No abstract

BackgroundNeurofibromatosis Type 1 (NF1) is a genetic disorder that disrupts central nervous system development and neuronal function. Cognitively, NF1 is characterized by difficulties with executive control and visuospatial abilities. Little is known about the neural substrates underlying these deficits. The current study utilized Blood-Oxygen-Level-Dependent (BOLD) functional MRI (fMRI) to explore the neural correlates of spatial working memory (WM) deficits in patients with NF1.MethodsBOLD images were acquired from 23 adults with NF1 (age M = 32.69; 61% male) and 25 matched healthy controls (age M = 33.08; 64% male) during an in-scanner visuo-spatial WM task. Whole brain functional and psycho-physiological interaction analyses were utilized to investigate neural activity and functional connectivity, respectively, during visuo-spatial WM performance. Participants also completed behavioral measures of spatial reasoning and verbal WM.ResultsRelative to healthy controls, participants with NF1 showed reduced recruitment of key components of WM circuitry, the left dorsolateral prefrontal cortex and right parietal cortex. In addition, healthy controls exhibited greater simultaneous deactivation between the posterior cingulate cortex (PCC) and temporal regions than NF1 patients. In contrast, NF1 patients showed greater PCC and bilateral parietal connectivity with visual cortices as well as between the PCC and the cerebellum. In NF1 participants, increased functional coupling of the PCC with frontal and parietal regions was associated with better spatial reasoning and WM performance, respectively; these relationships were not observed in controls.ConclusionsDysfunctional engagement of WM circuitry, and aberrant functional connectivity of ‘task-negative’ regions in NF1 patients may underlie spatial WM difficulties characteristic of the disorder.

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.