Abstract In light of the clinical evidence implicating dopamine in schizophrenia, and the prominent hypotheses put forth regarding alterations in dopaminergic transmission in this disease, molecular ...imaging has been used to examine multiple aspects of the dopaminergic system. Here we review the imaging methods used and compare the findings across the different molecular targets. Findings have converged to suggest early dysregulation in the striatum, especially in the rostral caudate, manifesting as excess synthesis and release. Recent data showed deficit extending to most cortical regions, and even to other extrastriatal subcortical regions not previously considered to be “hypodopaminergic” in schizophrenia. These findings yield a new topography for the dopaminergic dysregulation in schizophrenia. In this review we discuss the dopaminergic innervation within the individual projection fields to provide a topographical map of this dual dysregulation and explore potential cellular and circuit based mechanisms for brain region-dependent alterations in dopaminergic parameters. This refined knowledge is essential to better guide translational studies and efforts in early drug development.
Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). ...Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in non-neurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness.
Multidimensional progressive declines in the absence of standard biomarkers for neurodegeneration are observed commonly in the development of schizophrenia, and are accepted as consistent with ...neurodevelopmental etiological hypotheses to explain the origins of the disorder. Far less accepted is the possibility that neurodegenerative processes are involved as well, or even that key dimensions of function, such as cognition and aspects of biological integrity, such as white matter function, decline in chronic schizophrenia beyond levels associated with normal aging. We propose that recent research germane to these issues warrants a current look at the question of neurodegeneration. We propose the view that a neurodegenerative hypothesis provides a better explanation of some features of chronic schizophrenia, including accelerated aging, than is provided by neurodevelopmental hypotheses. Moreover, we suggest that neurodevelopmental influences in early life, including those that may extend to later life, do not preclude the development of neurodegenerative processes in later life, including some declines in cognitive and biological integrity. We evaluate these views by integrating recent findings in representative domains such as cognition and white and gray matter integrity with results from studies on accelerated aging, together with functional implications of neurodegeneration for our understanding of chronic schizophrenia.
Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before ...clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine's effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (≥35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.
Abstract The last fifteen years have seen a great increase in our understanding of the role of glutamate in schizophrenia (SCZ). The glutamate hypothesis focuses on disturbances in brain ...glutamatergic pathways and impairment in signaling at glutamate receptors. Proton Magnetic Resonance Spectroscopy (1 H-MRS) is an MR-based technique that affords investigators the ability to study glutamate function by measuring in vivo glutamatergic indices in the brains of individuals with SCZ.1 H-MRS studies have been performed comparing glutamatergic levels of individuals with SCZ and healthy control subjects or studying the effect of antipsychotic medications on glutamatergic levels. In this article we summarize the results of these studies by brain region. We will review the contribution of1 H-MRS studies to our knowledge about glutamatergic abnormalities in the brains of individuals with SCZ and discuss the implications for future research and clinical care.
Schizophrenia is a chronic neuropsychiatric disorder that causes distinct structural alterations within the brain. We hypothesize that deep learning applied to a structural neuroimaging dataset could ...detect disease-related alteration and improve classification and diagnostic accuracy. We tested this hypothesis using a single, widely available, and conventional T1-weighted MRI scan, from which we extracted the 3D whole-brain structure using standard post-processing methods. A deep learning model was then developed, optimized, and evaluated on three open datasets with T1-weighted MRI scans of patients with schizophrenia. Our proposed model outperformed the benchmark model, which was also trained with structural MR images using a 3D CNN architecture. Our model is capable of almost perfectly (area under the ROC curve = 0.987) distinguishing schizophrenia patients from healthy controls on unseen structural MRI scans. Regional analysis localized subcortical regions and ventricles as the most predictive brain regions. Subcortical structures serve a pivotal role in cognitive, affective, and social functions in humans, and structural abnormalities of these regions have been associated with schizophrenia. Our finding corroborates that schizophrenia is associated with widespread alterations in subcortical brain structure and the subcortical structural information provides prominent features in diagnostic classification. Together, these results further demonstrate the potential of deep learning to improve schizophrenia diagnosis and identify its structural neuroimaging signatures from a single, standard T1-weighted brain MRI.
Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad POMA and TS-134) were assessed in two ...Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = -0.41; p = 0.04, d = -0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = -0.36; p = 0.008, d = -0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = -0.56; p = 0.079, d = -0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.
Background Previous studies demonstrated increased striatal dopamine (DA) release after amphetamine challenge and increased striatal baseline occupancy of D2 receptors in patients with schizophrenia ...compared with control subjects. We report here on the relationship between these two aspects of DA release in drug-naïve patients with schizophrenia (SCZ) and matched healthy control subjects (HC). Methods Six drug-naïve SCZ and eight HC underwent single-photon emission computed tomography (SPECT) scans after bolus followed by constant infusion of (S)-(-)-3-123Iiodo-2-hydroxy-6-methoxy-N-(1-ethyl-2-pyrrolidinyl)methylbenzamide (123IIBZM) under three conditions to determine the equilibrium specific to non-displaceable binding potential (BPND ) for striatal D2 at baseline, after amphetamine administration and after DA depletion. Results Amphetamine induced decrease in BPND was positively correlated with BPND increase after DA depletion in SCZ ( p = .02) but not in HC ( p = .44). Additionally, both were significantly increased. Conclusions In drug-naïve patients with schizophrenia but not in control subjects, stimulated and baseline DA release are both increased and positively correlated. At the neuronal level this association suggests that capacity for storage in presynaptic terminals, measured with the amphetamine paradigm, and baseline intrasynaptic DA release, measured with the α-methyl-para-tyrosine (αMPT) paradigm, are associated in schizophrenia, both consistent with increased midbrain DA cells activity.
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