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Despite increasing prevalence and huge personal and societal burden, psychiatric diseases still lack treatments which can control symptoms for a large fraction of patients. Increasing insight into the neurobiology underlying these diseases has demonstrated wide-ranging aberrant activity and functioning in multiple brain circuits and networks. Together with varied presentation and symptoms, this makes one-size-fits-all treatment a challenge. There has been a resurgence of interest in the use of neurostimulation as a treatment for psychiatric diseases. Initial studies using continuous open-loop stimulation, in which clinicians adjusted stimulation parameters during patient visits, showed promise but also mixed results. Given the periodic nature and fluctuations of symptoms often observed in psychiatric illnesses, the use of device-driven closed-loop stimulation may provide more effective therapy. The use of a biomarker, which is correlated with specific symptoms, to deliver stimulation only during symptomatic periods allows for the personalized therapy needed for such heterogeneous disorders. Here, we provide the reader with background motivating the use of closed-loop neurostimulation for the treatment of psychiatric disorders. We review foundational studies of open- and closed-loop neurostimulation for neuropsychiatric indications, focusing on deep brain stimulation, and discuss key considerations when designing and implementing closed-loop neurostimulation.

Current neural prostheses can translate neural activity into control signals for guiding prosthetic devices, but poor performance limits practical application. Here the authors present a new cursor-control algorithm that approaches native arm control speed and accuracy, permits sustained uninterrupted use for hours, generalizes to more challenging tasks and provides repeatable high performance for years after implantation, thereby increasing the clinical viability of neural prostheses. Neural prostheses translate neural activity from the brain into control signals for guiding prosthetic devices, such as computer cursors and robotic limbs, and thus offer individuals with disabilities greater interaction with the world. However, relatively low performance remains a critical barrier to successful clinical translation; current neural prostheses are considerably slower, with less accurate control, than the native arm. Here we present a new control algorithm, the recalibrated feedback intention–trained Kalman filter (ReFIT-KF) that incorporates assumptions about the nature of closed-loop neural prosthetic control. When tested in rhesus monkeys implanted with motor cortical electrode arrays, the ReFIT-KF algorithm outperformed existing neural prosthetic algorithms in all measured domains and halved target acquisition time. This control algorithm permits sustained, uninterrupted use for hours and generalizes to more challenging tasks without retraining. Using this algorithm, we demonstrate repeatable high performance for years after implantation in two monkeys, thereby increasing the clinical viability of neural prostheses.

Deep brain stimulation has been used to treat severe, refractory obsessive-compulsive disorder (OCD) with variable outcomes across multiple anatomical targets. To overcome these limitations, we developed an invasive brain mapping paradigm in which electrodes were implanted across the OCD cortico-striato-thalamo-cortical circuit. We then performed extensive stimulation mapping during a multi-day inpatient stay to identify personalized therapeutic targets and characterize their downstream circuit effects. We found two targets within the right ventral capsule (VC) that acutely reduced OCD symptoms. Prolonged VC stimulation suppressed high frequency activity within the structurally and functionally connected orbitofrontal and cingulate cortex, which were identified to be cortical nodes encoding the severity of OCD symptoms. These VC sites were implanted for DBS and combined stimulation of these targets led to a rapid therapeutic response. This case provides the first proof-of-concept that invasive brain mapping can be used to guide a novel personalized, multi-site neuromodulation approach to treat refractory OCD.

Objective A major source of disability for people with epilepsy involves uncertainty surrounding seizure timing and severity. Although patients often report that long seizure‐free intervals are followed by more severe seizures, there is little experimental evidence supporting this observation. Optimal characterization of seizure severity is debated; however, seizure duration is associated with seizure type and can be quantified in electrographic recordings as a limited proxy of clinical seizure severity. Here, using chronic intracranial electroencephalography (cEEG), we investigate the relationship between interseizure interval (ISI) and duration of the subsequent seizure. Methods We performed a retrospective analysis of 14 subjects implanted with a responsive neurostimulation device (RNS System) that provides cEEG, including timestamps of electrographic seizures. We determined seizure durations for isolated seizures and for representative seizures from clusters determined through unsupervised methods. For each subject, the median ISI preceding long‐duration seizures, defined as the top quintile of seizure durations, was compared with the median ISI preceding seizures with durations in the residual quintiles. In a group analysis, the mean seizure duration and the proportion of long‐duration seizures were compared across ISI categories representing different lengths. Results For 5 out of 14 subjects (36%), the median ISI preceding long‐duration seizures was significantly greater than the median ISI preceding shorter‐duration seizures. In the group analysis, when ISI was categorized by length, the proportion of long‐duration seizures within the high ISI category was significantly higher than that of the low ISI category (P < 0.001). Significance By leveraging cEEG and accounting for seizure clusters, we found that the likelihood of long‐duration seizures positively correlates with ISI length, in a subset of individuals. These findings corroborate anecdotal clinical observations and support the existence of capacitor‐like long memory processes governing the dynamics of focal seizures.

