Resting-state functional connectivity in individuals with bipolar disorder during clinical remission: a systematic review

Resting-state functional connectivity in individuals with bipolar disorder during clinical remission: a systematic review


J Psychiatry Neurosci 2018;43(5):298-316

Sabrina K. Syan, PhD; Mara Smith, MD; Benicio N. Frey, MD, MSc, PhD; Raheem Remtulla, BHSc; Flavio Kapczinski, MSc, MD, PhD; Geoffrey B.C. Hall, PhD; Luciano Minuzzi, MD, PhD


Background: Bipolar disorder is chronic and debilitating. Studies investigating resting-state functional connectivity in individuals with bipolar disorder may help to inform neurobiological models of illness.

Methods: We conducted a systematic review with the following goals: to summarize the literature on resting-state functional connectivity in bipolar disorder during clinical remission (euthymia) compared with healthy controls; to critically appraise the literature and research gaps; and to propose directions for future research. We searched PubMed/MEDLINE, Embase, PsycINFO, CINAHL and grey literature up to April 2017.

Results: Twenty-three studies were included. The most consistent finding was the absence of differences in resting-state functional connectivity of the default mode network (DMN), frontoparietal network (FPN) and salience network (SN) between people with bipolar disorder and controls, using independent component analysis. However, 2 studies in people with bipolar disorder who were positive for psychosis history reported DMN hypoconnectivity. Studies using seed-based analysis largely reported aberrant resting-state functional connectivity with the amygdala, ventrolateral prefrontal cortex, cingulate cortex and medial prefrontal cortex in people with bipolar disorder compared with controls. Few studies used regional homogeneity or amplitude of low-frequency fluctuations.

Limitations: We found heterogeneity in the analysis methods used.

Conclusion: Stability of the DMN, FPN and SN may reflect a state of remission. Further, DMN hypoconnectivity may reflect a positive history of psychosis in patients with bipolar disorder compared with controls, highlighting a potentially different neural phenotype of psychosis in people with bipolar disorder. Resting-state functional connectivity changes between the amygdala, prefrontal cortex and cingulate cortex may reflect a neural correlate of subthreshold symptoms experienced in bipolar disorder euthymia, the trait-based pathophysiology of bipolar disorder and/or a compensatory mechanism to maintain a state of euthymia.

Submitted Sept. 2, 2017; Revised Dec. 21, 2017; Revised Jan. 19, 2018; Accepted Jan. 19, 2018; Published online first June 28, 2018

Acknowledgments: This research was supported by the Ontario Mental Health Foundation (Type-A Grant, B. Frey) and from J.P. Bickell Foundation (Medical Research Grant, B. Frey).

Affiliations: From the MiNDS Neuroscience Graduate Program, McMaster University (Syan, Frey, Kapczinski, Hall, Minuzzi); the Women’s Health Concerns Clinic (Syan, Frey, Remtulla, Minuzzi); the Mood Disorders Program, St. Joseph’s Healthcare (Frey, Kapczinski, Minuzzi); the Department of Psychiatry and Behavioural Neurosciences, McMaster University (Smith, Frey, Kapczinski, Minuzzi, Smith); and the Department of Psychology, Neuroscience and Behaviour, McMaster University (Hall), Hamilton, Ontario, Canada.

Competing interests: L. Minuzzi declares an Alternative Funding Plan Innovations Award and grants from the Brain & Behavioral Foundation, the Canadian Institutes of Health Research, the Hamilton Health Sciences Foundation and the Ontario Brain Institute. He has received speaker fees from Bristol-Myers Squibb, Lundbeck, Sunovion Pharmaceuticals, the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments. No other authors declare competing interests.

Contributors: S. Syan, B. Frey and L. Minuzzi designed the study. S. Syan, M. Smith and R. Remtulla acquired the data, which S. Syan, M. Smith, B. Frey, F. Kapczinski, G. Hall and L. Minuzzi analyzed. S. Syan, M. Smith, B. Frey and L. Minuzzi wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.170175

Correspondence to: L. Minuzzi, 100 West 5th Street, Suite C118, Hamilton, Ont., L8N 3K7;