UCLA

Emerging evidence indicates substantial genetic overlap between schizophrenia and bipolar disorder, but the neurobiological mechanisms underlying these shared susceptibility factors remain unclear. Examining the specific neural disruptions associated with susceptibility to these illnesses, and clarifying the nature of overlap between them, is critical to understanding the etiological bases of these disorders. In view of prior reports supporting working memory dysfunction as a candidate endophenotype of schizophrenia and bipolar disorder, we examined the neural mechanisms subserving working memory function in individuals carrying liability for both syndromes. To our knowledge, no prior neuroimaging study has simultaneously examined twin pairs discordant for schizophrenia and bipolar disorder to determine whether liability-related disruptions of working memory in the disorders overlap. We employed a trial-based spatial working memory task paradigm designed to separate activation in encoding and retrieval phases. As predicted, schizophrenia and bipolar probands as well as their non-affected co-twins

exhibited hypoactivation as well as hypoconnectivity in fronto-parietal working memory circuitry compared with controls, indicating significant endophenotypic overlap in aberrant task-related functional and network activation. These cortical alterations were significantly more pronounced during encoding phases of working memory compared with retrieval phases. Additionally, both proband groups showed hyperactivation in key nodes of the default network during retrieval phases of working memory, suggesting that failure to disengage this network during memory-guided response may represent an area of phenotypic overlap. These findings are consistent with previous evidence indicating overlapping functional alterations in schizophrenia and bipolar disorder and may inform models of mechanisms underpinning the apparent biological overlap between disorders, particularly in regards to encoding processes. Findings from this study help to characterize the nature of overlap and are consistent with a model of shared inheritance of working memory dysfunction in schizophrenia and bipolar disorder.