A ventromedial prefrontal dysrhythmia in obsessive-compulsive disorder is attenuated by nucleus accumbens deep brain stimulation

Background: Obsessive-compulsive disorder (OCD) has consistently been linked to abnormal frontostriatal activity. The electrophysiological disruption in this circuit, however, remains to be characterized. Objective/hypothesis: The primary goal of this study was to investigate the neuronal synchronization in OCD patients. We predicted aberrant oscillatory activity in frontal regions compared to healthy control subjects, which would be alleviated by deep brain stimulation (DBS) of the nucleus accumbens (NAc). Methods: We compared scalp EEG recordings from nine patients with OCD treated with NAc-DBS with recordings from healthy controls, matched for age and gender. Within the patient group, EEG activity was compared with DBS turned off vs. stimulation at typical clinical settings (3.5 V, frequency of stimulation 130 Hz, pulse width 60 ms). In addition, intracranial EEG was recorded directly from depth macro electrodes in the NAc in four OCD patients. Results: Cross-frequency coupling between the phase of alpha/low beta oscillations and amplitude of high gamma was significantly increased over midline frontal and parietal electrodes in patients when stimulation was turned off, compared to controls. Critically, in patients, beta (16-25 Hz)-gamma (110-166 Hz) phase amplitude coupling source localized to the ventromedial prefrontal cortex, and was reduced when NAc-DBS was active. In contrast, intracranial EEG recordings showed no beta-gamma phase amplitude coupling. The contribution of non-sinusoidal beta waveforms to this coupling are reported. Conclusion: We reveal an increased beta-gamma phase amplitude coupling in fronto-central scalp sensors in patients suffering from OCD, compared to healthy controls, which may derive from ventromedial prefrontal regions implicated in OCD and is normalized by DBS of the nucleus accumbens. This aberrant cross-frequency coupling could represent a biomarker of OCD, as well as a target for novel therapeutic approaches. (C) 2021 The Authors. Published by Elsevier Inc.This work was supported by Project grants SAF2015-65982-R from the Spanish Ministry of Economy and Competitiveness to BS and PSI2014-58654-JIN to JGR, an FPI Predoctoral Fellowship (BES-2016-079470) to ST, and BIAL Foundation Grant 119/12 to BS. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC-2018-COG 819814)

DBS Imaging on a group level (Treu et al. 2020) - Supplementary material

Data (Lead group file) and Walkthrough Tutorial for reproductio

Aumento de memoria en seres humanos mediante estimulación cerebral profunda del nucleo accumbens

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Psicología Biológica y de la Salud. Fecha de Lectura: 14-02-2022Esta tesis tiene embargado el acceso al texto completo hasta el 14-08-2023Existe una gran demanda de nuevas opciones de tratamiento para la pérdida de memoria y una de las vías que más interés acapara es el método de estimulación cerebral profunda (ECP). Sin embargo, los intentos anteriores para mejorar la memoria humana estimulando sustratos neuronales con evidentes implicaciones en la memoria, como el lóbulo temporal medial, no han mostrado un beneficio consistente. Una estrategia alternativa es estimular áreas cerebrales que modulan la memoria y que sufren una menor degeneración en procesos de demencia, como el núcleo accumbens (NAc), implicado en la mejora de la codificación de la memoria episódica. En esta tesis se presentan tres experimentos. Los dos primeros investigan el efecto de la ECP en el NAc (ECP-NAc) sobre la memoria en pacientes psiquiátricos de tres hospitales diferentes de España. El primer experimento demuestra que la ECP-NAc durante la codificación mejora la probabilidad del recuerdo posterior de imágenes que sobresalen perceptualmente, en relación con períodos sin estimulación en nueve pacientes recientemente implantados. En el segundo experimento, se aplicó la estimulación en doce pacientes tratados crónicamente con ECP. Tras un periodo de “lavado” de dos horas, la activación de la estimulación mejoró significativamente la precisión de la memoria espacial en un paradigma de navegación virtual. En ambos estudios, la mejora de la memoria se asoció a la estimulación de la misma zona del accumbens postero-dorso-medial, en el límite con el septum medial. El tercer estudio descrito en esta tesis analiza la electroencefalografía (EEG) en reposo registrada en el cuero cabelludo con ECP activada versus desactivada. Este estudio muestra un aumento del acoplamiento de la amplitud de actividad gamma a la fase de oscilaciones beta en la corteza prefrontal ventromedial en pacientes que sufren un trastorno obsesivo-compulsivo (TOC), en comparación con los controles sanos. El acoplamiento beta-gamma, putativamente patológico, se normalizó con la ECP del núcleo accumbens, aunque el grado de esta normalización no correlacione con la mejora de la memoria. Esta tesis caracteriza el efecto de la ECP-NAc sobre la sincronización de las oscilaciones neuronales en áreas corticales conectadas y establece un papel del NAc humano tanto en la VII memoria visual episódica como en la espacial en una población de pacientes de difícil acceso, proporcionando así conocimientos valiosos y una base empírica para el desarrollo de una nueva oportunidad terapéutica para los pacientes que sufren de una alteración en la memori

