Disrupted working memory circuitry and psychotic symptoms in 22q11.2 deletion syndrome

Abstract

22q11.2 deletion syndrome (22q11DS) is a recurrent genetic mutation that is highly penetrant for psychosis. Behavioral research suggests that 22q11DS patients exhibit a characteristic neurocognitive phenotype that includes differential impairment in spatial working memory (WM). Notably, spatial WM has also been proposed as an endophenotype for idiopathic psychotic disorder, yet little is known about the neurobiological substrates of WM in 22q11DS. In order to investigate the neural systems engaged during spatial WM in 22q11DS patients, we collected functional magnetic resonance imaging (fMRI) data while 41 participants (16 22q11DS patients, 25 demographically matched controls) performed a spatial capacity WM task that included manipulations of delay length and load level. Relative to controls, 22q11DS patients showed reduced neural activation during task performance in the intraparietal sulcus (IPS) and superior frontal sulcus (SFS). In addition, the typical increases in neural activity within spatial WM-relevant regions with greater memory load were not observed in 22q11DS. We further investigated whether neural dysfunction during WM was associated with behavioral WM performance, assessed via the University of Maryland letter-number sequencing (LNS) task, and positive psychotic symptoms, assessed via the Structured Interview for Prodromal Syndromes (SIPS), in 22q11DS patients. WM load activity within IPS and SFS was positively correlated with LNS task performance; moreover, WM load activity within IPS was inversely correlated with the severity of unusual thought content and delusional ideas, indicating that decreased recruitment of working memory-associated neural circuitry is associated with more severe positive symptoms. These results suggest that 22q11DS patients show reduced neural recruitment of brain regions critical for spatial WM function, which may be related to characteristic behavioral manifestations of the disorder.

Keywords: Copy number variation; Endophenotype; Executive function; Psychosis; Velocardiofacial syndrome.

Fig. 1

fMRI activity maps during performance on the spatial capacity working memory (SCAP) task. Blue maps represent neural activity in controls, green maps represent neural activity in 22q11DS patients, and red maps represent the between-group contrast of controls > 22q11DS patients. Brain orientations are labeled such that S = superior, I = inferior, P = posterior, and A = anterior; R = right and L = left. (a) Activation maps represent the contrast of all WM conditions combined (all loads and all delay length WM trials > Baseline), to investigate neural activity related to overall spatial WM performance. (b) Activation maps represent the contrast of high versus low WM load (Load 5 > Load 1), to investigate neural activity related to WM load. No regions showed significantly greater neural activity in 22q11DS vs. controls for these contrasts. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Relationship of WM load-related neural activity with behavioral measures (letter–number sequencing task performance and positive psychotic symptoms) in 22q11DS. (a) Represents the anatomically-defined left IPS and right SFS ROI (after adjusting for age and years of education) from which percent signal change was extracted for correlations with X-axis variables in b, c, and d. Brain orientations are labeled such that S = superior, I = inferior, P = posterior, and A = anterior; R = right and L = left. For b, c, and d the X-axis values represent the residuals of: (b) the letter–number sequencing task for 22q11DS patients and controls, with IPS percent signal change on the Y-axis (R² = 0.41 for 22q11DS patients; R² = 0.03 for controls), (c) the letter–number sequencing task for 22q11DS patients and controls, with SFS percent signal change on the Y-axis (R² = 0.26 for 22q11DS patients; R² = 0.052 for controls), (d) SIPS P1 (unusual thought content/delusional ideas) subscale for 22q11DS patients, with IPS percent signal change on the Y-axis, R² = 0.38, and (e) SIPS total positive symptoms for 22q11DS patients, with IPS percent signal change on the Y-axis, R² = 0.29. Residuals were calculated by regressing percent signal change and cognitive/clinical scores on age and gender, and are plotted for visualization purposes.