Mechanisms of deep brain stimulation for obsessive compulsive disorder: effects upon cells and circuits

Deep brain stimulation (DBS) has emerged as a safe, effective, and reversible treatment for a number of movement disorders. This has prompted investigation of its use for other applications including psychiatric disorders. In recent years, DBS has been introduced for the treatment of obsessive compulsive disorder (OCD), which is characterized by recurrent unwanted thoughts or ideas (obsessions) and repetitive behaviors or mental acts performed in order to relieve these obsessions (compulsions). Abnormal activity in cortico-striato-thalamo-cortical (CSTC) circuits including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), ventral striatum, and mediodorsal (MD) thalamus has been implicated in OCD. To this end a number of DBS targets including the anterior limb of the internal capsule (ALIC), ventral capsule/ventral striatum (VC/VS), ventral caudate nucleus, subthalamic nucleus (STN), and nucleus accumbens (NAc) have been investigated for the treatment of OCD. Despite its efficacy and widespread use in movement disorders, the mechanism of DBS is not fully understood, especially as it relates to psychiatric disorders. While initially thought to create a functional lesion akin to ablative procedures, it is increasingly clear that DBS may induce clinical benefit through activation of axonal fibers spanning the CSTC circuits, alteration of oscillatory activity within this network, and/or release of critical neurotransmitters. In this article we review how the use of DBS for OCD informs our understanding of both the mechanisms of DBS and the circuitry of OCD. We review the literature on DBS for OCD and discuss potential mechanisms of action at the neuronal level as well as the broader circuit level

Hexadirectional modulation of high-frequency electrophysiological activity in the human anterior medial temporal lobe maps visual space

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Human Verbal Memory Encoding Is Hierarchically Distributed in a Continuous Processing Stream.

Processing of memory is supported by coordinated activity in a network of sensory, association, and motor brain regions. It remains a major challenge to determine where memory is encoded for later retrieval. Here, we used direct intracranial brain recordings from epilepsy patients performing free recall tasks to determine the temporal pattern and anatomical distribution of verbal memory encoding across the entire human cortex. High γ frequency activity (65-115 Hz) showed consistent power responses during encoding of subsequently recalled and forgotten words on a subset of electrodes localized in 16 distinct cortical areas activated in the tasks. More of the high γ power during word encoding, and less power before and after the word presentation, was characteristic of successful recall and observed across multiple brain regions. Latencies of the induced power changes and this subsequent memory effect (SME) between the recalled and forgotten words followed an anatomical sequence from visual to prefrontal cortical areas. Finally, the magnitude of the memory effect was unexpectedly found to be the largest in selected brain regions both at the top and at the bottom of the processing stream. These included the language processing areas of the prefrontal cortex and the early visual areas at the junction of the occipital and temporal lobes. Our results provide evidence for distributed encoding of verbal memory organized along a hierarchical posterior-to-anterior processing stream

Electrophysiological Signatures of Spatial Boundaries in the Human Subiculum.

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1-4, 4-10, and 30-90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one\u27s own body

Deep Brain Stimulation for Obsessive Compulsive Disorder: Evolution of Surgical Stimulation Target Parallels Changing Model of Dysfunctional Brain Circuits

Obsessive compulsive disorder (OCD) is a common, disabling psychiatric disease characterized by persistent, intrusive thoughts and ritualistic, repetitive behaviors. Deep brain stimulation (DBS) is thought to alleviate OCD symptoms by modulating underlying disturbances in normal cortico-striato-thalamo-cortical (CSTC) circuitry. Stimulation of the ventral portion of the anterior limb of the internal capsule (ALIC) and underlying ventral striatum (“ventral capsule/ventral striatum” or “VC/VS” target) received U.S. FDA approval in 2009 for patients with severe, treatment-refractory OCD. Over the decades, DBS surgical outcome studies have led to an evolution in the electrical stimulation target. In parallel, advancements in neuroimaging techniques have allowed investigators to better visualize and define CSTC circuits underlying the pathophysiology of OCD. A critical analysis of these new data suggests that the therapeutic mechanism of DBS for OCD likely involves neuromodulation of a widespread cortical/subcortical network, accessible by targeting fiber bundles in the ventral ALIC that connect broad network regions. Future studies will include advances in structural and functional imaging, analysis of physiological recordings, and utilization of next-generation DBS devices. These tools will enable patient-specific optimization of DBS therapy, which will hopefully further improve outcomes

