Connectome signatures of neurocognitive abnormalities in euthymic bipolar I disorder

Abstract

Objectives: Connectomics have allowed researchers to study integrative patterns of neural connectivity in humans. Yet, it is unclear how connectomics may elucidate structure-function relationships in bipolar I disorder (BPI). Expanding on our previous structural connectome study, here we used an overlapping sample with additional psychometric and fMRI data to relate structural connectome properties to both fMRI signals and cognitive performance.

Methods: 42 subjects completed a neuropsychological (NP) battery covering domains of processing speed, verbal memory, working memory, and cognitive flexibility. 32 subjects also had fMRI data performing a Go/NoGo task.

Results: Bipolar participants had lower NP performance across all domains, but only working memory reached statistical significance. In BPI participants, processing speed was significantly associated with both white matter integrity (WMI) in the corpus callosum and interhemispheric network integration. Mediation models further revealed that the relationship between interhemispheric integration and processing speed was mediated by WMI, and processing speed mediated the relationship between WMI and working memory. Bipolar subjects had significantly decreased BA47 activation during NoGo vs. Go. Significant predictors of BA47 fMRI activations during the Go/NoGo task were its nodal path length (left hemisphere) and its nodal clustering coefficient (right hemisphere).

Conclusions: This study suggests that structural connectome changes underlie abnormalities in fMRI activation and cognitive performance in euthymic BPI subjects. Results support that BA47 structural connectome changes may be a trait marker for BPI. Future studies are needed to determine if these "connectome signatures" may also confer a biological risk and/or serve as predictors of relapse.

Keywords: Bipolar disorder; Cognition; Connectome; Go/nogo task; MRI; Response inhibition.

Figure 1. Cognitive domain performance z-scores for health control and bipolar subjects

While bipolar subjects demonstrated reduced performance across all domains, only working memory was significantly different (F = 4.6, p = .04, df = 1). Data are presented as a percentage of the mean performance for control subjects. Error bars indicate the standard error of the mean.

Figure 2. BA47 GoNoGo Activation Differences

A. Spherical BA47 regions of interest (yellow) were defined by the nogo minus go contrast and are depicted on a representative high-resolution anatomical image. Error bars denote standard error of the mean. B. Between-group whole-brain results display significantly greater activation in BA 47 (highlighted in green circles) in control subjects as compared to euthymic bipolar subjects during response inhibition.

Figure 3. Processing speed significantly correlates with network measures of interhemispheric integration in bipolar participants

A. Interhemispheric path length negatively correlates with processing speed (r = -.50, p = .017, q = .068, df = 20). B. Interhemispheric efficiency positively correlates processing speed (r = .54, p = .012, q = .068, df = 20).

Figure 4. Mediation Models

A. FA in the genu of the corpus callosum (GCC FA) is a significant mediator of the relationship between interhemispheric integration (measured by “graph distance” or path length between two hemispheres) and processing speed, which in turn mediates the association of FA and working memory. B. BA47 task activation mediates the relationship between BA47 nodal path lengths and performance during the Go/NoGo task. Unstandardized beta weights for significant variables are displayed on the models.