, limitations in sample size, few independent studies replicating the same methodology, and variability in the clinical profile of treated patients, given different definitions of treatment resistance or the presence of comorbidities, hamper definitive conclusions.

BACKGROUND:Parkinson's disease (PD) is primarily characterized by motor symptoms, but patients also experience a relatively high prevalence of non-motor symptoms, including emotional and cognitive impairments. While the subthalamic nucleus (STN) is a common target for deep brain stimulation to treat motor symptoms in PD, its role in emotion processing is still under investigation. This study examines the subthalamic neural oscillatory activities during facial emotion processing and its association with affective characteristics. METHODS:Twenty PD patients who underwent subthalamic deep brain stimulation surgery performed a facial-expression-recognition task while STN local field potential (LFP) and frontal electroencephalography (EEG) were recorded. The facial-emotion-induced time-frequency decomposition of the STN-LFP and the frontal EEG, as well as the LFP-EEG coherence, were analyzed. Furthermore, the correlation between STN activities and affective characteristics was examined. RESULTS:Facial expressions elicited increased delta-theta-band and decreased alpha-beta-band activities in STN-LFP. Reduced alpha-beta-band LFP desynchronization was correlated with the severity of apathy. Increased theta-band and decreased alpha-beta-band EEG activities responded to facial emotion. Notably, lower coherence between STN-LFP and frontal EEG in delta-theta-band activity and alpha-band activity correlated with the degree of anhedonia. CONCLUSION:These results indicate that subthalamic activities during facial emotion processing are associated with apathy and anhedonia, emphasizing the cognitive-limbic function of STN and its role as a physiological target for apathy neuromodulation in PD.

Background and aims:Dysregulation in instrumental control systems is implicated in compulsivity, a transdiagnostic construct proposed to underlie diverse maladaptive behaviors. While habit formation in reward-based learning is well-characterized, its role in avoidance learning remains less understood. Habitual avoidance may contribute to compulsive symptoms by impairing emotion regulation, a well-established correlate of compulsivity. To define these mechanisms, this study examined negative emotionality as a pathway linking habitual avoidance to compulsive behaviors. Methods:Five hundred adults completed the Avoidance Dynamics Task (ADT), a novel online-administered aversive devaluation paradigm assessing avoidance learning and habit strength, alongside validated self-report measures of compulsive behaviors (alcohol use, binge eating, binge watching, gambling, obsessive-compulsive symptoms) and internalizing symptoms (depression, anxiety). Mediation analysis tested whether internalizing symptoms accounted for associations between habitual avoidance and compulsive behavior severity. Results:Habitual avoidance, indexed by perseverative responses to devalued threat versus control cues (t = 3.5, p = .002), showed small-to-moderate positive associations with avoidance urges (ρ = .28, p < .001), regulatory control deficits (ρ = .17, p < .001), and internalizing symptoms (b = .15, p = .004). Internalizing symptoms fully mediated associations with all compulsive behaviors (b's = .05-.16, all p ≤ .01). Impaired avoidance learning was modestly associated with greater alcohol use (b = -.12, p = .03) and gambling (b = -.15, p = .02) severity. Exploratory analyses showed distinct avoidance patterns mapped onto cognitive (preoccupation, urges) versus behavioral (control, frequency) components of alcohol-related compulsivity. Conclusion:Habitual avoidance may represent a transdiagnostic behavioral marker of compulsivity. These findings underscore distinct vulnerability pathways across compulsive domains and support the use of remote tasks to phenotype maladaptive avoidance and related emotional dysregulation.

Psychiatric symptoms in Parkinson’s disease (PD) are highly prevalent and challenging to treat. This study maps oscillatory neural activity to diverse psychiatric symptoms in PD, using resting-state subthalamic nucleus (STN) local field potentials (LFPs) and frontal EEG in 75 PD patients undergoing deep brain stimulation (DBS). Our analysis revealed three levels of segregation: 1) Spectral: Depression was associated with increased alpha activity, apathy with elevated beta and frontal theta alongside reduced frontal beta, anxiety with decreased frontal low gamma, impulsivity with reduced low gamma and obsessive-compulsive disorders (OCD) with reduced delta activity. 2) Spatial: Depression and OCD localized to anatomical STN, apathy and impulsivity spanned both anatomical and electrophysiological STN, motor symptoms mapped to electrophysiological STN. 3) Structural connectivity: UK Biobank analyses revealed white matter pathways constraining STN oscillatory activity. These findings disentangle neurophysiological substrates of PD psychiatry, identifying symptom-specific biomarkers and informing targeted neuromodulation strategies.