Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 23 (4), 932-942

Cortical Abnormalities in Bipolar Disorder: An MRI Analysis of 6503 Individuals From the ENIGMA Bipolar Disorder Working Group

D P Hibar  1   2 L T Westlye  3   4   5 N T Doan  3   4 N Jahanshad  1 J W Cheung  1 C R K Ching  1   6 A Versace  7 A C Bilderbeck  8 A Uhlmann  9   10 B Mwangi  11 B Krämer  12 B Overs  13 C B Hartberg  3 C Abé  14 D Dima  15   16 D Grotegerd  17 E Sprooten  18 E Bøen  19 E Jimenez  20 F M Howells  9 G Delvecchio  21 H Temmingh  9 J Starke  9 J R C Almeida  22 J M Goikolea  20 J Houenou  23   24 L M Beard  25 L Rauer  12 L Abramovic  26 M Bonnin  20 M F Ponteduro  16 M Keil  27 M M Rive  28 N Yao  29   30 N Yalin  31 P Najt  32 P G Rosa  33   34 R Redlich  17 S Trost  27 S Hagenaars  35 S C Fears  36   37 S Alonso-Lana  38   39 T G M van Erp  40 T Nickson  35 T M Chaim-Avancini  33   34 T B Meier  41   42 T Elvsåshagen  3   43 U K Haukvik  3   44 W H Lee  18 A H Schene  45   46 A J Lloyd  47 A H Young  31 A Nugent  48 A M Dale  49   50 A Pfennig  51 A M McIntosh  35 B Lafer  33 B T Baune  52 C J Ekman  14 C A Zarate  48 C E Bearden  53   54 C Henry  23   55 C Simhandl  56 C McDonald  32 C Bourne  8   57 D J Stein  9   10 D H Wolf  25 D M Cannon  32 D C Glahn  29   30 D J Veltman  58 E Pomarol-Clotet  38   39 E Vieta  20 E J Canales-Rodriguez  38   39 F G Nery  33   59 F L S Duran  33   34 G F Busatto  33   34 G Roberts  60 G D Pearlson  29   30 G M Goodwin  8 H Kugel  61 H C Whalley  35 H G Ruhe  8   28   62 J C Soares  11 J M Fullerton  13   63 J K Rybakowski  64 J Savitz  42   65 K T Chaim  66   67 M Fatjó-Vilas  38   39 M G Soeiro-de-Souza  33 M P Boks  26 M V Zanetti  33   34 M C G Otaduy  66   67 M S Schaufelberger  33   34 M Alda  68 M Ingvar  14   69 M L Phillips  7 M J Kempton  16 M Bauer  51 M Landén  14   70 N S Lawrence  71 N E M van Haren  26 N R Horn  9 N B Freimer  72 O Gruber  12 P R Schofield  13   63 P B Mitchell  60 R S Kahn  26 R Lenroot  13   73 R Machado-Vieira  33   74 R A Ophoff  26   72 S Sarró  38   39 S Frangou  18 T D Satterthwaite  25 T Hajek  68   75 U Dannlowski  17 U F Malt  76   77 V Arolt  17 W F Gattaz  33 W C Drevets  78 X Caseras  79 I Agartz  3   19 P M Thompson  1 O A Andreassen  3   4
Affiliations

Cortical Abnormalities in Bipolar Disorder: An MRI Analysis of 6503 Individuals From the ENIGMA Bipolar Disorder Working Group

D P Hibar et al. Mol Psychiatry.

Abstract

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Conflict of interest statement

