Sameer A. Sheth

Human dorsal anterior cingulate cortex neurons mediate ongoing behavioural adaptation

The ability to optimize behavioural performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, is important in regulating cognitive control. Hypotheses about its function include guiding reward-based decision making, monitoring for conflict between competing responses and predicting task difficulty. Precise mechanisms of dACC function remain unknown, however, because of the limited number of human neurophysiological studies. Here we use functional imaging and human single-neuron recordings to show that the firing of individual dACC neurons encodes current and recent cognitive load. We demonstrate that the modulation of current dACC activity by previous activity produces a behavioural adaptation that accelerates reactions to cues of similar difficulty to previous ones, and retards reactions to cues of different difficulty. Furthermore, this conflict adaptation, or Gratton effect, is abolished after surgically targeted ablation of the dACC. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioural responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands it engenders accuracy by delaying responses.

Columnar Specificity of Microvascular Oxygenation and Volume Responses: Implications for Functional Brain Mapping

Cortical neurons with similar properties are grouped in columnar structures and supplied by matching vascular networks. The hemodynamic response to neuronal activation, however, is not well described on a fine spatial scale. We investigated the spatiotemporal characteristics of microvascular responses to neuronal activation in rat barrel cortex using optical intrinsic signal imaging and spectroscopy. Imaging was performed at 570 nm to provide functional maps of cerebral blood volume (CBV) changes and at 610 nm to estimate oxygenation changes. To emphasize parenchymal rather than large vessel contributions to the functional hemodynamic responses, we developed an ANOVA-based statistical analysis technique. Perfusion-based maps were compared with underlying neuroanatomy with cytochrome oxidase staining. Statistically determined CBV responses localized accurately to individually stimulated barrel columns and could resolve neighboring columns with a resolution better than 400 μm. Both CBV and early oxygenation responses extended beyond anatomical boundaries of single columns, but this vascular point spread did not preclude spatial specificity. These results indicate that microvascular flow control structures providing targeted flow increases to metabolically active neuronal columns also produce finely localized changes in CBV. This spatial specificity, along with the high contrast/noise ratio, makes the CBV response an attractive mapping signal. We also found that functional oxygenation changes can achieve submillimeter specificity not only during the transient deoxygenation (“initial dip”) but also during the early part of the hyperoxygenation. We, therefore, suggest that to optimize hemodynamic spatial specificity, appropriate response timing (using ≤2-3 sec changes) is more important than etiology (oxygenation or volume).

Functional neuroimaging of belief, disbelief, and uncertainty.

The difference between believing and disbelieving a proposition is one of the most potent regulators of human behavior and emotion. When one accepts a statement as true, it becomes the basis for further thought and action; rejected as false, it remains a string of words. The purpose of this study was to differentiate belief, disbelief, and uncertainty at the level of the brain.

Functional signal- and paradigm-dependent linear relationships between synaptic activity and hemodynamic responses in rat somatosensory cortex

Linear relationships between synaptic activity and hemodynamic responses are critically dependent on functional signal etiology and paradigm. To investigate these relationships, we simultaneously measured local field potentials (FPs) and optical intrinsic signals in rat somatosensory cortex while delivering a small number of electrical pulses to the hindpaw with varied stimulus intensity, number, and interstimulus interval. We used 570 and 610 nm optical signals to estimate cerebral blood volume (CBV) and oxygenation, respectively. The spatiotemporal evolution patterns and trial-by-trial correlation analyses revealed that CBV-related optical signals have higher fidelity to summed evoked FPs (ΣFPs) than oxygenation-derived signals. CBV-related signals even correlated with minute ΣFP fluctuations within trials of the same stimulus condition. Furthermore, hemodynamic signals (CBV and late oxygenation signals) increased linearly with ΣFP while varying stimulus number, but they exhibited a threshold and steeper gradient while varying stimulus intensity, suggesting insufficiency of the homogeneity property of linear systems and the importance of spatiotemporal coherence of neuronal population activity in hemodynamic response formation. These stimulus paradigm-dependent linear and nonlinear relationships demonstrate that simple subtraction-based analyses of hemodynamic signals produced by complex stimulus paradigms may not reflect a difference in ΣFPs between paradigms. Functional signal- and paradigm-dependent linearity have potentially profound implications for the interpretation of perfusion-based functional signals.

Deep brain stimulation for obsessive-compulsive disorder: past, present, and future

Obsessive-compulsive disorder (OCD) is a psychiatric illness that can lead to chronic functional impairment. Some patients with severe, chronic OCD have been treated with ablative neurosurgical techniques over the past 4 decades. More recently, deep brain stimulation (DBS) has been investigated as a therapy for refractory OCD, and the procedure was granted a limited humanitarian device exemption by the FDA in 2009. In this article, the authors review the development of DBS for OCD, describe the current understanding of the pathophysiological mechanisms of the disorder and how the underlying neural circuits might be modulated by DBS, and discuss the clinical studies that provide evidence for the use of this evolving therapy. The authors conclude with suggestions for how a combined basic science and translational research approach could drive the understanding of the neural mechanisms underlying OCD as well as the clinical effectiveness of DBS in the setting of recalcitrant disease.

MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma.

Significance Molecular analysis of surgically resected glioblastomas (GBM) samples has uncovered phenotypically and clinically distinct tumor subtypes. However, little is known about the molecular features of the glioma margins that are left behind after surgery. To address this key issue, we performed RNA-sequencing (RNA-seq) and histological analysis on MRI-guided biopsies from the contrast-enhancing core and nonenhancing margins of GBM. Computational deconvolution of the RNA-seq data revealed that cellular composition, including nonneoplastic cells, is a major determinant of the expression patterns at the margins of GBM. The different GBM subtypes show distinct expression patterns that relate the contrast enhancing centers to the nonenhancing margins of tumors. Understanding these patterns may provide a means to infer the molecular and cellular features of residual disease. Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtype-specific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM.

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.

Predictors of cranioplasty complications in stroke and trauma patients

OBJECT Decompressive craniectomy mandates subsequent cranioplasty. Complications of cranioplasty may be independent of the initial craniectomy, or they may be contingent upon the craniectomy. Authors of this study aimed to identify surgery- and patient-specific risk factors related to the development of surgical site infection and other complications following cranioplasty. METHODS A consecutive cohort of patients of all ages and both sexes who had undergone cranioplasty following craniectomy for stroke or trauma at a single institution in the period from May 2004 to May 2012 was retrospectively established. Patients who had undergone craniectomy for infectious lesions or neoplasia were excluded. A logistic regression analysis was performed to model and predict determinants related to infection following cranioplasty. RESULTS Two hundred thirty-nine patients met the study criteria. The overall rate of complication following cranioplasty was 23.85% (57 patients). Complications included, predominantly, surgical site infection, hydrocephalus, and new-onset seizures. Logistic regression analysis identified previous reoperation (OR 3.25, 95% CI 1.30-8.11, p = 0.01) and therapeutic indication for stroke (OR 2.45, 95% CI 1.11-5.39, p = 0.03) as significantly associated with the development of cranioplasty infection. Patient age, location of cranioplasty, presence of an intracranial device, bone flap preservation method, cranioplasty material, booking method, and time interval > 90 days between initial craniectomy and cranioplasty were not predictive of the development of cranioplasty infection. CONCLUSIONS Cranioplasty complications are common. Cranioplasty infection rates are predicted by reoperation following craniectomy and therapeutic indication (stroke). These variables may be associated with patient-centered risk factors that increase cranioplasty infection risk.

Basal Ganglia Neurons Dynamically Facilitate Exploration During Associative Learning

The basal ganglia (BG) appear to play a prominent role in associative learning, the process of pairing external stimuli with rewarding responses. Accumulating evidence suggests that the contributions of various BG components may be described within a reinforcement learning model, in which a broad repertoire of possible responses to environmental stimuli are evaluated before the most profitable one is chosen. The striatum receives diverse cortical inputs, providing a rich source of contextual information about environmental cues. It also receives projections from midbrain dopaminergic neurons, whose phasic activity reflects a reward prediction error signal. These coincident information streams are well suited for evaluating responses and biasing future actions toward the most profitable response. Still lacking in this model is a mechanistic description of how initial response variability is generated. To investigate this question, we recorded the activity of single neurons in the globus pallidus internus (GPi), the primary BG output nucleus, in nonhuman primates (Macaca mulatta) performing a motor associative learning task. A subset (29%) of GPi neurons showed learning-related effects, decreasing firing during the early stages of learning, then returning to higher baseline rates as associations were mastered. On a trial-by-trial basis, lower firing rates predicted exploratory behavior, whereas higher rates predicted an exploitive response. These results suggest that, during associative learning, BG output is initially permissive, allowing exploration of a variety of responses. Once a profitable response is identified, increased GPi activity suppresses alternative responses, sharpening the response profile and encouraging exploitation of the profitable learned behavior.

Deep brain stimulation: a mechanistic and clinical update.

Deep brain stimulation (DBS), the practice of placing electrodes deep into the brain to stimulate subcortical structures with electrical current, has been increasing as a neurosurgical procedure over the past 15 years. Originally a treatment for essential tremor, DBS is now used and under investigation across a wide spectrum of neurological and psychiatric disorders. In addition to applying electrical stimulation for clinical symptomatic relief, the electrodes implanted can also be used to record local electrical activity in the brain, making DBS a useful research tool. Human single-neuron recordings and local field potentials are now often recorded intraoperatively as electrodes are implanted. Thus, the increasing scope of DBS clinical applications is being matched by an increase in investigational use, leading to a rapidly evolving understanding of cortical and subcortical neurocircuitry. In this review, the authors discuss recent innovations in the clinical use of DBS, both in approved indications as well as in indications under investigation. Deep brain stimulation as an investigational tool is also reviewed, paying special attention to evolving models of basal ganglia and cortical function in health and disease. Finally, the authors look to the future across several indications, highlighting gaps in knowledge and possible future directions of DBS treatment.