TY - JOUR
T1 - Cognitive impairment and diminished neural responses constitute a biomarker signature of negative symptoms in psychosis
AU - Hudgens-Haney, Matthew E.
AU - Clementz, Brett A.
AU - Ivleva, Elena I.
AU - Keshavan, Matcheri S.
AU - Pearlson, Godfrey D.
AU - Gershon, Elliot S.
AU - Keedy, Sarah K.
AU - Sweeney, John A.
AU - Gaudoux, Florence
AU - Bunouf, Pierre
AU - Canolle, Benoit
AU - Tonner, Françoise
AU - Gatti-McArthur, Silvia
AU - Tamminga, Carol A
N1 - Funding Information:
We thank Brad Witte, Gregory Book, and Gaurav Poudyal for their contributions to data management; the small army of students and research assistants required to conduct a study of this scale; and the volunteers who contributed their time and effort to the Bipolar-Schizophrenia Network for Intermediate Phenotypes study. ME Hudgens-Haney and BA Clementz have served as consultants for Astellas, Inc. MS Keshavan is a consultant to Forum Pharmaceuticals and is the editor of Schizophrenia Research. JA Sweeney reports serving on an advisory board for Takeda. CA Tamminga has consulted for Intracellular Therapies (ITI, Inc.), PureTech Ventures, Eli Lilly Pharmaceuticals, Sunovion, Astellas, and Merck. She is also an unpaid volunteer for NAMI, Deputy Editor of the American Psychiatric Association, and an expert witness for Finnegan Henderson Farabow Garrett & Dunner, LLP. F Gaudoux, P Bunouf, B Canolle, F Tonner, and S Gatti-McArthur have been employed by Institut Recherche Pierre-Fabre. The other authors reported no biomedical financial interests or potential conflicts of interest. Funding for B-SNIP1 was provided by National Institutes of Health (NIH) grants MH077945, MH077862, MH077851, MH078113, MH085485. Partial funding for an early version of the current analysis was provided by Institut Recherche Pierre-Fabre. ME Hudgens-Haney was partially supported by National Institute of Health grant T32 MH0776690. These funding sources had no influence over the design and execution of the study, the final analyses, or interpretation of the data.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - The treatment of negative symptoms (NS) in psychosis represents an urgent unmet medical need given the significant functional impairment it contributes to psychosis syndromes. The lack of progress in treating NS is impacted by the lack of known pathophysiology or associated quantitative biomarkers, which could provide tools for research. This current analysis investigated potential associations between NS and an extensive battery of behavioral and brain-based biomarkers in 932 psychosis probands from the B-SNIP database. The current analyses examined associations between PANSS-defined NS and (1) cognition, (2) pro-/anti-saccades, (3) evoked and resting-state electroencephalography (EEG), (4) resting-state fMRI, and (5) tractography. Canonical correlation analyses yielded symptom-biomarker constructs separately for each biomarker modality. Biomarker modalities were integrated using canonical discriminant analysis to summarize the symptom-biomarker relationships into a “biomarker signature” for NS. Finally, distinct biomarker profiles for 2 NS domains (“diminished expression” vs “avolition/apathy”) were computed using step-wise linear regression. NS were associated with cognitive impairment, diminished EEG response amplitudes, deviant resting-state activity, and oculomotor abnormalities. While a connection between NS and poor cognition has been established, association to neurophysiology is novel, suggesting directions for future mechanistic studies. Each biomarker modality was related to NS in distinct and complex ways, giving NS a rich, interconnected fingerprint and suggesting that any one biomarker modality may not adequately capture the full spectrum of symptomology.
AB - The treatment of negative symptoms (NS) in psychosis represents an urgent unmet medical need given the significant functional impairment it contributes to psychosis syndromes. The lack of progress in treating NS is impacted by the lack of known pathophysiology or associated quantitative biomarkers, which could provide tools for research. This current analysis investigated potential associations between NS and an extensive battery of behavioral and brain-based biomarkers in 932 psychosis probands from the B-SNIP database. The current analyses examined associations between PANSS-defined NS and (1) cognition, (2) pro-/anti-saccades, (3) evoked and resting-state electroencephalography (EEG), (4) resting-state fMRI, and (5) tractography. Canonical correlation analyses yielded symptom-biomarker constructs separately for each biomarker modality. Biomarker modalities were integrated using canonical discriminant analysis to summarize the symptom-biomarker relationships into a “biomarker signature” for NS. Finally, distinct biomarker profiles for 2 NS domains (“diminished expression” vs “avolition/apathy”) were computed using step-wise linear regression. NS were associated with cognitive impairment, diminished EEG response amplitudes, deviant resting-state activity, and oculomotor abnormalities. While a connection between NS and poor cognition has been established, association to neurophysiology is novel, suggesting directions for future mechanistic studies. Each biomarker modality was related to NS in distinct and complex ways, giving NS a rich, interconnected fingerprint and suggesting that any one biomarker modality may not adequately capture the full spectrum of symptomology.
KW - Biotype
KW - Bipolar disorder
KW - EEG
KW - Multivariate statistics
KW - Oculomotor
KW - Schizophrenia
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U2 - 10.1093/schbul/sbaa001
DO - 10.1093/schbul/sbaa001
M3 - Article
C2 - 32043133
AN - SCOPUS:85090701074
VL - 46
SP - 1269
EP - 1281
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
SN - 0586-7614
IS - 5
ER -