title: 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.
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA ; Department of Psychology, 1285 Franz Hall, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Montojo
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ibrahim
authors.affiliation: Feinstein Institute for Medical Research, Zucker Hillside Hospital, North Shore-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Karlsgodt
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chow
authors.affiliation: Department of Psychology, 1285 Franz Hall, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Hilton
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Jonas
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Vesagas
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, University of California, Los Angeles, Los Angeles, CA 90095, USA ; Department of Psychology, 1285 Franz Hall, University of California, Los Angeles, Los Angeles, CA 90095, USA ; Brain Research Institute, 695 Charles E Young Drive S, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Bearden
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000503:physiopathology*; D063132:Connectome / Q000379:methods; D004062:DiGeorge Syndrome / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008569:Memory Disorders / Q000503:physiopathology*; D008570:Memory, Short-Term; D009415:Nerve Net / Q000503:physiopathology*; D009434:Neural Pathways / Q000503:physiopathology; D011618:Psychotic Disorders / Q000175:diagnosis / Q000503:physiopathology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D065852:Spatial Memory; D055815:Young Adult
keywords: Copy number variation; Endophenotype; Executive function; Psychosis; Velocardiofacial syndrome