Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

1Major depressive disorder (MDD) is the single most common psychiatric disorder, affecting approximately 350 million people each year. Even so, its pathogenesis and profile of effects in the brain are still not clear. Therefore, in 2013, we initiated the MDD Working Group within the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium (http://enigma.ini.usc.edu/) in which researchers around the world collaborate to boost statistical power to elucidate brain abnormalities in MDD. Recently, we reported subcortical volume differences between MDD patients and healthy controls that were related to clinical characteristics, based on data from 8927 individuals using an individual participant data-based meta-analysis approach. Subcortical volume differences were the greatest in the hippocampus, with the strongest effects in recurrent or early-onset patients. Here we present results on cortical structural differences in an even larger sample (N=10 105).

2With regard to cortical structural abnormalities in MDD, prior magnetic resonance imaging (MRI) studies, summarized in retrospective meta-analyses of individually published works, mainly implicate the (para)limbic circuitry, including dorsomedial prefrontal cortex (PFC), orbitofrontal cortex (OFC) and (rostral) anterior cingulate cortex (ACC), albeit with large variability across studies.,,,, Findings are inconclusive regarding the temporal and lateral PFC., Inconsistencies arise owing to differences in scanning and analysis methods, the limited power to detect subtle effects in small samples and clinical variations in medication status, lifetime disease burden, age at disease onset and adult vs adolescent study samples.

3Differences in data acquisition protocols and processing and differences in statistical analyses performed are a key source of heterogeneity. For example, different techniques for assessing morphometric deficits in MDD are used. Many studies use automated MRI analyses such as voxel-based morphometry, which avoid labour-intensive manual tracings and improve reproducibility. Others use surface-based methods that generate detailed maps of cortical thickness and surface area, which may differ in their underlying cellular mechanisms and genetic control. In addition, retrospective meta-analyses sometimes only include focused or hypothesis-driven studies adopting a region of interest approach (for example, ACC, OFC) with no information on other regions or studies that use coarse or unspecific anatomical regions such as ‘frontal lobe'.,,,,, These approaches may not resolve more subtle or localized patterns of effects.

4Here we addressed some of these issues by performing the largest coordinated worldwide meta-analysis of cortical structural abnormalities in patients diagnosed with MDD relative to healthy controls. We extracted cortical thickness and surface area estimates in 2148 MDD patients and 7957 healthy individuals using harmonized data analysis strategies across all sites. Compared to healthy controls, adult MDD studies generally report cortical thinning, but adolescent MDD studies have reported both cortical thinning and thickening,,, during mid-to-late adolescence. These apparent differences prompted us to analyse adolescent and adult patients separately, with adults defined here as individuals aged >21 years. We set the age cut-off for adult versus adolescent analyses at ⩽21 years, based on 1) evidence of accelerated cortical thinning followed by decelerated thinning in young adulthood during normal brain development and 2) the presence of a positive correlation between depressive symptoms and ventromedial PFC in individuals with MDD up to 22 years old. Additional stratifying variables were single vs recurrent episodes, antidepressant medication use, index episode severity and, in the adult sample, adolescent- vs adult-onset.

5The ENIGMA MDD Working Group currently includes 20 international groups with neuroimaging and clinical data from MDD patients and healthy controls (participating sites are mapped in Supplementary Figure S1). Overall, we analysed data from 10 105 people, including 2148 MDD patients and 7957 healthy controls. Each sample's demographics are detailed in Supplementary Table S1 and clinical characteristics in Supplementary Table S2. Supplementary Table S3 lists exclusion criteria for study enrolment. All participating sites obtained approval from local institutional review boards and ethics committees, and all study participants provided written informed consent.

6Structural T1-weighted MRI brain scans were acquired at each site and analysed locally using harmonized analysis and quality-control protocols from the ENIGMA consortium; in this case, all cortical parcellations were performed with the freely available and validated segmentation software FreeSurfer (versions 5.1 and 5.3). Image acquisition parameters and software descriptions are given in Supplementary Table S4. Segmentations of 68 (34 left and 34 right) cortical gray matter regions based on the Desikan–Killiany atlas and two whole-hemisphere measures were visually inspected and statistically evaluated for outliers following standardized ENIGMA protocols (http://enigma.ini.usc.edu/protocols/imaging-protocols). Further details on image exclusion criteria and quality control may be found in Supplementary Information SI1.

