P1-009: GENDER DIFFERENCES IN MEMORY-RELATED FUNCTIONAL CONNECTIVITY IN AGING AND GENETIC RISK FOR AD

Background While genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. Despite this, few studies have investigated electrophysiological connectivity in this high-risk group. Studying children with 22q11.2DS provides a unique paradigm to identify brain markers of neurodevelopmental impairment and to relate these to underlying biology. Methods Magnetoencephalography (MEG) was used to investigate resting-state cortical oscillatory patterns in 34 children with 22q11.2DS and 25 controls aged 10-17 years old. Oscillatory activity and functional connectivity across six frequency bands were compared between groups. Regression analyses were used to explore the relationships between these measures, IQ and neurodevelopmental symptoms. Results Children with 22q11.2DS had atypical oscillatory activity and functional connectivity across multiple frequency bands (delta, beta and gamma bands). In the 22q11.2DS group, low frequency (alpha band) activity was negatively associated with cognitive ability and positively associated with ASD and ADHD symptoms. Frontal high frequency (gamma band) activity and connectivity were positively associated with ASD and ADHD symptoms, while posterior gamma activity was negatively associated with ASD symptoms. Conclusions These findings highlight that haploinsufficiency at the 22q11.2 locus alters both local and long-range cortical circuitry, which could be a mechanism underlying neurodevelopmental vulnerability in this high risk group.

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Resting-state functional connectivity and psychopathology in Klinefelter syndrome (47, XXY)

10.1101/2020.12.15.422868 ◽

2020 ◽

Author(s):

Ethan T. Whitman ◽

Siyuan Liu ◽

Erin Torres ◽

Allysa Warling ◽

Kathleen Wilson ◽

...

Keyword(s):

Functional Connectivity ◽

Resting State ◽

Genetic Risk ◽

Klinefelter Syndrome ◽

Brain Connectivity ◽

Brain Anatomy ◽

Imaging Data ◽

Resting State Functional Connectivity ◽

Dorsolateral Prefrontal ◽

Neuroimaging Study

Klinefelter syndrome (47, XXY; Henceforth: XXY syndrome) is a high impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first neuroimaging study to map resting-state functional connectivity (rsFC) changes in XXY syndrome and ask how these might relate to brain anatomy and psychopathology. We collected resting state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males. We implemented a brain-wide screen to identify regions with altered global rsFC in XXY vs. XY males, and then used seed-based analysis to decompose these alterations. We further compared rsFC changes with regional changes in brain volume from voxel-based morphometry and tested for correlations between rsFC and symptom variation within XXY syndrome. We found that XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC), associated with overconnectivity with diverse rsFC networks. Regional rsFC changes were partly coupled to regional volumetric changes in XXY syndrome. Within the precuneus, variation in DLPFC rsFC within XXY syndrome was correlated with the severity of psychopathology in XXY individuals. Our findings provide the first view of altered functional brain connectivity in XXY syndrome and delineate links between these alterations and those relating to both brain anatomy and psychopathology. Taken together, these insights advance biological understanding of XXY syndrome as a disorder in its own right, and as a model of genetic risk for psychopathology more broadly.

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