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Functional MRI Predicting Intervention Outcome in Early Psychosis.

Identification of youths early in the psychosis process presents a challengebut also anopportunity to relatebrain-based measures to course of illness. The heterogeneity in disease progression is substantial, and identifying potential biomarkers can elucidate mechanisms and thus guide targeted interventions as envisioned by precision medicine (1). Neuroimaging-based parameters have been increasingly applied to investigate the relation between treatment variables and neuroanatomic measures such as brain volume, cortical thickness, graymatter density, whitematter integrity and connectivity and, to a more limited extent, functional measures such as resting-state connectivity and cerebral perfusion. Conspicuously limited are studies that use functionalMRI (fMRI) to examine regional activation in response to task demands (2). This relative absence is notable given that failure to recruit the underlying circuitry when performing a task is likely the proximate cause for cognitive deficits, as activated fMRI parameters provide better predictors of performance than resting-state measures (3) and therefore may relate to outcome. Indeed, as Smucny and colleagues (4) point out in this issue of the Journal, there are only a handful of fMRI studies with small samples that have attempted to link abnormalities in activation to intervention outcomes. The article by Smucny and colleagues (4) builds on extensive experience implementing a cognitive control continuous performance task in the study of psychotic disorders. Smucny et al. probed the underlying circuitry in a subsample of research participants who were included in subsequent early psychosis specialty care. The authors report that only the fMRI-based measure of cognitive control obtained at baseline had a 70% predictive value of defined improvement status on the Brief Psychiatric Rating Scale a year later. The article attests to the extensive attention and deliberations the authors had to undertake to integrate their rigorous experimental approach with “real world” care early in the course of psychosis. Ascertainment bias, image processing across scanners (1.5-T and 3.0-T scanners), and analytic approaches must be considered and are well detailed in the article. The authors recognize the study limitations, including a relatively small sample, the naturalistic design, and the sparse data on potential factors that can contribute to outcome. Other measures that could be related to clinical presentation and course include genetic vulnerability, comorbidity, environmental or socioeconomic deprivation, stressful life events, and family setting (5, 6). Furthermore, the study examined a single region and a single task. There are methods to administer more extensive neurocognitive testing in the scanner that identify domain-specific patterns of activation (7). In all likelihood, heterogeneity of psychosis relates to variations in specific or distributed brain systems that differentially associate with course and outcome. Therefore, while the study offers a unique contribution toward identifying potential biomarkers of early progression of psychosis, as the authors recognize, theirs is afirst stepon a long road. Perhaps as remarkable as the accomplishment of this study is the paucity of treatment studies inwhich biomarkers related to brain circuitry activation are obtained along with equally rigorous clinical data. It is concerning that only a handful of studies have related brain circuitry activation parameters to illness measures of improvement early in the course of psychosis. Whatmay account for the scarcity of informative research on acute and longer-term relation of brain-behavior activation measures to clinical parameters, such as symptom improvement and functional outcome? This dearth of studies on task-activated fMRI may relate to the complexity of administering well-controlled tasks in a scanner, challenges in standardizing tasks and settings across sites, the relatively low signal-to-noise ratio, the requirement for active participant engagement, and the high computational demands. It is difficult to set up standardized activation paradigms across sites and studies. Neuroanatomic and resting-state connectivity studies do not require cooperation of research participants beyond their agreement to spend time in the scanner without excessive head motion. In contrast, task-related fMRI studies require equipping the scannerwith input and output devices and ensuring that the participants understand the task and are awake and fully engaged in its performance. Furthermore, the low signalto-noise ratio of the blood-oxygen-level-dependent contrast necessitates more extensive image processing and It is concerning that only a handful of studies have related brain circuitry activation parameters to illness measures of improvement early in the course of psychosis.