Anissa Abi-Dargham

BACKGROUND: Despite longstanding interest in the central cholinergic system in schizophrenia, cholinergic imaging studies in patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography (PET) study using [18 F]-VAT, a new radiotracer which targets the vesicular acetylcholine transporter (VAChT) as a proxy measure of acetylcholine transmission capacity, in patients with schizophrenia, and explored relationships of VAChT with clinical symptoms and cognition...

BACKGROUND: Schizophrenia (SCZ) is marked by working memory (WM) deficits, which predict poor functional outcome. While most functional magnetic resonance imaging studies of WM in SCZ have focused on the dorsolateral prefrontal cortex (PFC), some recent work suggests that the medial PFC (mPFC) may play a role. We investigated whether task-evoked mPFC deactivation is associated with WM performance and whether it mediates deficits in SCZ. In addition, we investigated associations between mPFC deactivation and cortical dopamine release...

The phenotype of schizophrenia, regardless of etiology, represents the most studied psychotic disorder with respect to neurobiology and distinct phases of illness. The early phase of illness represents a unique opportunity to provide effective and individualized interventions that can alter illness trajectories. Developmental age and illness stage, including temporal variation in neurobiology, can be targeted to develop phase-specific clinical assessment, biomarkers, and interventions. We review an earlier model whereby an initial glutamate signaling deficit progresses through different phases of allostatic adaptation, moving from potentially reversible functional abnormalities associated with early psychosis and working memory dysfunction, and ending with difficult-to-reverse structural changes after chronic illness...

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The field of psychiatry is hampered by a lack of robust, reliable and valid biomarkers that can aid in objectively diagnosing patients and providing individualized treatment recommendations. Here we review and critically evaluate the evidence for the most promising biomarkers in the psychiatric neuroscience literature for autism spectrum disorder, schizophrenia, anxiety disorders and post-traumatic stress disorder, major depression and bipolar disorder, and substance use disorders. Candidate biomarkers reviewed include various neuroimaging, genetic, molecular and peripheral assays, for the purposes of determining susceptibility or presence of illness, and predicting treatment response or safety...

No abstract text is available yet for this article.

RATIONALE: Characterizing the neuroanatomical basis of serotonergic abnormalities in severe, chronic, impulsive aggression will allow for rational treatment selection, development of novel therapeutics, and biomarkers to identify at-risk individuals. OBJECTIVES: The aim of this study is to identify associations between regional serotonin transporter (5-HTT) availability and trait and state aggression, as well as response to the anti-aggressive effects of fluoxetine...

No abstract text is available yet for this article.

The Research Domain Criteria (RDoC) initiative aims to organize research according to domains of brain function. Dysfunction within these domains leads to psychopathology that is classically measured with rating scales. Examining the correspondence between the specific measures assessed within rating scales and RDoC domains is necessary to assess the needs for new RDoC-focused scales. Such RDoC-focused scales have the potential of allowing translation of this work into the clinical domain of measuring psychopathology and designing treatment...

Multiple lines of evidence suggest a potential role for the kappa dynorphin system in schizophrenia and its therapeutics. Kappa stimulation acutely and chronically modulates dopamine in opposite ways, where acutely it decreases dopamine transmission and chronically it increases it and it can induce D2 sensitization. In addition, pharmacological evidence from studies using agonist and antagonists at KOR have indicated a therapeutic potential of KOR antagonists for psychosis. We present here a brief overview of the evidence supporting this viewpoint...

No abstract text is available yet for this article.

Major depressive disorder (MDD) is characterized by behavioral and neural abnormalities in processing both rewarding and aversive stimuli, which may impact motivational and affective symptoms. Learning paradigms have been used to assess reinforcement encoding abnormalities in MDD and their association with dysfunctional incentive-based behavior, but how the valence and context of information modulate this learning is not well understood. To address these gaps, we examined responses to positive and negative reinforcement across multiple temporal phases of information processing...

Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated...

BACKGROUND: Recent studies have established a clear topographical and functional organization of projections to and from complex subdivisions of the striatum. Manual segmentation of these functional subdivisions is labor-intensive and time-consuming, and automated methods are not as reliable as manual segmentation. PURPOSE: To utilize multitask learning (MTL) as a method to segment subregions of the striatum consisting of pre-commissural putamen (prePU), pre-commissural caudate (preCA), post-commissural putamen (postPU), post-commissural caudate (postCA), and ventral striatum (VST)...

BACKGROUND: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is a validated measure of neuromelanin concentration in the substantia nigra-ventral tegmental area (SN-VTA) complex and is a proxy measure of dopaminergic function with potential as a noninvasive biomarker. The development of generalizable biomarkers requires large-scale samples necessitating harmonization approaches to combine data collected across sites. PURPOSE: To develop a method to harmonize NM-MRI across scanners and sites...

The past four decades have seen enormous efforts placed on a search for molecular markers of schizophrenia using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In this narrative review, we cast a broad net to define and summarize what researchers have learned about schizophrenia from molecular imaging studies. Some PET studies of brain energy metabolism with the glucose analogue FDGhave have shown a hypofrontality defect in patients with schizophrenia, but more generally indicate a loss of metabolic coherence between different brain regions...

Patients at clinical high-risk (CHR) for psychosis show elevations in [18 F]DOPA uptake, an estimate of dopamine (DA) synthesis capacity, in the striatum predictive of conversion to schizophrenia. Intrasynaptic DA levels can be inferred from imaging the change in radiotracer binding at D2 receptors due to a pharmacological challenge. Here, we used methylphenidate, a DA reuptake inhibitor, and [11 C]-(+)-PHNO, to measure synaptic DA availability in CHR both in striatal and extra-striatal brain regions. Fourteen unmedicated, nonsubstance using CHR individuals and 14 matched control subjects participated in the study...

OBJECTIVE: Recent evidence supports the use of neuromelanin-sensitive MRI (NM-MRI) as a novel tool to investigate dopamine function in the human brain. The authors investigated the NM-MRI signal in individuals with cocaine use disorder, compared with age- and sex-matched control subjects, based on previous imaging studies showing that this disorder is associated with blunted presynaptic striatal dopamine. METHODS: NM-MRI and T1 -weighted images were acquired from 20 participants with cocaine use disorder and 35 control subjects...

RATIONALE: Previous research has suggested that schizotypal personality disorder (SPD), a condition that shares clinical and cognitive features with schizophrenia, may be associated with elevated striatal dopamine functioning; however, there are no published studies of dopamine release within subregions of the striatum in SPD. OBJECTIVES: To characterize dopamine release capacity in striatal subregions and its relation to clinical and cognitive features in SPD. METHODS: We used positron emission tomography with [11 C]raclopride and an amphetamine challenge to measure dopamine D2-receptor availability (binding potential, BPND ), and its percent change post-amphetamine (∆BPND ) to index amphetamine-induced dopamine release, in subregions of the striatum in 16 SPD and 16 healthy control participants...

Current treatments for the symptoms of schizophrenia are only effective for positive symptoms in some individuals, and have considerable side effects that impact compliance. Thus, there is a need to investigate the efficacy of other compounds in treating both positive and negative symptoms. We conducted a meta-analysis of English language placebo-controlled clinical trials of naloxone, naltrexone, nalmefene, and buprenorphine in patients with schizophrenia to determine whether pan-opioid antagonists have therapeutic efficacy on positive, negative, or total symptoms...