title: Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder.
abstract: Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA sfears@mednet.ucla.edu.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Fears
authors.affiliation: 2 Academisch Medisch Centrum, Department of Paediatric Neurology/Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: Remmelt
authors.initials: R
authors.lastname: Schür
authors.affiliation: 3 University Medical Centre Utrecht, Neuroscience, Utrecht, The Netherlands.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sjouwerman
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Service
authors.affiliation: 4 Cell and Molecular Biology Research Centre, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
authors.forename: Carmen
authors.initials: C
authors.lastname: Araya
authors.affiliation: 4 Cell and Molecular Biology Research Centre, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
authors.forename: Xinia
authors.initials: X
authors.lastname: Araya
authors.affiliation: 4 Cell and Molecular Biology Research Centre, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
authors.forename: Julio
authors.initials: J
authors.lastname: Bejarano
authors.affiliation: 5 Department of Psychiatry, Yale University and Olin Neuropsychiatric Research Centre, Institute of Living, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Knowles
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Juliana
authors.initials: J
authors.lastname: Gomez-Makhinson
authors.affiliation: 6 Grupo de Investigación en Psiquiatría [Research Group in Psychiatry (GIPSI)], Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia. Medellín, Colombia.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Lopez
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Ileana
authors.initials: I
authors.lastname: Aldana
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Terri M
authors.initials: TM
authors.lastname: Teshiba
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Zvart
authors.initials: Z
authors.lastname: Abaryan
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Noor B
authors.initials: NB
authors.lastname: Al-Sharif
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Navarro
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Tishler
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Altshuler
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Bartzokis
authors.affiliation: 7 Department of Psychiatry and Family Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors.forename: Javier I
authors.initials: JI
authors.lastname: Escobar
authors.affiliation: 5 Department of Psychiatry, Yale University and Olin Neuropsychiatric Research Centre, Institute of Living, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Glahn
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: 6 Grupo de Investigación en Psiquiatría [Research Group in Psychiatry (GIPSI)], Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia. Medellín, Colombia.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Jaramillo
authors.affiliation: 4 Cell and Molecular Biology Research Centre, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Macaya
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA 8 BioCiencias Laboratory, Guatemala, Guatemala.
authors.forename: Julio
authors.initials: J
authors.lastname: Molina
authors.affiliation: 9 Department of Psychiatry, University of California, San Francisco, California, USA.
authors.forename: Victor I
authors.initials: VI
authors.lastname: Reus
authors.affiliation: 10 Department of Health Research and Policy, Stanford University, Stanford, California, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sabatti
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA 11 Department of Human Genetics, University of California, Los Angeles, California, USA.
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Freimer
authors.affiliation: 1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Bearden
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D055815:Young Adult
keywords: bipolar disorder; component phenotype; neurocognition; pedigrees; structural MRI; temperament