Abraham Ribicoff Research Facilities

New Haven, CT, United States

Abraham Ribicoff Research Facilities

New Haven, CT, United States

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Anticevic A.,Yale University | Anticevic A.,Center for the Translational Neuroscience of Alcoholism | Anticevic A.,Abraham Ribicoff Research Facilities | Cole M.W.,Washington University in St. Louis | And 16 more authors.
Cerebral Cortex | Year: 2014

Schizophrenia is a devastating neuropsychiatric syndrome associated with distributed brain dysconnectivity that may involve large-scale thalamo-cortical systems. Incomplete characterization of thalamic connectivity in schizophrenia limits our understanding of its relationship to symptoms and to diagnoses with shared clinical presentation, such as bipolar illness, which may exist on a spectrum. Using resting-state functional magnetic resonance imaging, we characterized thalamic connectivity in 90 schizophrenia patients versus 90 matched controls via: (1) Subject-specific anatomically defined thalamic seeds; (2) anatomical and data-driven clustering to assay within-thalamus dysconnectivity; and (3) machine learning to classify diagnostic membership via thalamic connectivity for schizophrenia and for 47 bipolar patients and 47 matched controls. Schizophrenia analyses revealed functionally related disturbances: Thalamic over-connectivity with bilateral sensory-motor cortices, which predicted symptoms, but thalamic under-connectivity with prefrontal-striatal-cerebellar regions relative to controls, possibly reflective of sensory gating and top-down control disturbances. Clustering revealed that this dysconnectivity was prominent for thalamic nuclei densely connected with the prefrontal cortex. Classification and cross-diagnostic results suggest that thalamic dysconnectivity may be a neural marker for disturbances across diagnoses. Present findings, using one of the largest schizophrenia and bipolar neuroimaging samples to date, inform basic understanding of large-scale thalamo-cortical systems and provide vital clues about the complex nature of its disturbances in severe mental illness. © The Author 2013. Published by Oxford University Press.


Anticevic A.,Yale University | Anticevic A.,Abraham Ribicoff Research Facilities | Anticevic A.,Hartford HospitalCT | Yang G.,Yale University | And 11 more authors.
Schizophrenia Bulletin | Year: 2014

Empirical and theoretical studies implicate thalamocortical circuits in schizophrenia, supported by emerging resting-state functional connectivity studies (rs-fcMRI). Similar but attenuated alterations were found in bipolar disorder (BD). However, it remains unknown if segregated loops within thalamocortical systems show distinct rs-fcMRI alterations in schizophrenia. For instance, the mediodorsal (MD) nucleus, known to project to prefrontal networks, may be differently altered than the lateral geniculate nucleus (LGN), known to project to the occipital cortex. Also, it remains unknown if these circuits show different patterns of alterations in BD as a function of psychosis history, which may be associated with a more severe clinical course. We addressed these questions in 90 patients with chronic schizophrenia and 73 remitted BD patients (33 with psychosis history) matched to 146 healthy comparison subjects. We hypothesized that the MD vs LGN would show dissociations across diagnostic groups. We found that MD and LGN show more qualitative similarities than differences in their patterns of dysconnectivity in schizophrenia. In BD, patterns qualitatively diverged between thalamic nuclei although these effects were modest statistically. BD with psychosis history was associated with more severe dysconnectivity, particularly for the MD nucleus. Also, the MD nucleus showed connectivity reductions with the cerebellum in schizophrenia but not in BD. Results suggest dissociations for thalamic nuclei across diagnoses, albeit carefully controlling for medication is warranted in future studies. Collectively, these findings have implications for designing more precise neuroimaging-driven biomarkers that can identify common and divergent large-scale network perturbations across psychiatric diagnoses with shared symptoms. © 2014 © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.