Background Psoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors. Case presentation A 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis. Conclusion Patients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.

Introduction Sleep is a highly stereotyped phenomenon that is ubiquitous across species. Although behaviorally appearing as a homogeneous process, sleep has been recognized as cortically heterogenous and locally dynamic. PET/fMRI studies have provided key insights into regional activation and deactivation with sleep onset, but they lack the high temporal resolution and electrophysiology for understanding neural interactions. Using simultaneous electrocorticography (EEG) and magnetoencephalography (MEG) imaging, we systematically characterize whole-brain neural oscillations and identify frequency specific, cortically-based patterns associated with sleep onset. Methods In this study, 14 healthy subjects underwent simultaneous EEG and MEG imaging. Sleep states were determined by scalp EEG. Eight 15s artifact-free epochs, e.g. 120s sensor time series, were selected to represent each behavioral state: N1, N2 and wake. Atlas-based source reconstruction was performed using adaptive beamforming methods. Functional connectivity measures were computed using imaginary coherence and across regions of interests (ROIs, segmentation of 210 cortical regions with Brainnetome Atlas) in multiple frequency bands, including delta (1-4Hz), theta (4-8Hz), alpha (8-12Hz), sigma (12-15Hz), beta (15-30Hz), and gamma (30-50Hz). Directional phase transfer entropy (PTE) was also evaluated to determine the direction of information flow with transition to sleep. Results We show that the transition to sleep is encoded in a spatially and temporally specific dynamic pattern of whole-brain functional connectivity. With sleep onset, there is increased functional connectivity diffusely within the delta frequency, while spatially specific profiles in other frequency bands, e.g. increased fronto-temporal connectivity in the alpha frequency band and fronto-occipital connectivity in the theta band. In addition, rather than a decoupling of anterior-posterior regions with transition to sleep, there is a spectral shift to delta frequencies observed in the synchrony and information flow of neural activity. Conclusion Sleep onset is cortically heterogeneous, composed of spatially and temporally specific patterns of whole-brain functional connectivity, which may play an essential role in the transition to sleep. Support (if any) Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the NIH under Award Number (5TL1TR001871-05 to JMF). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

INTRODUCTION Intracranial electrode monitoring is fundamentally important for epilepsy surgery evaluations. Currently, there is an emerging debate over the optimal approach between subdural grids and stereoelectroencephalography (SEEG). Our institution utilizes two strategies for intracranial EEG ictal recordings: 1) a “hybrid” approach, whereby patients receive combined subdural grid and intraoperative neuronavigation-based depth electrode implantations, and 2) SEEG. METHODS A retrospective review was performed on consecutive patients that underwent hybrid or SEEG implantation from July 2012 to July 2019. Intracranial recordings were utilized in patients with putative seizure onset regions that were MR-negative, poorly localized, and/or abutting eloquent cortex. Hemorrhagic and non-hemorrhagic complications, neurological deficit at discharge, success of localizing seizure focus, one-year Engel I outcomes, and electrode locations. RESULTS 99 hybrid and 44 SEEG procedures were performed. Hemorrhagic complication rates were similar (SEEG: 8%; hybrid: 7.1%, P = .96). SEEG hemorrhages were all intra-axial, whereas hybrid hemorrhages were all extra-axial. Neurological deficits from hybrid cases were quickly reversed with prompt hematoma evacuation, while SEEG was associated with more severe deficits at discharge (P < .01). There was no difference in non-hemorrhagic complications (P = .24). Hybrid cases had higher density of electrode contacts (hybrid: 122.1±28.5, SEEG: 89.8±34.2, P < .01), with more sampling of eloquent cortices. SEEG electrodes were more likely to be located in white matter (SEEG: 34.0%, hybrid: 9.2%, P < .01). CONCLUSION The hybrid and SEEG approaches resulted in similar, relatively low hemorrhage rates in our institutional series. An important difference, however, is that SEEG-related hemorrhages in eloquent brain regions resulted in lasting neurological deficits. Grid-related subdural hemorrhages did not lead to any long-standing injury. The decision to use hybrid or SEEG should tailor the characteristics of either approach to the localization question(s) for a given patien.