A Unified Functional Network Target for Deep Brain Stimulation in Obsessive-Compulsive Disorder

BACKGROUND: Multiple deep brain stimulation (DBS) targets have been proposed for treating intractable obsessivecompulsive disorder (OCD). Here, we investigated whether stimulation effects of different target sites would be mediated by one common or several segregated functional brain networks. METHODS: First, seeding from active electrodes of 4 OCD patient cohorts (N = 50) receiving DBS to anterior limb of the internal capsule or subthalamic nucleus zones, optimal functional connectivity profiles for maximal Yale-Brown Obsessive Compulsive Scale improvements were calculated and cross-validated in leave-one-cohort-out and leave-one-patient-out designs. Second, we derived optimal target-specific connectivity patterns to determine brain regions mutually predictive of clinical outcome for both targets and others predictive for either target alone. Functional connectivity was defined using resting-state functional magnetic resonance imaging data acquired in 1000 healthy participants. RESULTS: While optimal functional connectivity profiles showed both commonalities and differences between target sites, robust cross-predictions of clinical improvements across OCD cohorts and targets suggested a shared network. Connectivity to the anterior cingulate cortex, insula, and precuneus, among other regions, was predictive regardless of stimulation target. Regions with maximal connectivity to these commonly predictive areas included the insula, superior frontal gyrus, anterior cingulate cortex, and anterior thalamus, as well as the original stereotactic targets. CONCLUSIONS: Pinpointing the network modulated by DBS for OCD from different target sites identified a set of brain regions to which DBS electrodes associated with optimal outcomes were functionally connected-regardless of target choice. On these grounds, we establish potential brain areas that could prospectively inform additional or alternative neuromodulation targets for obsessive-compulsive disorder

A unified connectomic target for deep brain stimulation in obsessive-compulsive disorder

Multiple surgical targets for treating obsessive-compulsive disorder with deep brain stimulation (DBS) have been proposed. However, different targets may modulate the same neural network responsible for clinical improvement. We analyzed data from four cohorts of patients (N=50) that underwent DBS to the anterior limb of the internal capsule (ALIC), the nucleus accumbens or the subthalamic nucleus (STN). The same fiber bundle was associated with optimal clinical response in cohorts targeting either structure. This bundle connected frontal regions to the STN. When informing the tract target based on the first cohort, clinical improvements in the second could be significantly predicted, and vice versa. To further confirm results, clinical improvements in eight patients from a third center and six patients from a fourth center were significantly predicted based on their stimulation overlap with this tract. Our results show that connectivity-derived models may inform clinical improvements across DBS targets, surgeons and centers. The identified tract target is openly available in atlas form. Li et al. analyzed structural connectivity of deep brain stimulation electrodes in 50 patients suffering from obsessive-compulsive disorder operated at four centers. Connectivity to a specific tract within the anterior limb of the internal capsule was associated with optimal treatment response across cohorts, surgeons and centers