AMM has received funding from Lilly, Janssen and Pfizer. It is unconnected with the current work. TvE has a contract with Otsuka Pharmaceutical Inc. The contract is not related to this work. UFM participated in the speaker’s bureau for Lundbeck Norway and was a consultant for Takeda Pharmaceuticals. ACB has received salaries from P1vital Ltd, which is unrelated to this work. PGR trained personnel for Janssen Pharmaceuticals. It is unconnected with the current work. DPH and WCD are employed by Janssen Research and Development, LLC. MB has received grant/research support from Deutsche Forschungsgemeinschaft (DFG), Bundesministeriums für Bildung und Forschung (BMBF), American Foundation of Suicide Prevention. MB is/has been a consultant for AstraZeneca, Bristol Myers Squibb, Ferrer Internacional, Janssen, Lilly, Lundbeck, Merz, Neuraxpharm, Novartis, Otsuka, Servier, Takeda, and has received speaker honoraria from AstraZeneca, GlaxoSmithKline, Lilly, Lundbeck, Otsuka and Pfizer, which is all unrelated to this work. OAA has received speaker’s honorarium from Lundbeck, Otsuka and Lilly. The remaining authors declare no conflicts of interest. All authors have contributed to and approved the contents of this manuscript.

Figures

Figure 1
Figure 1
Cortical thinning in adult patients with bipolar disorder compared with healthy controls. Cohen’s d effect sizes are plotted for each region of interest on the cortical surface of a template image. Only significant regions are shown; non-significant regions are colored in gray.
Figure 2
Figure 2
Cortical thinning in adult patients with bipolar disorder associated with duration of illness. Pearson’s correlation r effect sizes are plotted for each region of interest on the cortical surface of a template image. Only significant regions are shown; non-significant regions are colored in gray.
Figure 3
Figure 3
Cortical thickening in adult patients with bipolar disorder associated with lithium treatment. Cohen’s d effect sizes are plotted for each region of interest on the cortical surface of a template image. Only significant regions are shown; non-significant regions are colored in gray.
Figure 4
Figure 4
Cortical thinning in adult patients with bipolar disorder associated with antiepileptic treatment. Cohen’s d effect sizes are plotted for each region of interest on the cortical surface of a template image. Only significant regions are shown; non-significant regions are colored in gray.