Sleep is a highly stereotyped phenomenon, requiring robust spatial and temporal coordination of neural activity. How the brain coordinates neural activity with sleep onset can provide insight into the physiological functions subserved by sleep and pathologic phenomena associated with sleep onset. We quantified whole-brain network changes in synchrony and information flow during the transition from wake to non-rapid eye movement (NREM) sleep using magnetoencephalography imaging in healthy subjects. In addition, we performed computational modeling to infer excitatory and inhibitory properties of local neural activity. The sleep transition was identified to be encoded in spatially and temporally specific patterns of local and long-range neural synchrony. Patterns of information flow revealed that mesial frontal regions receive hierarchically organized inputs from broad cortical regions upon sleep onset. Finally, biophysical neural mass modeling demonstrated spatially heterogeneous properties of cortical excitation-to-inhibition from wake to NREM. Together, these findings reveal whole-brain corticocortical structure in the sleep-wake transition and demonstrate the orchestration of local and long-range, frequency-specific cortical interactions that are fundamental to sleep onset.Competing Interest StatementThe authors have declared no competing interest.Footnotes* This version includes updates to the text and nomenclature.

SALL4, which is expressed in fetal but not adult liver, is reexpressed in a subgroup of hepatocellular cancers associated with a poor prognosis. In mice, treatment aimed at inhibiting SALL4 has antitumor effects. Hepatocellular carcinoma is the third leading cause of cancer-related deaths globally. Although the epidemiologic risk factors for hepatocellular carcinoma are well known, 1 the molecular mechanisms underlying hepatocarcinogenesis are not well characterized. Elucidation of these mechanisms may allow identification of new candidates for therapeutic targeting. Although surgery, liver transplantation, and radiologic intervention may be viable options for patients with early-stage disease, the prognosis associated with advanced-stage hepatocellular carcinoma remains bleak. 2 Combination chemotherapy has not improved overall survival but has nonetheless been in wide use for many years because of its possible role in palliation. The need to understand the molecular pathogenesis . . .

Background Healthy food nudges may be more, or especially, effective among groups experiencing socioeconomic disadvantage. We investigated the modifying role of socioeconomic and demographic characteristics in the effectiveness of nudge interventions targeting healthy foods in real-world grocery store settings on food purchasing patterns. Methods We pooled individual participant data from multiple trials. Eligible trials were identified via a PubMed search and selected based on having a controlled real-world design, testing a nudging intervention promoting healthy purchases, while collecting participants’ sociodemographic and purchasing data. Out of four eligible trials, three had longitudinal measurements, one consisted of a single time point, two were randomised and two were not. Applied nudges consisted of a combination of placement nudges (focussing on availability or positioning) and property nudges (presentation and/or information). Harmonised data included dichotomised socioeconomic and demographic variables and the percentage of purchased fruits and vegetables of total purchases. Multilevel meta-regression based on linear mixed-effects models were used to explore modifying effects using two approaches: longitudinal and cross-sectional analyses. Results The analytical sample in the longitudinal analysis comprised of 638 participants, who were predominantly female (76.3%), had a lower education attainment (67.7%), and a mean age of 46.6 years (SD 13.5). These characteristics were similar in the cross-sectional analysis ( n  = 855). Compared to control group participants, there was no main effect of healthy food nudges on the percentage of fruit and vegetable purchases by intervention group participants in the longitudinal analysis (β = 0.00; 95%CI -0.03, 0.09). This main effect was not modified by educational attainment (β group*higher education  = -0.06; -0.40, 0.02), sex (β group*females  = 0.13; -0.00, 0.61) nor age (β group*older adults  = -0.05; -0.39, 0.02). Results from the cross-sectional analysis were comparable. Conclusions This pooled analyses of four controlled trials did not find evidence supporting the hypothesis that grocery store nudge interventions of healthy foods work more effectively among groups experiencing socioeconomic disadvantage. Future studies are needed to address the identified limitations through rigorous trial design using comprehensive interventional strategies, standardised outcome measures, while also evaluating context-specific approaches. Such insights will help to better understand the equity of nudging interventions in grocery store settings and the potential for reducing diet-related health disparities. Trial registrations The trial of Ayala et al. (2022) was retrospectively registered at ClinicalTrials.gov (NCT01475526; at 14 November 2011, https://clinicaltrials.gov/study/NCT01475526 ), the of Huitink et al. (2020) was retrospectively registered in the ISRCTN registry (ISRCTN39440735; at 5 September 2018, https://doi.org/10.1186/ISRCTN39440735 ), the of Vogel et al. (2024) was retrospectively registered at ClinicalTrials.gov (NCT03518151; at 24 April 2018, https://clinicaltrials.gov/study/NCT03518151 ), and finally of Stuber et al. (2024) was registered in the Dutch Trial Register (ID NL7064, at 30 May 2018, https://www.onderzoekmetmensen.nl/en/trial/20990 ).