Evidence is rapidly accumulating that rare, recurrent copy number variants (CNVs) represent large effect risk factors for neuropsychiatric disorders. 22q11.2 Deletion Syndrome (22q11DS; Velo-Cardio-Facial Syndrome (VCFS) or DiGeorge Syndrome) is the most common known contiguous gene deletion syndrome, and is associated with diverse neuropsychiatric disorders across the lifespan. One of the most intriguing aspects of the syndrome is the variability in clinical and cognitive presentation: children with 22q11DS have high prevalence of autism spectrum (ASD), attention deficit, and anxiety disorders, as well as psychotic-like features, and up to 30% of adolescents and adults develop schizophrenia-like psychosis. Recently, cases of early-onset Parkinson’s Disease in adults have been reported, collectively suggesting a role for disrupted dopaminergic neurotransmission in the observed neuropsychiatric phenotypes. There is also some evidence that 22q11DS-associated ASD and schizophrenia represent two unrelated phenotypic manifestations, consistent with a neuropsychiatric pleiotropy model. This genetic lesion thus provides a unique model for the discovery of specific genomic risk and (potentially) protective factors for neuropsychiatric disease. Here we provide an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder’s heterogeneous presentation are reviewed. Because of its known genetic etiology, animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system.

Summary Establishing what information is actively maintained in working memory (WM) and how it is represented and controlled is essential to understanding how such information guides future behavior. WM has traditionally been investigated in terms of the maintenance of stimulus-specific information, such as locations or words. More recently, investigators have emphasized the importance of rules that establish relationships between those stimuli and the pending response. The current study used a mental arithmetic task with fMRI to test whether updating of numbers (i.e. stimuli) and updating of mathematical operations (i.e. rules) in WM relies on the same neural system. Results indicate that while a common network is activated by both types of updating, rule updating preferentially activates prefrontal cortex while number updating preferentially activates parietal cortex. The results suggest that both numbers and rules are maintained in WM, but they are different types of information that are controlled independently.

ObjectiveLovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras‐MAPK pathway and associated with learning disabilities. We conducted a randomized double‐blind placebo‐controlled trial to assess lovastatin's effects on cognition and behavior in patients with NF1.MethodForty‐four NF1 patients (mean age 25.7+/−11.6 years; 64% female) were randomly assigned to 14 weeks of lovastatin (N = 23; maximum dose of 80 mg/day for adult participants and 40 mg/day for children) or placebo (N = 21). Based on findings in the mouse model, primary outcome measures were nonverbal learning and working memory. Secondary outcome measures included verbal memory, attention, and self/parent‐reported behavioral problems, as well as tolerability of medication. Participants also underwent neuroimaging assessments at baseline and 14 weeks, to determine whether neural biomarkers were associated with treatment response. Linear mixed models assessed for differential treatment effects on outcome measures.ResultsTwelve participants dropped from the study prior to completion (8 placebo, 4 lovastatin), resulting in 32 completers (15 placebo, 17 lovastatin). Lovastatin was well‐tolerated, with no serious adverse events. Differential improvement favoring lovastatin treatment was observed for one primary (working memory; effect size f 2 = 0.70, P < 0.01) and two secondary outcome measures (verbal memory, f 2 = 0.19, P = 0.02, and adult self‐reported internalizing problems, f 2 = 0.26, P = 0.03). Exploratory moderator analyses revealed that higher baseline neural activity in frontal regions was associated with larger treatment effects.InterpretationThese preliminary results suggest beneficial effects of lovastatin on some learning and memory functions, as well as internalizing symptoms in patients with NF1.

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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.