Functional neuroimaging abnormalities in youth with psychosis spectrum symptoms

Abstract

Importance: 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.

Design, setting, and participants: 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).

Main outcomes and measures: 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 and relevance: 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.

Figure 1. fMRI paradigms

Two fMRI tasks were employed, counterbalancing order across subjects. The fractal n-back task is shown on the left. Working memory was tested with complex geometric figures (fractals), with three levels of memory load (0-back, 1-back, 2-back) across blocks. In the 0-back condition, participants responded with a button press to a specified target fractal. For the 1-back condition, participants responded if the current fractal was identical to the previous one; in the 2-back condition, participants responded if the current fractal was identical to the item presented two trials previously. Each condition consisted of a 20-trial block (60 s); each level was repeated over three blocks. The target-foil ratio was 1:3 in all blocks with 45 targets and 135 foils overall. Each fractal was presented for 500ms, followed by an inter-stimulus interval of 2500ms. The emotion identification task is shown on the right. Faces expressing one of five emotional categories (happy, sad, anger, fear, neutral) were displayed in a pseudorandomized event-related design; there were 12 faces in each category. Subjects decided which emotion was expressed on each face. Emotional expressions were grouped into threatening (anger, fear) and non-threatening (happy, sad) emotions for analysis. Faces were displayed for 5.5 seconds, followed by a variable (0.5–18.5s) interval displaying a complex fixation crosshair matched to faces on perceptual qualities.

Figure 2. Executive system hypofunction during the N-back Task

A) The contrast evaluating the effect of working memory load (2-back > 0-back) robustly recruited executive function regions including dACC and DLPFC, with a qualitatively similar regional pattern in both TD and PS groups (thresholded Z 12–16 for display). B) PS showed significantly reduced activation in these regions (significant clusters shown in blue, Z>3.09 p<.05).

Figure 3. Amygdala hyperactivation to Threat in the Emotion Processing Task

A) Facial emotion processing activated amygdala and other regions implicated in emotion and face processing, with a qualitatively similar regional pattern in both TD and PS groups (thresholded Z 12–16 for display). B) PS showed significantly greater activation in bilateral amygdala (significant clusters shown in red, Z>3.09 p<.05).