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Brain. 2015 Jul;138(Pt 7):2087-102. doi: 10.1093/brain/awv106. Epub 2015 May 5.

Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder.

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1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA
2 Academisch Medisch Centrum, Department of Paediatric Neurology/Emma Children's Hospital, Amsterdam, The Netherlands.
3 University Medical Centre Utrecht, Neuroscience, Utrecht, The Netherlands.
1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA.
4 Cell and Molecular Biology Research Centre, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.
5 Department of Psychiatry, Yale University and Olin Neuropsychiatric Research Centre, Institute of Living, Hartford Hospital, Hartford, Connecticut, USA.
6 Grupo de Investigación en Psiquiatría [Research Group in Psychiatry (GIPSI)], Departamento de Psiquiatría, Facultad de Medicina, Universidad de Antioquia. Medellín, Colombia.
7 Department of Psychiatry and Family Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
1 Department of Psychiatry and Biobehavioural Science, University of California, Los Angeles, California, USA 8 BioCiencias Laboratory, Guatemala, Guatemala.
9 Department of Psychiatry, University of California, San Francisco, California, USA.
10 Department of Health Research and Policy, Stanford University, Stanford, California, USA.
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.


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.


bipolar disorder; component phenotype; neurocognition; pedigrees; structural MRI; temperament

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