The neuropsychological basis of bipolar disorder

Abstract

Bipolar disorder (BP) is a major, disabling mental illness. Study one examined the neuropsychological performance for a group of individuals with soft bipolar spectrum (SBP), who manifest subthreshold hypomanic syndromes that fall short of the criteria for BP. Its second aim was to validate the bipolar nature of SBP from the perspective of cognitive function by comparing neuropsychological performance between SBP and other types of mood disorder, including unipolar depression (UP), bipolar I, and bipolar II disorder. Study two and Study three followed up with offspring of parents with BP, who were genetically at risk for BP. Recently clinical staging models have been suggested for BP, in which high-risk (HR) and ultra-high-risk (UHR) stages represent the early stages that precede the onset of BP. In the HR stage, individuals with risk for BP manifest no or non-specific, mild symptoms. While the UHR stage is a further stage of HR, in which individuals manifest varying subthreshold syndromes. In applying the clinical staging model, Study two investigated whether cognitive deficits are inherited phenotype (neurocognitive endophenotypes) or associated with illness course. Study three examined the pathophysiological alterations in the offspring across the HR and UHR stages and searched for the neural correlates of cognitive deficits identified in Study two from the prospective of gray matter (GM) volumes and brain network topology. Findings were that patients with SBP displayed a wide range of cognitive deficits compared with healthy controls (HCs). SBP differed from UP not only in clinical characteristics and external validators for BP (e.g a family history of BP), but also in neurocognitive function. Cognitive deficits in SBP were similar to bipolar II, but significantly less impaired than bipolar I disorder. Moreover, the HR offspring displayed cognitive deficits in verbal learning and memory, suggestive of neurocognitive endophenotypes (inherited phenotype). The UHR offspring emerged with cognitive deficits in processing speed and visual learning and memory, suggesting that the deficits may be associated with disease progression and thus representing risk of developing full-blown BP. Furthermore, the HR offspring exhibited decreased GM volumes in the right orbitofrontal region and cerebellum compared with HCs. Compared with the HR offspring, the UHR offspring displayed increased GM volumes in the following regions: the right superior frontal gyrus, posterior cingulate cortex, left parietal cortex, and left middle and inferior occipital gyrus. GM volumes in some of these regions were associated with processing speed. Finally, at the regional-level network analysis, both the HR and UHR offspring displayed fewer degrees of the inferior occipital gyrus when compared with HCs, suggestive of less connections of this region with others. At the whole brain level network analysis, the UHR offspring, compared with the HR offspring, exhibited upward shifted small world property which reflects high clustering and efficiency in the brain networks. Compared with the HCs, the UHR offspring had significantly lower assortativity property, suggestive of vulnerability. Our data support the bipolar nature of SBP and that some pathophysiological changes and cognitive deficits may become apparent prior to the official onset of bipolar disorder.