Altered orbitofrontal sulcogyral patterns in gambling disorder: a multicenter study

Gambling disorder is a serious psychiatric condition characterized by decision-making and reward processing impairments that are associated with dysfunctional brain activity in the orbitofrontal cortex (OFC). However, it remains unclear whether OFC functional abnormalities in gambling disorder are accompanied by structural abnormalities. We addressed this question by examining the organization of sulci and gyri in the OFC. This organization is in place very early and stable across life, such that OFC sulcogyral patterns (classified into Types I, II, and III) can be regarded as potential pre-morbid markers of pathological conditions. We gathered structural brain data from nine existing studies, reaching a total of 165 individuals with gambling disorder and 159 healthy controls. Our results, supported by both frequentist and Bayesian statistics, show that the distribution of OFC sulcogyral patterns is skewed in individuals with gambling disorder, with an increased prevalence of Type II pattern compared with healthy controls. Examination of gambling severity did not reveal any significant relationship between OFC sulcogyral patterns and disease severity. Altogether, our results provide evidence for a skewed distribution of OFC sulcogyral patterns in gambling disorder and suggest that pattern Type II might represent a pre-morbid structural brain marker of the disease. It will be important to investigate more closely the functional implications of these structural abnormalities in future work.Y.L. was supported by the National Natural Science Foundation of China (Grant No. 31600929) and the Fundamental Research Funds for the Central Universities (010914380002). G.S. was supported by a Veni grant from the Netherlands Organization for Scientific Research (Grant No. 016.155.218). J.J. was supported by the Academy of Finland (Grant No. 295580), the Finnish Medical Foundation, and the Finnish Foundation for Alcohol Studies. V.K. was supported by the Academy of Finland (Grant No. 256836) and the Finnish Foundation for Alcohol Studies. S.G. and H.R.S. were supported by the Danish Council for Independent Research in Social Sciences through a grant to Thomas Ramsøy (“Decision Neuroscience Project”; Grant No. 0601-01361B) and by the Lundbeck Foundation through a Grant of Excellence (“ContAct”; Grant No. R59 A5399). A.G. was supported by Deutsche Forschungsgemeinschaft (DFG) HE2597/15–1, HE2597/15–2, and DFG Graduiertenkolleg 1589/2 “Sensory Computation in Neural Systems”. N.R.-S. was supported by a research grant by the Senatsverwaltung für Gesundheit und Soziales, Berlin, Germany (Grant No. 002–2008/I B 35). C.M.R.d.L. and J.C.P. were supported by a grant from the Spanish Government (Ministerio de Economía y Competitividad, Secretaría de Estado de Investigación, Desarrollo e Innovación; Convocatoria 2017 de Proyectos I+D de Excelencia, Spain; co-funded by the Fondo Europeo de Desarrollo Regional, FEDER, European Union; Grant No. PSI2017–85488-P). J.-C. D. was supported by “LABEX ANR-11-LABEX-0042” of Université de Lyon within the program Investissements d’Avenir (ANR-11-IDEX-007) operated by the French National Research Agency and by a grant from the Fondation pour la Recherche Médicale (Grant No. DPA20140629796)

Cortisol, cognition and the ageing prefrontal cortex

The structural and functional decline of the ageing human brain varies by brain region, cognitive function and individual. The underlying biological mechanisms are poorly understood. One potentially important mechanism is exposure to glucocorticoids (GCs; cortisol in humans); GC production is increasingly varied with age in humans, and chronic exposure to high levels is hypothesised to result in cognitive decline via cerebral remodelling. However, studies of GC exposure in humans are scarce and methodological differences confound cross-study comparison. Furthermore, there has been little focus on the effects of GCs on the frontal lobes and key white matter tracts in the ageing brain. This thesis therefore examines relationships among cortisol levels, structural brain measures and cognitive performance in 90 healthy, elderly community-dwelling males from the Lothian Birth Cohort 1936. Salivary cortisol samples characterised diurnal (morning and evening) and reactive profiles (before and after a cognitive test battery). Structural variables comprised Diffusion Tensor Imaging measures of major brain tracts and a novel manual parcellation method for the frontal lobes. The latter was based on a systematic review of current manual methods in the context of putative function and cytoarchitecture. Manual frontal lobe brain parcellation conferred greater spatial and volumetric accuracy when compared to both single- and multi-atlas parcellation at the lobar level. Cognitive ability was assessed via tests of general cognitive ability, and neuropsychological tests thought to show differential sensitivity to the integrity of frontal lobe sub-regions. The majority of, but not all frontal lobe test scores shared considerable overlap with general cognitive ability, and cognitive scores correlated most consistently with the volumes of the anterior cingulate. This is discussed in light of the diverse connective profile of the cingulate and a need to integrate information over more diffuse cognitive networks according to proposed de-differentiation or compensation in ageing. Individuals with higher morning, evening or pre-test cortisol levels showed consistently negative relationships with specific regional volumes and tract integrity. Participants whose cortisol levels increased between the start and end of cognitive testing showed selectively larger regional volumes and lower tract diffusivity (correlation magnitudes <.44). The significant relationships between cortisol levels and cognition indicated that flatter diurnal slopes or higher pre-test levels related to poorer test performance. In contrast, higher levels in the morning generally correlated with better scores (correlation magnitudes <.25). Interpretation of all findings was moderated by sensitivity to type I error, given the large number of comparisons conducted. Though there were limited candidates for mediation analysis, cortisol-function relationships were partially mediated by tract integrity (but not sub-regional frontal volumes) for memory and post-error slowing. This thesis offers a novel perspective on the complex interplay among glucocorticoids, cognition and the structure of the ageing brain. The findings suggest some role for cortisol exposure in determining age-related decline in complex cognition, mediated via brain structure