title: Functional neuroimaging abnormalities in youth with psychosis spectrum symptoms.
abstract: OBJECTIVE
  The 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.
  
  
  OBJECTIVE
  To examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing.
  
  
  METHODS
  The 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).
  
  
  METHODS
  Two 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.
  
  
  RESULTS
  In 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
  The 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.
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Wolf
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Theodore D
authors.initials: TD
authors.lastname: Satterthwaite
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Calkins
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Kosha
authors.initials: K
authors.lastname: Ruparel
authors.affiliation: Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Elliott
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Hopson
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Chad T
authors.initials: CT
authors.lastname: Jackson
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Karthik
authors.initials: K
authors.lastname: Prabhakaran
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Warren B
authors.initials: WB
authors.lastname: Bilker
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
mesh_terms: D000293:Adolescent; D000679:Amygdala / Q000002:abnormalities* / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000503:physiopathology*; D002648:Child; D003071:Cognition; D004644:Emotions; D056344:Executive Function; D005149:Facial Expression; D005260:Female; D059907:Functional Neuroimaging / Q000379:methods*; D006801:Humans; D007406:Interview, Psychological; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term; D009483:Neuropsychological Tests; D010364:Pattern Recognition, Visual; D010641:Phenotype; D017397:Prefrontal Cortex / Q000002:abnormalities / Q000503:physiopathology; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology*; D012559:Schizophrenia / Q000503:physiopathology; D012565:Schizophrenic Psychology; D012720:Severity of Illness Index; D013647:Task Performance and Analysis; D055815:Young Adult