Longitudinal changes in hippocampal volume in the Edinburgh High Risk Study of Schizophrenia

Abstract Schizophrenia is associated with structural brain abnormalities that are likely to be present before disease onset. It remains unclear to what extent these represent general vulnerability indicators or are associated with the developing clinical state itself. It also remains unclear whether such state or trait alterations may be evident at any given time-point, or whether they progress over time. To investigate this, structural brain scans were acquired at two time-points (mean scan-interval 1.87 years) in a cohort of young unaffected individuals at high familial risk of schizophrenia (baseline, n = 142; follow-up, n = 64) and healthy controls (baseline, n = 36; follow-up, n = 18). Sub-cortical reconstructions of the hippocampus and amygdala were generated using the longitudinal pipeline available with Freesurfer. The high risk cohort was subdivided into individuals that remained well during the study (HR[well], baseline, n = 68; follow-up, n = 30), transient and/or partial symptoms that were insufficient to support a formal diagnosis (HR[symp], baseline, n = 57; follow-up, n = 26) and individuals that subsequently developed schizophrenia according to ICD-10 criteria (HR[ill], baseline, n = 17; follow-up, n = 8). Longitudinal change in the hippocampus and amygdala was compared, focusing first on overall differences between high-risk individuals and controls and then on sub-group differences within the high-risk cohort. We found a significantly altered developmental trajectory for all high risk individuals compared to controls, with controls showing a significant increase in hippocampal volume over time compared to those at high risk. We did not find evidence of altered longitudinal trajectories based on clinical outcome within the high risk cohort. These results suggest that an altered developmental trajectory of hippocampal volume is associated with a general familial predisposition to develop schizophrenia, as this alteration was not related to subsequent clinical outcome.