Similar articles

See all similar articles

Cited by 53 articles

  • ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.
    Thompson PM, Jahanshad N, Ching CRK, Salminen LE, Thomopoulos SI, Bright J, Baune BT, Bertolín S, Bralten J, Bruin WB, Bülow R, Chen J, Chye Y, Dannlowski U, de Kovel CGF, Donohoe G, Eyler LT, Faraone SV, Favre P, Filippi CA, Frodl T, Garijo D, Gil Y, Grabe HJ, Grasby KL, Hajek T, Han LKM, Hatton SN, Hilbert K, Ho TC, Holleran L, Homuth G, Hosten N, Houenou J, Ivanov I, Jia T, Kelly S, Klein M, Kwon JS, Laansma MA, Leerssen J, Lueken U, Nunes A, Neill JO, Opel N, Piras F, Piras F, Postema MC, Pozzi E, Shatokhina N, Soriano-Mas C, Spalletta G, Sun D, Teumer A, Tilot AK, Tozzi L, van der Merwe C, Van Someren EJW, van Wingen GA, Völzke H, Walton E, Wang L, Winkler AM, Wittfeld K, Wright MJ, Yun JY, Zhang G, Zhang-James Y, Adhikari BM, Agartz I, Aghajani M, Aleman A, Althoff RR, Altmann A, Andreassen OA, Baron DA, Bartnik-Olson BL, Marie Bas-Hoogendam J, Baskin-Sommers AR, Bearden CE, Berner LA, Boedhoe PSW, Brouwer RM, Buitelaar JK, Caeyenberghs K, Cecil CAM, Cohen RA, Cole JH, Conrod PJ, De Brito SA, de Zwarte SMC, Dennis EL, Desrivieres S, Dima D, Ehrlich S, Esopenko C, Fairchild G, Fisher SE, Fouche JP, Francks C, Frangou S, Franke B, Garavan HP, Glahn DC, Groenewold NA, Gurholt TP, Gutman BA, Hahn T, Harding IH, Hernaus D, Hibar DP, Hillary FG, Hoogman M, Hulshoff Pol HE, Jalbrzikowski M, Karkashadze GA, Klapwijk ET, Knickmeyer RC, Kochunov P, Koerte IK, Kong XZ, Liew SL, Lin AP, Logue MW, Luders E, Macciardi F, Mackey S, Mayer AR, McDonald CR, McMahon AB, Medland SE, Modinos G, Morey RA, Mueller SC, Mukherjee P, Namazova-Baranova L, Nir TM, Olsen A, Paschou P, Pine DS, Pizzagalli F, Rentería ME, Rohrer JD, Sämann PG, Schmaal L, Schumann G, Shiroishi MS, Sisodiya SM, Smit DJA, Sønderby IE, Stein DJ, Stein JL, Tahmasian M, Tate DF, Turner JA, van den Heuvel OA, van der Wee NJA, van der Werf YD, van Erp TGM, van Haren NEM, van Rooij D, van Velzen LS, Veer IM, Veltman DJ, Villalon-Reina JE, Walter H, Whelan CD, Wilde EA, Zarei M, Zelman V; ENIGMA Consortium. Thompson PM, et al. Transl Psychiatry. 2020 Mar 20;10(1):100. doi: 10.1038/s41398-020-0705-1. Transl Psychiatry. 2020. PMID: 32198361 Free PMC article. Review.
  • Morphometry and gyrification in bipolar disorder and schizophrenia: A comparative MRI study.
    Madeira N, Duarte JV, Martins R, Costa GN, Macedo A, Castelo-Branco M. Madeira N, et al. Neuroimage Clin. 2020 Feb 19;26:102220. doi: 10.1016/j.nicl.2020.102220. Online ahead of print. Neuroimage Clin. 2020. PMID: 32146321 Free PMC article.
  • Structural abnormality in schizophrenia versus bipolar disorder: A whole brain cortical thickness, surface area, volume and gyrification analyses.
    Madre M, Canales-Rodríguez EJ, Fuentes-Claramonte P, Alonso-Lana S, Salgado-Pineda P, Guerrero-Pedraza A, Moro N, Bosque C, Gomar JJ, Ortíz-Gil J, Goikolea JM, Bonnin CM, Vieta E, Sarró S, Maristany T, McKenna PJ, Salvador R, Pomarol-Clotet E. Madre M, et al. Neuroimage Clin. 2020;25:102131. doi: 10.1016/j.nicl.2019.102131. Epub 2019 Dec 13. Neuroimage Clin. 2020. PMID: 31911343 Free PMC article.
  • Mechanisms Underlying the Hyperexcitability of CA3 and Dentate Gyrus Hippocampal Neurons Derived From Patients With Bipolar Disorder.
    Stern S, Sarkar A, Stern T, Mei A, Mendes APD, Stern Y, Goldberg G, Galor D, Nguyen T, Randolph-Moore L, Kim Y, Rouleau G, Bang A, Alda M, Santos R, Marchetto MC, Gage FH. Stern S, et al. Biol Psychiatry. 2019 Oct 1:S0006-3223(19)31743-3. doi: 10.1016/j.biopsych.2019.09.018. Online ahead of print. Biol Psychiatry. 2019. PMID: 31732108
  • Genetic Predisposition and Disease Expression of Bipolar Disorder Reflected in Shape Changes of the Anterior Limbic Network.
    Lu CF, Wu YT, Teng S, Wang PS, Tu PC, Su TP, Jao CW, Li CT. Lu CF, et al. Brain Sci. 2019 Sep 19;9(9):240. doi: 10.3390/brainsci9090240. Brain Sci. 2019. PMID: 31546815 Free PMC article.
See all "Cited by" articles

References

    1. Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry 2011; 68: 241–251. - PMC - PubMed
    1. Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet 2016; 387: 1561–1572. - PubMed
    1. McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003; 60: 497–502. - PubMed
    1. Wray NR, Gottesman II. Using summary data from the danish national registers to estimate heritabilities for schizophrenia, bipolar disorder, and major depressive disorder. Front Genet 2012; 3: 118. - PMC - PubMed
    1. Calabrese JR, Rapport DJ, Kimmel SE, Shelton MD. Controlled trials in bipolar I depression: focus on switch rates and efficacy. Eur Neuropsychopharmacol 1999; 9(Suppl 4): S109–S112. - PubMed

Publication types

MeSH terms

Feedback