Anticevic A.,Yale University | Anticevic A.,Center for the Translational Neuroscience of Alcoholism | Anticevic A.,Abraham Ribicoff Research Facilities | Repovs G.,University of Ljubljana | And 4 more authors.
Schizophrenia Research | Year: 2012

Characterizing working memory (WM) abnormalities represents a fundamental challenge in schizophrenia research given the impact of cognitive deficits on life outcome in patients. In prior work we demonstrated that dorsolateral prefrontal cortex (DLPFC) activation was related to successful distracter resistance during WM in healthy controls, but not in schizophrenia. Although understanding the impact of regional functional deficits is critical, functional connectivity abnormalities among nodes within WM networks may constitute a final common pathway for WM impairment. Therefore, this study tested the hypothesis that schizophrenia is associated with functional connectivity abnormalities within DLPFC networks during distraction conditions in WM. 28 patients and 24 controls completed a delayed non-verbal WM task that included transient visual distraction during the WM maintenance phase. We computed DLPFC whole-brain task-based functional connectivity (tb-fcMRI) specifically during the maintenance phase in the presence or absence of distraction. Results revealed that patients failed to modulate tb-fcMRI during distracter presentation in both cortical and sub-cortical regions. Specifically, controls demonstrated reductions in tb-fcMRI between DLPFC and the extended amygdala when distraction was present. Conversely, patients failed to demonstrate a change in coupling with the amygdala, but showed greater connectivity with medio-dorsal thalamus. While controls showed more positive coupling between DLPFC and other prefrontal cortical regions during distracter presentation, patients failed to exhibit such a modulation. Taken together, these findings support the notion that observed distracter resistance deficit involves a breakdown in coupling between DLPFC and distributed regions, encompassing both subcortical (thalamic/limbic) and control region connectivity. © 2012.


Anticevic A.,University of Sichuan | Anticevic A.,Yale University | Anticevic A.,Abraham Ribicoff Research Facilities | Hu X.,University of Sichuan | And 15 more authors.
Journal of Neuroscience | Year: 2015

Strong evidence implicates prefrontal cortex (PFC) as a major source of functional impairment in severe mental illness such as schizophrenia. Numerous schizophrenia studies report deficits in PFC structure, activation, and functional connectivity in patients with chronic illness, suggesting that deficient PFC functional connectivity occurs in this disorder. However, the PFC functional connectivity patterns during illness onset and its longitudinal progression remain uncharacterized. Emerging evidence suggests that early-course schizophrenia involves increased PFC glutamate, which might elevate PFC functional connectivity. To test this hypothesis, we examined 129 non-medicated, human subjects diagnosed with early-course schizophrenia and 106 matched healthy human subjects using both whole-brain data-driven and hypothesis-driven PFC analyses of resting-state fMRI. We identified increased PFC connectivity in early-course patients, predictive of symptoms and diagnostic classification, but less evidence for “hypoconnectivity.” At the whole-brain level, we observed “hyperconnectivity” around areas centered on the default system, with modest overlap with PFC-specific effects. The PFC hyperconnectivity normalized for a subset of the sample followed longitudinally (n = 25), which also predicted immediate symptom improvement. Biologically informed computational modeling implicates altered overall connection strength in schizophrenia. The initial hyperconnectivity, which may decrease longitudinally, could have prognostic and therapeutic implications. © 2015 the authors.


Anticevic A.,Yale University | Anticevic A.,Center for the Translational Neuroscience of Alcoholism | Anticevic A.,Abraham Ribicoff Research Facilities | Tang Y.,Liaoning Medical University | And 11 more authors.
Schizophrenia Bulletin | Year: 2014

