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: Supplementary material
Further details of the three groups and their clinical assessment
The lifetime or current presence of psychiatric symptoms (including depression), apart from BD, was not an exclusion factor for either AR or control subjects. This ecological approach has been used by similar studies of individuals at high genetic risk for BD ADDIN EN.CITE Nurnberger JI Jr.20111(Nurnberger JI Jr., 2011)1117Nurnberger JI Jr., McInnis M, Reich W, Kastelic E, Wilcox HC, Glowinski A, et al,A high-risk study of bipolar disorder: Childhood clinical phenotypes as precursors of major mood disordersArchives of General Psychiatry Archives of General Psychiatry 1012-1020682011(HYPERLINK \l "_ENREF_16" \o "Nurnberger JI Jr., 2011 #1"Nurnberger JI Jr. et al., 2011). In total, 288 participants were scanned. Five AR and 2 BD participants were removed because of excessive head movement, and 2 controls were removed because of poor contrast. In order to minimize the potential impact on brain structure of age differences between groups within this developmental period, we then selected a subgroup of participants from the remaining 281 scans by individually matching on gender and to be within 2 years of age. Thirty-eight subjects were matched across all three groups and an additional 34 participants were matched between the AR and control groups. All participants are involved in an ongoing longitudinal study of individuals at-risk for BD aged 12-30 years; the current report is of the cross-sectional data obtained at entry into the study. AR and BD participants were recruited from families who had previously participated in a bipolar disorder pedigree molecular genetics study or a specialized bipolar disorder research clinic, or were otherwise recruited from clinicians, mental health consumer organisations, or from the community using electronic and print media publicity, and notice boards in local communities. Control subjects were recruited via print and electronic media, and noticeboards in universities and local communities. The study was approved by the human research ethics committee of the University of New South Wales, and complies with the guidelines of the Australian National Health and Medical Research Council.
The subjects aged between 12-21 years are also involved in an ongoing longitudinal collaborative high-risk study with a U.S. National Institute of Mental Health funded consortium headed by Dr John Nurnberger which is based at Indiana University, Johns Hopkins University, Washington University in St. Louis, and Michigan University ADDIN EN.CITE Nurnberger20112(Nurnberger, 2011)2217Nurnberger, John IMcInnis, MelvinReich, WendyKastelic, ElizabethWilcox, Holly CGlowinski, AnneMitchell, PhilipFisher, CarrieErpe, MarianoGershon, Elliot SA high-risk study of bipolar disorder: childhood clinical phenotypes as precursors of major mood disordersArchives of General Psychiatry Archives of General Psychiatry1012-1020681020110003-990X(HYPERLINK \l "_ENREF_17" \o "Nurnberger, 2011 #2"Nurnberger et al., 2011). As this US-Australian collaboration involves common clinical assessments for participants aged 12-21years, in some cases different age-appropriate instruments were used for the younger (12-21years) and older (22-30 years) age groups in this sample, and thus these are reported separately. Both age groups shared consensus Best-Estimate DSM-IV current and lifetime diagnoses derived from semi-structured diagnostic interviews. Brain imaging studies were only undertaken in the Australian sample.
The K-SADS-BP combines items from the K-SADS Present and Lifetime Version ADDIN EN.CITE Kaufman J19973(Kaufman J, 1997)3317Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, et al, Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity dataJournal of the American Academy of Child and Adolescent Psychiatry Journal of the American Academy of Child and Adolescent Psychiatry 980-988361997(HYPERLINK \l "_ENREF_10" \o "Kaufman J, 1997 #3"Kaufman J et al., 1997), and uses extended sections on depression, mania and Attention Deficit Hyperactivity Disorder (ADHD) derived from the Washington University in St Louis K-SADS (WASH-U K-SADS) to elicit detailed information on pre-pubertal mania, rapid-cycling, attentional and sub-threshold bipolar symptoms ADDIN EN.CITE Geller B20014(Geller B, 2001)4417Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL, Delbello MP, Soutullo C, Reliability of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sectionsJournal of the American Academy of Child and Adolescent Psychiatry Journal of the American Academy of Child and Adolescent Psychiatry 450-455402001(HYPERLINK \l "_ENREF_4" \o "Geller B, 2001 #4"Geller B et al., 2001). For participants aged under 21, clinicians completed the Childrens Global Assessment Scale (CGAS). For participants aged between 22 and 30, clinicians completed the Global Assessment Scale (GAS).
