Abstract
BackgroundHippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum. Moreover, there is strong translational evidence that preserving the maturation of hippocampal networks in mice models prevents the progression of cognitive deficits. However, the developmental trajectory of hippocampal functional connectivity (HFC) and its contribution to psychosis is not well characterized in the human population. 22q11 deletion syndrome (22q11DS) offers a unique model for characterizing early neural correlates of schizophrenia. MethodsWe acquired resting-state functional magnetic resonance imaging in 242 longitudinally repeated scans from 84 patients with 22q11DS (30 with moderate to severe positive psychotic symptoms) and 94 healthy control subjects in the age span of 6 to 32 years. We obtained bilateral hippocampus to whole-brain functional connectivity and employed a novel longitudinal multivariate approach by means of partial least squares correlation to evaluate the developmental trajectory of HFC across groups. ResultsRelative to control subjects, patients with 22q11DS failed to increase HFC with frontal regions such as the dorsal part of the anterior cingulate cortex, prefrontal cortex, and supplementary motor area. Concurrently, carriers of the deletion had abnormally higher HFC with subcortical dopaminergic areas. Remarkably, this aberrant maturation of HFC was more prominent during midadolescence and was mainly driven by patients exhibiting subthreshold positive psychotic symptoms. ConclusionsOur findings suggest a critical period of prefrontal cortex–hippocampal–striatal circuit dysmaturation, particularly during late adolescence, which in light of current translation evidence could be a target for short-term interventions to potentially achieve long-lasting rescue of circuit dysfunctions associated with psychosis.
Highlights
Hippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum
partial least squares correlation (PLS-C) analysis on longitudinal data of seed-to-voxel hippocampal functional connectivity (HFC) resulted in one significant component (LCs; p, .001) (Figure 3), which captured both overall differences in HFC across cohorts, as revealed by a stable diagnosis effect, and
It can be interpreted that patients fail to develop a positive HFC with dorsal part of the anterior cingulate cortex (dACC) and supplementary motor areas, and the HFC remains negative within these regions
Summary
Hippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum. The developmental trajectory of hippocampal functional connectivity (HFC) and its contribution to psychosis is not well characterized in the human population. METHODS: We acquired resting-state functional magnetic resonance imaging in 242 longitudinally repeated scans from 84 patients with 22q11DS (30 with moderate to severe positive psychotic symptoms) and 94 healthy control subjects in the age span of 6 to 32 years. We obtained bilateral hippocampus to whole-brain functional connectivity and employed a novel longitudinal multivariate approach by means of partial least squares correlation to evaluate the developmental trajectory of HFC across groups. Carriers of the deletion had abnormally higher HFC with subcortical dopaminergic areas. This aberrant maturation of HFC was more prominent during midadolescence and was mainly driven by patients exhibiting subthreshold positive psychotic symptoms. CONCLUSIONS: Our findings suggest a critical period of prefrontal cortex–hippocampal–striatal circuit dysmaturation, during late adolescence, which in light of current translation evidence could be a target for short-term interventions to potentially achieve long-lasting rescue of circuit dysfunctions associated with psychosis
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