Nimodipine Protects Vascular and Cognitive Function in an Animal Model of Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease is a common cause of vascular cognitive impairment and dementia. There is an urgent need for preventative treatments for vascular cognitive impairment and dementia, and reducing vascular dysfunction may provide a therapeutic route. Here, we investigate whether the chronic administration of nimodipine, a central nervous system-selective dihydropyridine calcium channel blocking agent, protects vascular, metabolic, and cognitive function in an animal model of cerebral small vessel disease, the spontaneously hypertensive stroke-prone rat. METHODS: Male spontaneously hypertensive stroke-prone rats were randomly allocated to receive either a placebo (n=24) or nimodipine (n=24) diet between 3 and 6 months of age. Animals were examined daily for any neurological deficits, and vascular function was assessed in terms of neurovascular and neurometabolic coupling at 3 and 6 months of age, and cerebrovascular reactivity at 6 months of age. Cognitive function was evaluated using the novel object recognition test at 6 months of age. RESULTS: Six untreated control animals were terminated prematurely due to strokes, including one due to seizure, but no treated animals experienced strokes and so had a higher survival (P=0.0088). Vascular function was significantly impaired with disease progression, but nimodipine treatment partially preserved neurovascular coupling and neurometabolic coupling, indicated by larger (P<0.001) and more prompt responses (P<0.01), and less habituation upon repeated stimulation (P<0.01). Also, animals treated with nimodipine showed greater cerebrovascular reactivity, indicated by larger dilation of arterioles (P=0.015) and an increase in blood flow velocity (P=0.001). This protection of vascular and metabolic function achieved by nimodipine treatment was associated with better cognitive function (P<0.001) in the treated animals. CONCLUSIONS: Chronic treatment with nimodipine protects from strokes, and vascular and cognitive deficits in spontaneously hypertensive stroke-prone rat. Nimodipine may provide an effective preventive treatment for stroke and cognitive decline in cerebral small vessel disease.

Connectome-wide Functional Connectivity Abnormalities in Youth With Obsessive-Compulsive Symptoms.

BACKGROUND: Obsessive-compulsive symptomatology (OCS) is common in adolescence but usually does not meet the diagnostic threshold for obsessive-compulsive disorder. Nevertheless, both obsessive-compulsive disorder and subthreshold OCS are associated with increased likelihood of experiencing other serious psychiatric conditions, including depression and suicidal ideation. Unfortunately, there is limited information on the neurobiology of OCS. METHODS: Here, we undertook one of the first brain imaging studies of OCS in a large adolescent sample (analyzed n = 832) from the Philadelphia Neurodevelopmental Cohort. We investigated resting-state functional magnetic resonance imaging functional connectivity using complementary analytic approaches that focus on different neuroanatomical scales, from known functional systems to connectome-wide tests. RESULTS: We found a robust pattern of connectome-wide, OCS-related differences, as well as evidence of specific abnormalities involving known functional systems, including dorsal and ventral attention, frontoparietal, and default mode systems. Analysis of cerebral perfusion imaging and high-resolution structural imaging did not show OCS-related differences, consistent with domain specificity to functional connectivity. CONCLUSIONS: The brain connectomic associations with OCS reported here, together with early studies of its clinical relevance, support the potential for OCS as an early marker of psychiatric risk that may enhance our understanding of mechanisms underlying the onset of adolescent psychopathology.