Alterations in circuits involving the amygdala have been repeatedly implicated in schizophrenia neuropathology, given their role in stress, affective salience processing, and psychosis onset. Disturbances in amygdala whole-brain functional connectivity associated with schizophrenia have yet to be fully characterized despite their importance in psychosis. Moreover, it remains unknown if there are functional alterations in amygdala circuits across illness phases. To evaluate this possibility, we compared whole-brain amygdala connectivity in healthy comparison subjects (HCS), individuals at high risk (HR) for schizophrenia, individuals in the early course of schizophrenia (EC-SCZ), and patients with chronic schizophrenia (C-SCZ). We computed whole-brain resting-state connectivity using functional magnetic resonance imaging at 3T via anatomically defined individual-specific amygdala seeds. We identified significant alterations in amygdala connectivity with orbitofrontal cortex (OFC), driven by reductions in EC-SCZ and C-SCZ (effect sizes of 1.0 and 0.97, respectively), but not in HR for schizophrenia, relative to HCS. Reduced amygdala- OFC coupling was associated with schizophrenia symptom severity (r = .32, P < .015). Conversely, we identified a robust increase in amygdala connectivity with a brainstem region around noradrenergic arousal nuclei, particularly for HR individuals relative to HCS (effect size = 1.54), but not as prominently for other clinical groups. These results suggest that deficits in amygdala-OFC coupling could emerge during the initial episode of schizophrenia (EC-SCZ) and may present as an enduring feature of the illness (C-SCZ) in association with symptom severity but are not present in individuals with elevated risk for developing schizophrenia. Instead, in HR individuals, there appears to be increased connectivity in a circuit implicated in stress response. © The Author 2013.


Picciotto M.R.,Abraham Ribicoff Research Facilities | Brabant C.,Abraham Ribicoff Research Facilities | Brabant C.,University of Liège | Einstein E.B.,Abraham Ribicoff Research Facilities | And 2 more authors.
Brain Research | Year: 2010

Like a number of neuropeptides, galanin can alter neural activity in brain areas that are important for both stress-related behaviors and responses to drugs of abuse. Accordingly, drugs that target galanin receptors can alter behavioral responses to drugs of abuse and can modulate stress-related behaviors. Stress and drug-related behaviors are interrelated: stress can promote drug-seeking, and drug exposure and withdrawal can increase activity in brain circuits involved in the stress response. We review here what is known about the ability of galanin and galanin receptors to alter neuronal activity, and we discuss potential mechanisms that may underlie the effects of galanin on behaviors involved in responses to stress and addictive drugs. Understanding the mechanisms underlying galanin's effects on neuronal function in brain regions related to stress and addiction may be useful in developing novel therapeutics for the treatment of stress- and addiction-related disorders. © 2009 Elsevier B.V. All rights reserved.


Niciu M.J.,Yale University | Niciu M.J.,Abraham Ribicoff Research Facilities | Kelmendi B.,University of Vermont | Sanacora G.,Yale University | Sanacora G.,Abraham Ribicoff Research Facilities
Pharmacology Biochemistry and Behavior | Year: 2012

This introductory article to the special edition on glutamate neurotransmission in neuropsychiatric disorders provides an overview of glutamate neurotransmitter system physiology and pharmacology. Glutamate was only relatively recently recognized as the major excitatory neurotransmitter in the mammalian brain, in part due to its ubiquitous nature and diverse metabolic roles within the CNS. The extremely high concentration of glutamate in brain tissue paired with its excitotoxic potential requires tight physiological regulation of extracellular glutamate levels and receptor signaling in order to assure optimal excitatory neurotransmission but limits excitotoxic damage. In order to achieve this high level of control, the system has developed a complex physiology with multiple regulatory processes modulating glutamate metabolism, release, receptor signaling, and uptake. The basic physiology of the various regulatory components of the system including the rich receptor pharmacology is briefly reviewed. Potential contributions from each of the system's components to the pathophysiology of neuropsychiatric illnesses are briefly discussed, as are the many new pharmacological targets for drug development provided by the system, especially as they pertain to the proceeding preclinical and clinical articles in this issue. © 2011 Elsevier Inc. All rights reserved.