Normative vs. patient-specific brain connectivity in deep brain stimulation

Brain connectivity profiles seeding from deep brain stimulation (DBS) electrodes have emerged as informative tools to estimate outcome variability across DBS patients. Given the limitations of acquiring and processing patient-specific diffusion-weighted imaging data, a number of studies have employed normative atlases of the human connectome. To date, it remains unclear whether patient-specific connectivity information would strengthen the accuracy of such analyses. Here, we compared similarities and differences between patient-specific, disease-matched and normative structural connectivity data and estimation of clinical improvement that they may generate. Data from 33 patients suffering from Parkinson's Disease who underwent surgery at three different centers were retrospectively collected. Stimulation-dependent connectivity profiles seeding from active contacts were estimated using three modalities, namely either patient-specific diffusion-MRI data, disease-matched or normative group connectome data (acquired in healthy young subjects). Based on these profiles, models of optimal connectivity were constructed and used to estimate the clinical improvement in out of sample data. All three modalities resulted in highly similar optimal connectivity profiles that could largely reproduce findings from prior research based on a novel multi-center cohort. In a data-driven approach that estimated optimal whole-brain connectivity profiles, out-of-sample predictions of clinical improvements were calculated. Using either patient-specific connectivity (R = 0.43 at p = 0.001), an age- and disease-matched group connectome (R = 0.25, p = 0.048) and a normative connectome based on healthy/young subjects (R = 0.31 at p = 0.028), significant predictions could be made and underlying optimal connectivity profiles were highly similar. Our results of patient-specific connectivity and normative connectomes lead to similar main conclusions about which brain areas are associated with clinical improvement. Still, although results were not significantly different, they hint at the fact that patient-specific connectivity may bear the potential of estimating slightly more variance when compared to group connectomes. Furthermore, use of normative connectomes involves datasets with high signal-to-noise acquired on specialized MRI hardware, while clinical datasets as the ones used here may not exactly match their quality. Our findings support the role of DBS electrode connectivity profiles as a promising method to investigate DBS effects and to potentially guide DBS programming

Clinical features of brain metastasis from salivary gland tumors

Salivary gland tumors comprise a group of 24 tumor subtypes with a wide range of clinical behaviors and propensities for metastasis. Several prognostic factors have been identified that help predict the development of systemic metastases, most commonly to the lung, liver, or bone. Metastases to the brain are rare. To better understand the behavior of salivary gland tumors that metastasise to the brain, we performed a retrospective cohort analysis on a series of patients to highlight features of their medical and surgical management. From 2007 to 2011, a database of 4117 elective craniotomies were queried at a single institution to identify patients surgically treated for salivary gland metastases to the brain. Three patients were identified. Histologic subtypes included salivary duct carcinoma, poorly differentiated carcinoma, and papillary mucinous adenocarcinoma. They had all undergone previous treatment for their primary malignancy. The mean time to intracranial metastasis was 48 months from initial diagnosis (range, 14–91 months). Treatment for intracranial metastases included surgical resection, whole brain radiation, stereotactic radiosurgery, and chemotherapy. Intracranial metastases from salivary gland tumors are rare, present years after diagnosis of the primary tumor, and are treatable with multimodality therapy

Lateralized hippocampal oscillations underlie distinct aspects of human spatial memory and navigation

The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1–3-Hz “low theta” band increases when viewing subsequently remembered object–location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition