Clinical correlation but no elevation of striatal dopamine synthesis capacity in two independent cohorts of medication-free individuals with schizophrenia.

Dysregulation of dopamine systems has been considered a foundational driver of pathophysiological processes in schizophrenia, an illness characterized by diverse domains of symptomatology. Prior work observing elevated presynaptic dopamine synthesis capacity in some patient groups has not always identified consistent symptom correlates, and studies of affected individuals in medication-free states have been challenging to obtain. Here we report on two separate cohorts of individuals with schizophrenia spectrum illness who underwent blinded medication withdrawal and medication-free neuroimaging with [18F]-FDOPA PET to assess striatal dopamine synthesis capacity. Consistently in both cohorts, we found no significant differences between patient and matched, healthy comparison groups; however, we did identify and replicate robust inverse relationships between negative symptom severity and tracer-specific uptake widely throughout the striatum: [18F]-FDOPA specific uptake was lower in patients with a greater preponderance of negative symptoms. Complementary voxel-wise and region of interest analyses, both with and without partial volume correction, yielded consistent results. These data suggest that for some individuals, striatal hyperdopaminergia may not be a defining or enduring feature of primary psychotic illness. However, clinical differences across individuals may be significantly linked to variability in striatal dopaminergic tone. These findings call for further experimentation aimed at parsing the heterogeneity of dopaminergic systems function in schizophrenia.

Bridging the gene-behavior divide through neuroimaging deletion syndromes: Velocardiofacial (22q11.2 Deletion) and Williams (7q11.23 Deletion) syndromes.

Investigating the relationship between genes and the neural substrates of complex human behavior promises to provide essential insight into the pathophysiology of mental disorders. One approach to this inquiry is through neuroimaging of individuals with microdeletion syndromes that manifest in specific neuropsychiatric phenotypes. Both Velocardiofacial syndrome (VCFS) and Williams syndrome (WS) involve haploinsufficiency of a relatively small set of identified genes on the one hand and association with distinct, clinically relevant behavioral and cognitive profiles on the other hand. In VCFS, there is a deletion in chromosomal region 22q11.2 and a resultant predilection toward psychosis, poor arithmetic proficiency, and low performance intelligence quotients. In WS, there is a deletion in chromosomal region 7q11.23 and a resultant predilection toward hypersociability, non-social anxiety, impaired visuospatial construction, and often intellectual impairment. Structural and functional neuroimaging studies have begun not only to map these well-defined genetic alterations to systems-level brain abnormalities, but also to identify relationships between neural phenotypes and particular genes within the critical deletion regions. Though neuroimaging of both VCFS and WS presents specific, formidable methodological challenges, including comparison subject selection and accounting for neuroanatomical and vascular anomalies in patients, and many questions remain, the literature to date on these syndromes, reviewed herein, constitutes a fruitful "bottom-up" approach to defining gene-brain relationships.

Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions.

Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D2 receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D2 receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [15O]-water and [18F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.

Executive function, neural circuitry, and genetic mechanisms in schizophrenia.

After decades of research aimed at elucidating the pathophysiology and etiology of schizophrenia, it has become increasingly apparent that it is an illness knowing few boundaries. Psychopathological manifestations extend across several domains, impacting multiple facets of real-world functioning for the affected individual. Even within one such domain, arguably the most enduring, difficult to treat, and devastating to long-term functioning-executive impairment-there are not only a host of disrupted component processes, but also a complex underlying dysfunctional neural architecture. Further, just as implicated brain structures (eg, dorsolateral prefrontal cortex) through postmortem and neuroimaging techniques continue to show alterations in multiple, interacting signaling pathways, so too does evolving understanding of genetic risk factors suggest multiple molecular entry points to illness liability. With this expansive network of interactions in mind, the present chapter takes a systems-level approach to executive dysfunction in schizophrenia, by identifying key regions both within and outside of the frontal lobes that show changes in schizophrenia and are important in cognitive control neural circuitry, summarizing current knowledge of their relevant functional interactions, and reviewing emerging links between schizophrenia risk genetics and characteristic executive circuit aberrancies observed with neuroimaging methods.

Catechol-o-methyltransferase valine(158)methionine genotype and resting regional cerebral blood flow in medication-free patients with schizophrenia.

BACKGROUND: A valine(158)methionine (val(158)met) polymorphism in catechol-O-methyltransferase (COMT) modulates cortical dopaminergic catabolism and has been associated with schizophrenia. Consistent with schizophrenia itself, during cognitive tasks, the risk (val) allele predicts less efficient prefrontal cortex (PFC) physiology and worse performance, while during aversive stimuli viewing, this allele predicts less limbic activation. Task-independent effects of this polymorphism in schizophrenia have not yet been characterized. METHODS: Twenty-five medication-free patients (28 +/- 6 years; 19 male patients) and 47 healthy individuals (29 +/- 8 years; 33 male individuals) were genotyped for the COMT val(158)met polymorphism and underwent two 60-second radiolabeled water ([(15)O]H(2)O) regional cerebral blood flow (rCBF) positron emission tomography scans (10 mCi/scan) during rest. Data were analyzed with a random-effects general linear model using COMT genotype as a covariate. RESULTS: In patients, but not healthy individuals, val (risk) allele load predicted less regional cerebral blood flow in the right dorsolateral PFC, right superior temporal gyrus, and left precuneus, but greater rCBF in the amygdala and parahippocampal gyrus. CONCLUSIONS: In schizophrenia, brain structures important for executive and affective processing show activity that is differentially predicted by COMT allelic variation in an opposing manner even at rest, providing evidence for the salience of prefrontal dopaminergic tone in task-independent, basal-level neural activity.