Abdallah C.G.,Abraham Ribicoff Research Facilities | Abdallah C.G.,Veterans Affairs Connecticut Healthcare System | Niciu M.J.,Abraham Ribicoff Research Facilities | Fenton L.R.,Veterans Affairs Connecticut Healthcare System | And 7 more authors.
Psychotherapy and Psychosomatics | Year: 2014

Background: Previous studies have demonstrated that antidepressant medication and electroconvulsive therapy increase occipital cortical γ-aminobutyric acid (GABA) in major depressive disorder (MDD), but a small pilot study failed to show a similar effect of cognitive-behavioral therapy (CBT) on occipital GABA. In light of these findings we sought to determine if baseline GABA levels predict treatment response and to broaden the analysis to other metabolites and neurotransmitters in this larger study. Methods: A total of 40 MDD outpatients received baseline proton magnetic resonance spectroscopy (1H-MRS), and 30 subjects completed both pre- and post-CBT 1H-MRS; 9 CBT nonresponders completed an open-label medication phase followed by an additional/3rd 1H-MRS. The magnitude of treatment response was correlated with occipital amino acid neurotransmitter levels. Results: Baseline GABA did not predict treatment outcome. Furthermore, there was no significant effect of CBT on GABA levels. However, we found a significant group × time interaction (F1, 28 = 6.30, p = 0.02), demonstrating reduced glutamate in CBT responders, with no significant glutamate change in CBT nonresponders. Conclusions: These findings corroborate the lack of effect of successful CBT on occipital cortical GABA levels in a larger sample. A reduction in glutamate levels following treatment, on the other hand, correlated with successful CBT and antidepressant medication response. Based on this finding and other reports, decreased occipital glutamate may be an antidepressant response biomarker. Healthy control comparator and nonintervention groups may shed light on the sensitivity and specificity of these results. © 2014 S. Karger AG, Basel.


Ahn K.,VA Connecticut Healthcare System | Ahn K.,Abraham Ribicoff Research Facilities | Ahn K.,Yale University | Gil R.,Columbia University | And 7 more authors.
Neuropsychopharmacology | Year: 2011

Several lines of evidence from post-mortem, brain imaging, and genetic studies in schizophrenia patients suggest that Gamma-amino butyric acid (GABA) deficits may contribute to the pathophysiology of schizophrenia. Pharmacological induction of a transient GABA-deficit state has been shown to enhance vulnerability of healthy subjects to the psychotomimetic effects of various drugs. Exacerbating or creating a GABA deficit was hypothesized to induce or unmask psychosis in schizophrenia patients, but not in healthy controls. To test this hypothesis, a transient GABA deficit was pharmacologically induced in schizophrenia patients and healthy controls using iomazenil, an antagonist and partial inverse agonist of the benzodiazepine receptor. In a double-blind, randomized, placebo-controlled study, clinically stable chronic schizophrenia patients (n13) received iomazenil (3.7 g administered intravenously over 10 min). Psychosis was measured using the Brief Psychiatric Rating Scale and perceptual alterations were measured using the Clinician Administered Dissociative Symptoms Scale before and after iomazenil administration. These data were compared with the effects of iomazenil in healthy subjects (n20). Iomazenil produced increases in psychotic symptoms and perceptual alterations in schizophrenia patients, but not in healthy controls. The greater vulnerability of schizophrenia patients to the effects of iomazenil relative to controls provides further support for the GABA-deficit hypothesis of schizophrenia. © 2011 American College of Neuropsychopharmacology. All rights reserved.


Abdallah C.G.,Yale University | Abdallah C.G.,National Center for Posttraumatic Stress Disorder | Sanacora G.,Yale University | Sanacora G.,Abraham Ribicoff Research Facilities | And 6 more authors.
Annual Review of Medicine | Year: 2015

Ketamine is the prototype for a new generation of glutamate-based antidepressants that rapidly alleviate depression within hours of treatment. Over the past decade, there has been replicated evidence demonstrating the rapid and potent antidepressant effects of ketamine in treatment-resistant depression. Moreover, preclinical and biomarker studies have begun to elucidate the mechanism underlying the rapid antidepressant effects of ketamine, offering a new window into the biology of depression and identifying a plethora of potential treatment targets. This article discusses the efficacy, safety, and tolerability of ketamine, summarizes the neurobiology of depression, reviews the mechanisms underlying the rapid antidepressant effects of ketamine, and discusses the prospects for next-generation rapid-acting antidepressants. © 2015 by Annual Reviews.

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