Supplementary Table S1. Mean region of interest values per group
Surface Area (cm2)Thickness (mm)Gray Matter Volume (cm3)White Matter Volume (cm3)ControlAt-RiskBipolarControlAt-RiskBipolarControlAt-RiskBipolarControlAt-RiskBipolarMean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD)Mean (SD)Frontal LobeCaudal anterior-cingulate cortex7.14 (1.42)7.60 (1.32)7.31 (1.06)2.85 (0.18)2.92 (0.19)2.875 (0.18)2.26 (0.48)2.46 (0.50)2.31 (0.40)3.01 (0.48)3.17 (0.48)3.07 (0.38)Caudal middle frontal gyrus22.51 (3.44)23.28 (3.72)23.29 (3.41)2.785 (0.13)2.80 (0.14)2.77 (0.13)7.04 (1.15)7.36 (1.31)7.23 (1.16)6.23 (0.97)6.47 (0.97)6.53 (0.87)Lateral orbital frontal cortex26.23 (3.20)27.20 (3.16)27.00 (2.78)3.025 (0.15)3.04 (0.145)2.975 (0.125)8.52 (1.08)8.98 (1.15)8.65 (1.00)6.61 (0.89)6.90 (0.88)6.84 (0.76)Medial orbital frontal cortex18.06 (2.20)18.80 (2.43)18.13 (1.92)2.805 (0.17)2.78 (0.16)2.75 (0.135)5.75 (0.74)5.99 (0.88)5.66 (0.65)3.52 (0.56)3.61 (0.60)3.50 (0.48)Frontal pole2.52 (0.37)2.52 (0.35)2.46 (0.37)3.16 (0.24)3.14 (0.255)3.1 (0.195)1.11 (0.20)1.11 (0.17)1.06 (0.17)0.32 (0.06)0.32 (0.06)0.31 (0.05)Pars opercularis15.54 (2.33)16.21 (2.60)15.85 (1.97)2.87 (0.13)2.88 (0.13)2.85 (0.16)5.05 (0.77)5.32 (1.00)5.07 (0.67)3.54 (0.66)3.54 (0.71)3.67 (0.53)Pars orbitalis7.08 (0.77)7.33 (0.89)7.17 (0.79)3.11 (0.20)3.08 (0.18)3.04 (0.18)2.78 (0.33)2.91 (0.40)2.75 (0.34)1.07 (0.18)1.10 (0.16)1.08 (0.16)Pars triangularis
13.96 (2.45)14.51 (2.21)14.10 (1.56)2.79 (0.17)2.80 (0.16)2.76 (0.12)4.48 (0.84)4.71 (0.86)4.43 (0.49)3.16 (0.60)3.31 (0.52)3.27 (0.40)Rostral anterior cingulate cortex7.59 (1.32)8.19 (1.66)7.86 (0.70)3.23 (0.18)3.18 (0.18)3.18 (0.16)2.77 (0.51)2.96 (0.62)2.81 (0.36)2.37 (0.35)2.50 (0.40)2.50 (0.33)Rostral middle frontal gyrus 58.25 (7.98)60.11 (8.35)59.72 (6.81)2.64 (0.14)2.66 (0.14)2.6
(0.1)18.07 (2.80)18.87 (3.03)18.13 (2.21)12.80 (1.98)13.20 (2.17)13.18 (1.70)Superior frontal gyrus71.12 (8.97)73.38 (8.87)72.58 (7.85)3.07 (0.14)3.06 (0.15)3.03 (0.12)25.07 (3.14)25.95 (3.44)25.13 (2.61)18.02 (2.83)18.51 (2.73)18.67 (2.25)Temporal LobeEntorhinal cortex3.82 (0.66)3.83 (0.67)3.76 (0.62)3.81 (0.25)3.79 (0.23)3.85 (0.26)2.02 (0.33)1.99 (0.35)2.02 (0.27)0.78 (0.18)0.79 (0.15)0.78 (0.14)Parahippocampal gyrus0.69 (0.10)
0.73 (0.11)
0.72 (0.12)
3.09 (0.25)3.075 (0.27)2.98 (0.27)2.47 (0.33)2.56 (0.36)2.44 (0.34)1.71 (0.30)1.81 (0.29)1.81 (0.34)Superior temporal gyrus36.46 (4.04)37.53 (4.41)37.27 (4.26)3.075 (0.14)3.075 (0.16)3.065 (0.16)12.93 (1.65)13.27 (1.96)13.00 (1.53)7.14 (1.10)7.31 (1.12)7.37 (1.00)Temporal pole4.45 (0.45)4.50 (0.55)4.52 (0.49)4.06 (0.22)4.05 (0.21)4.08 (0.12)2.68 (0.29)2.70 (0.29)2.73 (0.26)0.68 (0.11)0.68 (0.11)0.70 (0.11)Transverse temporal gyrus3.99 (0.59)4.05 (0.63)4.12 (0.57)2.60 (0.19)2.65 (0.22)2.57 (0.24)1.16 (0.18)1.19 (0.21)1.16 (0.17)0.73 (0.08)0.74 (0.11)0.76 (0.12)InsulaInsula22.55 (2.93)22.80 (2.75)23.17 (2.63)3.31 (0.15)3.31 (0.15)3.29 (0.12)7.43 (1.01)7.56 (0.94)7.50 (0.83)9.21 (1.22)9.36 (1.07)9.69 (1.12)SubcorticalLateral ventricle N/AN/AN/AN/AN/AN/A5.53 (3.01)5.87 (3.63)5.62 (2.86)N/AN/AN/AInferior lateral ventricleN/AN/AN/AN/AN/AN/A0.20 (0.08)0.19 (0.12)0.20 (0.11)N/AN/AN/ACerebellum cortexN/AN/AN/AN/AN/AN/A17.29 (3.27)17.23 (2.06)16.79 (2.28)N/AN/AN/ACerebellum white matterN/AN/AN/AN/AN/AN/A59.189 (6.92)60.91 (6.96)58.21 (6.11)N/AN/AN/AThalamusN/AN/AN/AN/AN/AN/A7.67 (0.76)7.48 (0.83)7.70 (0.66)N/AN/AN/ACaudateN/AN/AN/AN/AN/AN/A3.81
