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.

Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development

“…Most functional changes are seen in association cortices, particularly the frontal cortices, and are detected during performance of complex cognitive tasks. There is reduced activity in medial frontal association cortical regions during a task that assesses working memory a key component of executive dysfunction (Montojo et al, 2014). Executive function, required for problem solving and task flexibility, is perturbed in all disorders of cortical circuit development (Kenworthy et al, 2009; Montojo et al, 2014; van Os and Kapur, 2009).…”

“…There is reduced activity in medial frontal association cortical regions during a task that assesses working memory a key component of executive dysfunction (Montojo et al, 2014). Executive function, required for problem solving and task flexibility, is perturbed in all disorders of cortical circuit development (Kenworthy et al, 2009; Montojo et al, 2014; van Os and Kapur, 2009). This apparent divergence of association cortical function in 22q11DS patients is further supported by analysis of resting state network activity (Debbane et al, 2012).…”

Performance on a computerized neurocognitive battery in 22q11.2 deletion syndrome: A comparison between US and Israeli cohorts

“…Additionally, Azuma et al found that patients with 22q11DS have reduced activation of fusiform-extrastriate cortices, anterior cingulate cortex and superomedial prefrontal cortices when viewing increasing intensity of expression of fear and disgust (Azuma et al, 2015). Notably, reduced activation of abovementioned brain regions that are implicated in inhibitory control, working memory and facial emotion processing were further correlated with levels of impulsivity, subthreshold psychotic symptoms and social difficulties, respectively (Azuma et al, 2015; Montojo et al, 2014; Montojo et al, 2015). Resting state studies have consistently found decreased connectivity within the default mode network (DMN) and lack of age-related maturation of these networks (Debbane et al, 2012; Padula et al, 2015; Schreiner et al, 2014).…”

“…Montojo et al found that individuals with 22q11DS had reduced activation of frontal cortical and basal ganglia regions that are associated with response inhibition during the Stop-signal task when compared to matched controls (Montojo et al, 2015). In another study, Montojo et al showed that individuals with 22q11DS had reduced activation of intraparietal sulcus and superior frontal sulcus during spatial working memory task compared to matched controls (Montojo et al, 2014). Additionally, Azuma et al found that patients with 22q11DS have reduced activation of fusiform-extrastriate cortices, anterior cingulate cortex and superomedial prefrontal cortices when viewing increasing intensity of expression of fear and disgust (Azuma et al, 2015).…”

White matter microstructural deficits in 22q11.2 deletion syndrome

“…For example, the SLF connects aspects of the parietal lobe with frontal cortex, including the DLPFC. As such, disruption of the SLF is associated with poorer working memory, an ability often affected in 22q11DS (Bava et al, 2011; Montojo et al, 2014). Moreover, one previous study found lower AD in 22q11DS (Kikinis et al, 2012), but no associations with cognition were reported.…”