7We examined group differences in cortical thickness and surface area between patients and controls within each sample using multiple linear regression models. In the primary analysis, the outcome measures were from each of 70 cortical regions of interest (68 regions and two whole-hemisphere average thickness or total surface area measures). A binary indicator of diagnosis (0=controls, 1=patients) was the predictor of interest. All models were adjusted for age and sex. Additional covariates were included whenever necessary to control for scanner differences within each sample. To ease comparisons with prior work,, effect size estimates were calculated using Cohen's d metric computed from the t-statistic of the diagnosis indicator variable from the regression models. Similarly, for models testing interactions (that is, sex-by-diagnosis and age-by-diagnosis) a multiplicative predictor was the predictor of interest with the main effect of each predictor included in the model and the effect size was calculated using the same procedure.

8To detect potentially different effects of major depression with age, we separately analysed adolescent (age ⩽21 years) and adult participants (>21 years). Within the adolescent and adult divisions, we tested stratified models that split patients based on stage of illness (first episode vs recurrent). Furthermore, we examined associations between symptom severity at the time of scanning using the 17-item Hamilton Depression Rating Scale (HDRS-17) and the Beck Depression Inventory (BDI-II) and cortical thickness and surface area. Within the adult division, we stratified patients based on age at illness onset (adolescent-onset ⩽21 years; adult-onset >21 years). Results of models that split patients based on antidepressant use at the time of their scan are reported in Supplementary Information SI1. Included samples and total sample sizes for each model are listed in the tables in 'Results' section. Throughout the manuscript, we report P-values corrected for multiple comparisons using the Benjamini–Hochberg procedure to ensure a false-discovery rate (FDR) limited at 5% for 70 measures (34 left hemisphere regions, 34 right hemisphere regions and 2 full-hemisphere measures, for left and right).

9All regression models and effects size estimates were computed at each site separately and a final Cohen's d effect size estimate was obtained using an inverse variance-weighted random-effect meta-analysis model in R (metafor package, version 1.9-118). Only for the meta-analyses on correlation with symptom severity scores and number of episodes in recurrent patients, predictors were treated as continuous variables, so effect sizes were expressed as partial-correlation Pearson's r after removing nuisance variables (age, sex, and scan site). The final meta-analysed partial-correlation r was estimated with the same inverse variance-weighted random-effect meta-analysis model. See Supplementary Information SI1 for full meta-analysis details.

10The methods and results of the moderator analyses, using meta-regression analyses to test whether individual site characteristics explained a significant proportion of the variance in effect sizes across sites in the meta-analyses, are reported in Supplementary Information SI1.

11We found significant and consistent thinner cortices in the frontal and temporal lobes of adult depressed patients (N=1902) compared to controls (N=7658) in the bilateral medial OFC, fusiform gyrus, insula, rostral anterior and posterior cingulate cortex and unilaterally in the left middle temporal gyrus, right inferior temporal gyrus and right caudal ACC (see Figure 1 for significant regions, Supplementary Figure S11 for forest plots and Table 1 for full cortical thickness effects). Regions are listed in all tables in order of effect size, from the strongest to the weakest effect size. None of the regions analysed showed significant differences in cortical surface area (Supplementary Table S19) or evidence of sex-by-diagnosis or age-by-diagnosis interaction effects (Supplementary Tables S5, S6, S20 and S21).

12Adult patients with recurrent depression (N=1302) compared to controls (N=7450) revealed cortical thinning in left medial OFC (Supplementary Figures S2 and S12). First-episode patients (N=535) compared to controls (N=7253) showed more widespread cortical thinning in bilateral fusiform gyrus, rostral ACC and insula and left medial orbitofrontal and superior frontal cortex, right caudal anterior and posterior cingulate cortex and right isthmus cingulate cortex (Supplementary Figures S3 and S13). No differences were detected between recurrent and first-episode patients (Supplementary Table S9). Similar to the overall MDD group analysis, no cortical surface area differences were detected (Supplementary Tables S22–S24), and we found no significant correlations between thickness and surface area and the number of depressive episodes in recurrent patients (N=496; Supplementary Table S10).

13Cortical thinning was observed in patients with an adult age of illness onset (>21 years, N=1214) compared to controls (N=3329) in bilateral insula, rostral anterior, posterior and isthmus cingulate cortex, fusiform gyrus, medial OFC, right caudal ACC and right inferior temporal gyrus (Supplementary Figures S4 and S14). We did not detect significant differences in cortical thickness in patients with an adolescent age of onset (⩽21 years, N=472), compared to controls (N=2885), (Supplementary Table S12) and when comparing adolescent-onset and adult-onset patients directly (Supplementary Table S13). Similarly, no surface area differences were detected in these subgroup analyses (Supplementary Tables S26–S28).