(0.52)3.87 (0.53)3.71 (0.41)N/AN/AN/APutamenN/AN/AN/AN/AN/AN/A5.68 (0.68)5.85 (0.73)5.78 (0.41)N/AN/AN/APallidumN/AN/AN/AN/AN/AN/A1.68 (0.20)1.69 (0.20)1.66 (0.16)N/AN/AN/AHippocampusN/AN/AN/AN/AN/AN/A4.48 (0.39)4.55 (0.43)4.41
(0.43)N/AN/AN/AAmygdalaN/AN/AN/AN/AN/AN/A1.79 (0.20)1.83 (0.15)1.78 (0.24)N/AN/AN/AAccumbens areaN/AN/AN/AN/AN/AN/A0.69
(0.09)0.72 (0.10)0.70 (0.08)N/AN/AN/A
N/A- not applicable.Group effects significant prior to, but not after, correcting for multiple tests
Prior to correcting for multiple tests and after adjusting for age, gender, and ICV: AR showed increased gray matter volume compared to controls in the lateral orbital frontal cortex, caudal anterior-cingulate cortex, pars orbitalis, and accumbens area (for these ROIs pairwise comparisons were significant in the absence of group effects); BD participants showed increased white matter volume in the rostral anterior cingulate cortex compared to controls; and BD participants showed increased white matter volume in the insula compared to controls and AR participants. When ICV/SA was removed as a covariate, AR participants showed increased white matter volume in the rostral anterior cingulate cortex and parahippocampal surface area compared to controls.
Group x hemisphere interactions significant prior to, but not after, correcting for multiple tests
Prior to correcting for multiple tests and after adjusting for age, gender, and ICV, AR participants showed increased gray matter volume compared to controls, in the left rostral anterior cingulate cortex and right lateral orbital frontal cortex volume. When ICV was removed as a covariate, BD participants showed increased gray matter volume in the lateral orbital frontal cortex compared to controls, and reduced parahippocampal surface area compared to AR participants. A number of within group hemisphere effects were evident where the direction of the difference was generally consistent across groups.
Discussion of ROIs
Prior to correcting for multiple tests, and after adjusting for age, gender, and ICV, compared to controls high-risk participants showed increased grey matter volume in a number of regions (yellow ROIs in Supplementary Fig. S1). These regions deserve further consideration. For example previous studies of individuals at high genetic risk of BD have reported no differences in the grey matter volume of the ACC ADDIN EN.CITE ADDIN EN.CITE.DATA (HYPERLINK \l "_ENREF_7" \o "Hajek, 2008 #5"Hajek et al., 2008, HYPERLINK \l "_ENREF_9" \o "Hajek, 2010 #6"Hajek et al., 2010), whilst others have found a negative correlation between grey matter volume in this region and genetic liability scores for BD in a high-risk cohort ADDIN EN.CITE McDonald20047(McDonald, 2004)7717McDonald, ColmBullmore, Edward TSham, Pak CChitnis, XavierWickham, HarveyBramon, ElviraMurray, Robin MAssociation of Genetic Risks for Schizophrenia and Bipolar DisorderWith Specific and Generic Brain Structural EndophenotypesArchives of General PsychiatryArchives of General Psychiatry974-984611020040003-990X(HYPERLINK \l "_ENREF_13" \o "McDonald, 2004 #7"McDonald et al., 2004). Supporting our finding of increased OFC volume in high-risk subjects, a prospective study of children who converted to bipolar disorder observed a greater increase in OFC volume over time in these individuals than healthy controls ADDIN EN.CITE ADDIN EN.CITE.DATA (HYPERLINK \l "_ENREF_5" \o "Gogtay, 2007 #8"Gogtay et al., 2007).
However, a recent ROI study identified a smaller OFC in bipolar subjects and their unaffected relatives compared to healthy controls ADDIN EN.CITE Eker20149(Eker, 2014)9917