Neural complexity as a potential translational biomarker for psychosis.
The adaptability of the human brain to the constantly changing environment is reduced in patients with psychotic disorders, leading to impaired cognitive functions. Brain signal complexity, which may reflect adaptability, can be readily quantified via resting-state functional magnetic resonance imaging (fMRI) signals. We hypothesized that resting-state brain signal complexity is altered in psychotic disorders, and is correlated with cognitive impairment.



We assessed 156 healthy controls (HC) and 330 probands, including 125 patients with psychotic bipolar disorder (BP), 107 patients with schizophrenia (SZ), 98 patients with schizoaffective disorder (SAD) and 230 of their unaffected first-degree relatives (76 BPR, 79 SADR, and 75 SZR) from four sites of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Using multi-scale entropy analysis, we determined whether patients and/or relatives had pathologic differences in complexity of resting-state fMRI signals toward regularity (reduced entropy in all time scales), or toward uncorrelated randomness (increased entropy in fine time scales that decays as the time scale increases) and how these complexity differences might be associated with cognitive impairment.



Compared to HC subjects, proband groups showed either decreased complexity toward regularity or toward randomness. SZ probands showed decreased complexity toward regular signal in hypothalamus, and BP probands in left inferior occipital, right precentral and left superior parietal regions, whereas no brain region with decreased complexity toward regularity was found in SAD probands. All proband groups showed significantly increased brain signal randomness in dorsal and ventral prefrontal cortex (PFC), and unaffected relatives showed no complexity differences in PFC regions. SZ had the largest area of involvement in both dorsal and ventral PFC. BP and SAD probands shared increased brain signal randomness in ventral medial PFC, BP and SZ probands shared increased brain signal randomness in ventral lateral PFC, whereas SAD and SZ probands shared increased brain signal randomness in dorsal medial PFC. Only SZ showed increased brain signal randomness in dorsal lateral PFC. The increased brain signal randomness in dorsal or ventral PFC was weakly associated with reduced cognitive performance in psychotic probands.



These observations support the loss of brain complexity hypothesis in psychotic probands. Furthermore, we found significant differences as well as overlaps of pathologic brain signal complexity between psychotic probands by DSM diagnoses, thus suggesting a biological approach to categorizing psychosis based on functional neuroimaging data.
Massachusetts Mental Health Center, Boston, MA, USA; Division of Public Psychiatry, Beth Israel Deaconess Medical Center/Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Brandon
B
Hager
Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Taipei Veterans General Hospital/School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Albert C
AC
Yang
Massachusetts Mental Health Center, Boston, MA, USA; Division of Public Psychiatry, Beth Israel Deaconess Medical Center/Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Roscoe
R
Brady
Departments of Psychiatry and Neuroscience, Yale University School of Medicine, New Haven, and the Institute of Living, Hartford Hospital, Hartford, CT, USA.
Shashwath
S
Meda
Departments of Psychology and Neuroscience, Bio-Imaging Research Center, University of Georgia, Athens, USA.
Brett
B
Clementz
Departments of Psychiatry and Neuroscience, Yale University School of Medicine, New Haven, and the Institute of Living, Hartford Hospital, Hartford, CT, USA.
Godfrey D
GD
Pearlson
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
John A
JA
Sweeney
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, USA.
Carol
C
Tamminga
Massachusetts Mental Health Center, Boston, MA, USA; Division of Public Psychiatry, Beth Israel Deaconess Medical Center/Department of Psychiatry, Harvard Medical School, Boston, MA, USA. Electronic address: mkeshava@bidmc.harvard.edu.
Matcheri
M
Keshavan
D000223:Adaptation, Psychological / Q000502:physiology*; D000328:Adult; D015415:Biomarkers / Q000032:analysis; D001714:Bipolar Disorder / Q000000981:diagnostic imaging / Q000503:physiopathology* / Q000523:psychology; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology; D003071:Cognition; D060825:Cognitive Dysfunction / Q000503:physiopathology* / Q000523:psychology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000503:physiopathology; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000503:physiopathology* / Q000523:psychology; D012146:Rest / Q000502:physiology / Q000523:psychology
D015415:Biomarkers
Multiscale entropy; Neural complexity; Psychosis; Schizophrenia, schizoaffective disorder, psychotic bipolar disorder