LINKING VERBAL MEMORY DEFICITS, HIPPOCAMPAL VOLUME, AND FUNCTIONING: SEX DIFFERENCES ARE CRUCIAL

Abstract Background Verbal memory (VM) is one of the most affected cognitive domains in individuals with a first episode of psychosis (FEP). In the general population, there are well-documented sex differences in VM such that males perform worse than females. This has implications for understanding cognitive deficits in psychosis given that male patients present with more severe negative symptoms and poorer functional outcomes, both of which are associated with cognitive deficits. There lacks, however, a clear understanding of how VM deficits might contribute to males’ poorer functioning. From a neuroanatomical perspective, VM relies on a network of brain regions, including the hippocampus (HC) as an important hub in the acquisition of new information. Interestingly, many of the brain regions that differ between males and females, including the HC, show structural abnormalities in psychosis. Thus, consideration of sex differences may be essential for better characterizing and understanding brain alterations in psychosis and their effects on cognition. The aims of the current research were to: (1) evaluate whether the propensity for poorer functional outcomes among FEP males is mediated by sex differences in VM; and (2) investigate whether HC volume mediates the effect of sex on VM. Methods 137 FEP (90 males, 47 females) and 81 controls (55 males, 26 females) completed a VM task (Wechsler Memory Scale or CogState Research Battery) and a structural MRI scan (1.5 Tesla). Patients were additionally assessed for negative symptoms (Scale for the Assessment of Negative Symptoms) at baseline and functioning (Social and Occupational Functioning Assessment Scale) at 1-year follow-up. Performance of the matched control group was used as normative data to derive VM z-scores. HC volumes were computed for each subject and hemisphere using the MAGeT brain algorithm. Mediation analyses were conducted using the PROCESS macro with SPSS. The behavioral model (‘sex VM negative symptoms functioning’) was performed in patients only, controlling for education; the imaging model (‘sex HC volume VM’) was performed in both groups and additionally controlled for age and total brain volume. Significance was assessed at 95% confidence intervals. Results The effect of sex on functioning at 1-year follow-up was fully mediated by verbal memory capacity and negative symptoms (β=0.54, CI=[0.12, 1.12]. Importantly, neither VM nor negative symptoms alone mediated the relationship between sex and functioning at 1-year follow-up. Left and right HC volumes, which were larger in males than in females in both groups, demonstrated a suppression effect on the relation between sex and verbal memory in patients (left HC: β=-0.21, CI=[-0.39, -0.07]; right HC: β=-0.24, CI=[-0.45,-0.09]), but not in controls (left HC: β=0.04, CI=[-0.14, 0.24]; right HC: β=0.06, CI=[-0.13,0.25]). Discussion This study reveals that sex differences in VM are robust and influence functioning through negative symptoms in FEP. Given that males are typically overrepresented in psychosis samples, it is possible that male patients chiefly contribute to associations between negative symptoms and neurocognitive impairments observed in previous studies in which sex was not explicitly examined. Further, our results suggest that the role of the HC in memory may be differentially affected by sex. This second model was specific to FEP, indicating that certain structure-function relationships are not consistent between patients and controls. Overall, such findings highlight the need to consider sex differences when developing personalized treatment plans and highlight neurocognitive deficits as a promising avenue for treatment.