• Daniel H Wolf, Theodore D Satterthwaite, Monica E Calkins, Kosha Ruparel, Mark A Elliott, Ryan D Hopson, Chad T Jackson, Karthik Prabhakaran, Warren B Bilker, Hakon Hakonarson, Ruben C Gur, and Raquel E Gur.
• Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
• JAMA Psychiatry. 2015 May 1;72(5):456-65.

ImportanceThe continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS symptoms should be associated with neural abnormalities similar to those found in help-seeking clinical risk individuals and in schizophrenia. To our knowledge, functional neuroimaging has not previously been applied in large population-based PS samples and can help us understand the neural architecture of psychosis more broadly and identify brain phenotypes beyond symptoms that are associated with the extended psychosis phenotype.ObjectiveTo examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing.Design, Setting, And ParticipantsThe Philadelphia Neurodevelopmental Cohort is a genotyped, prospectively accrued, population-based sample of almost 10,000 youths who received a structured psychiatric evaluation and a computerized neurocognitive battery. The study was conducted at an academic and children's hospital health care network, between November 1, 2009 to November 30, 2011. A subsample of 1445 youths underwent neuroimaging, including functional magnetic resonance imaging tasks examined herein. Participants were youth aged 11 to 22 years old identified through structured interview as having PS features (PS group) (n = 260) and typically developing (TD) comparison youth without significant psychopathology (TD group) (n = 220).Main Outcomes And MeasuresTwo functional magnetic resonance imaging paradigms were used: a fractal n-back working memory task probing executive system function and an emotion identification task probing amygdala responses to threatening faces.ResultsIn the n-back task, working memory evoked lower activation in the PS group than the TD group throughout the executive control circuitry, including dorsolateral prefrontal cortex (cluster-corrected P < .05). Within the PS group, dorsolateral prefrontal cortex activation correlated with cognitive deficits (r = .32, P < .001), but no correlation was found with positive symptom severity. During emotion identification, PS demonstrated elevated responses to threatening facial expressions in amygdala, as well as left fusiform cortex and right middle frontal gyrus (cluster-corrected P < .05). The response in the amygdala correlated with positive symptom severity (r = .16, P = .01) but not with cognitive deficits.Conclusions And RelevanceThe pattern of functional abnormalities observed in the PS group is similar to that previously found in schizophrenia and help-seeking risk samples. Specific circuit dysfunction during cognitive and emotion-processing tasks is present early in the development of psychopathology and herein could not be attributed to chronic illness or medication confounds. Hypoactivation in executive circuitry and limbic hyperactivation to threat could reflect partly independent risk factors for PS symptoms, with the former relating to cognitive deficits that increase the risk for developing psychotic symptoms and the latter contributing directly to positive psychotic symptoms.

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