STRIATAL FUNCTIONAL CONNECTIVITY PATTERN ASSOCIATED WITH EMOTIONAL SYMPTOMS AND COGNITIVE PERFORMANCE IN MANIC/HYPOMANIC, EUTHYMIC AND DEPRESSIVE STATES OF BIPOLAR DISORDER

Abstract Background Striatum is a key node in reward circuit and aberrant striatal functional connectivity (FC) underlies the pathophysiology of bipolar disorder (BD) (Dandash et al., 2018, Karcher et al., 2019) (Teng et al., 2013) (Altinay et al., 2016). However, it is unknown how striatal FC abnormalities are related to the disorder itself (trait effects) or to manic/hypomanic and depressive states (state effects), and whether dimensional functional abnormalities of the striatum would be a critical mechanism underlying the symptomatology of BD across mood states, particularly both emotional symptoms and cognitive performance. Aims & Objectives We primarily aimed to investigate striatal FC abnormalities in BD in different mood states, with secondary analyses examining associations among striatal connectivity, emotional symptoms and cognitive performance. Method Ninety-three bipolar subjects: 31 manic/hypomanic (BDM), 31 depressed (BDD) and 31 euthymic (BDE) and 32 healthy controls (HCs) underwent structural and resting-state functional MRI and completed the Wisconsin card sorting test (WCST) and continuous performance test (CPT). Bipolar subjects were assessed using the 17-item Hamilton Rating Scale for Depression, Young Mania Rating Scale and Positive and Negative Affect Schedule. First, striatal subregion FC was compared between patients with BD in different mood states and HCs. Second, a multivariate data-driven approach, partial least squares (PLS) analysis, was used to explore dimensional associations between striatal connectivity and the symptomatology (i.e., emotional and cognitive profile) in bipolar subjects. Finally, a post-hoc analysis was conducted to compare the striatal FC scores and behavioral scores (which represent the association between FC and the symptomatology) among subjects in different mood states. Results The inferior and superior ventral striatum and ventral rostral putamen (VRP) seed showed significant FC with dorsolateral frontal cortex, caudate, angular and thalamus among four groups. Compared to HCs, the FC between the bilateral VRP and the right ventrolateral thalamus was increased in all bipolar subgroups. Compared to BDD and BDE subjects, BDM subjects showed higher FC in bilateral VSs-dorsolateral prefrontal cortex, left VSs-right caudate, and right VRP-left angular. A distinctive striatal connectivity pattern was found in BD, which was positively associated with manic symptom, positive affect, percentage of error, perseverative and non-perseverative error responses in WCST, and total error responses in CPT. Post hoc analysis revealed that BDM had the highest scores and BDD had the lowest scores in both striatal FC and behavioral scores. Discussion & Conclusion Trait- and state- related striatal FC changes are present in BD. A dimensional FC abnormality in striatal subregions was found to be scaled with symptomatology across mood states, and a categorical difference was found among bipolar subgroups in composite variables that represent the association between FC and the symptomatology. These findings lay an emphasis on the dominated role of the striatum in the psychopathology of BD and provide evidence that mood instability and cognitive deficits in BD may be associated with aberrant striatal functional connectivity (Pacifico and Davis, 2017, Ashok et al., 2017). References DANDASH, O., YUCEL, M., DAGLAS, R., PANTELIS, C., MCGORRY, P., BERK, M. &FORNITO, A. 2018. Differential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania. Transl Psychiatry, 8, 59. KARCHER, N. R., ROGERS, B. P. &WOODWARD, N. D. 2019. Functional Connectivity of the Striatum in Schizophrenia and Psychotic Bipolar Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging, 4, 956-965. TENG, S., LU, C. F., WANG, P. S., HUNG, C. I., LI, C. T., TU, P. C., SU, T. P. &WU, Y. T. 2013. Classification of bipolar disorder using basal-ganglia-related functional connectivity in the resting state. Annu Int Conf IEEE Eng Med Biol Soc, 2013, 1057-60. ALTINAY, M. I., HULVERSHORN, L. A., KARNE, H., BEALL, E. B. &ANAND, A. 2016. Differential Resting-State Functional Connectivity of Striatal Subregions in Bipolar Depression and Hypomania. Brain Connect, 6, 255-65. PACIFICO, R. &DAVIS, R. L. 2017. Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder. Mol Psychiatry, 22, 441-449. ASHOK, A. H., MARQUES, T. R., JAUHAR, S., NOUR, M. M., GOODWIN, G. M., YOUNG, A. H. &HOWES, O. D. 2017. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Molecular psychiatry, 22, 666-679.