14None of the cortical thickness measurements were correlated with symptom severity at study inclusion using the HDRS-17 (N=776) and BDI-II (N=943) questionnaires (Supplementary Tables S17 and S18). For surface area measurements, no associations were found with the HDRS-17 (Supplementary Table S32) and weak negative correlations were detected for BDI-II scores and surface area of the bilateral precuneus, left frontal pole and left postcentral gyrus (Supplementary Table S33, Supplementary Figures S7 and S17).

15Left and right hemisphere total surface area was smaller in depressed adolescent patients (N=213) compared to adolescent controls (N=294). Regionally, surface area reductions were observed in bilateral lingual gyrus and pericalcarine gyrus, left lateral occipital cortex, left medial OFC, left precentral gyrus, right inferior parietal cortex, right superior frontal gyrus and right postcentral gyrus (see Figure 2 and Supplementary Figure S18 and Table 2 for full tabulation of effects). No cortical thickness differences were detected between adolescent MDD patients and controls (Supplementary Table S34). Further, no cortical regions showed age-by-diagnosis or sex-by-diagnosis interaction effects (Supplementary Tables S35, S36, S45 and S46).

16Adolescents with recurrent depression (N=104) showed reductions in left and right hemisphere overall surface area compared to controls (N=142). Regionally, surface area reductions were observed in bilateral inferior parietal cortex and caudal middle frontal gyrus and left fusiform gyrus, left lateral occipital cortex, left precuneus, left superior parietal cortex, left medial OFC, right banks of the superior temporal sulcus, right lingual gyrus, right pericalcarine gyrus and right postcentral gyrus (Supplementary Figures S8 and S19, Supplementary Table S48). First-episode patients (N=80) showed no detectable differences, when compared to controls (N=154) or the recurrent adolescent MDD group (Supplementary Tables S47 and S49). No cortical thickness differences were found in adolescent MDD for first-episode or recurrence subgroups (Supplementary Tables S37–S39); similarly, no correlations with the number of episodes were detected for surface area or thickness in recurrent adolescent MDD patients (Supplementary Tables S40 and S50).

17We did not detect significant differences in cortical thickness or surface area when examining the effects of symptom severity at study inclusion using the HDRS-17 (N=134) questionnaire (Supplementary Tables S44 and S54), whereas BDI-II scores were available only for a small group of adolescent patients (N=31), precluding meaningful comparisons.

18Results of the moderator analyses can be found in the Supplementary Information.

19In the largest analysis to date of cortical structural measures, we applied an individual participant data-based meta-analytic approach to brain MRI data from >10 000 people, of whom around one-fifth were affected by MDD. We found significant differences in cortical brain structures in adolescent and adult MDD and specific associations with clinical characteristics.

20Adult MDD patients had cortical thickness deficits in 13 (of 68) regions examined. Cortical thinning was generally observed bilaterally, in regions that encompassed the medial PFC, rostral anterior and posterior cingulate cortex, insula and fusiform gyrus. Unilateral effects were observed in left middle temporal gyrus and right inferior temporal and right caudal ACC. Our findings of lower cortical thickness in medial PFC and ACC are consistent with prior meta-analyses.,,,,, Our findings extend previous findings by demonstrating structural abnormalities in the temporal lobe (middle and inferior temporal and fusiform gyri), posterior cingulate cortex and insula. The large sample also adds to our understanding of how reproducible and consistent these effects are likely to be when surveying cohorts worldwide.

21A key feature of these regions is their close interaction with the limbic system, consistent with the general pathophysiological model of MDD that posits dysfunctional limbic–cortical circuits., The dorsal and rostral ACC are functionally heterogeneous, supporting task monitoring, conflict detection, emotion regulation, social cognition and executive functions. The insular cortex is similarly multifunctional and engaged in visceroception, autonomic response regulation and attentional switches (for example, Menon and Uddin). These regions show consistent structural differences in this cross-sectional morphometric study that may contribute to the broad spectrum of emotional, cognitive and behavioural disturbances observed in MDD.

22Although effect sizes were relatively small (d −0.08 to −0.13, percentage of difference −0.5% to −1.3%, with overall low-to-medium heterogeneity among studies; that is, I2 for most regions between 0% and 50%) and in the range of previously reported hippocampal volume reduction, the medial OFC showed the largest effect sizes (d −0.13, percentage of difference −1.1%). The lower medial wall of the PFC (medial OFC according to the Desikan–Killiany atlas in FreeSurfer) contains the subgenual ACC (sgACC), subcallosal gyrus and medial OFC and has dense connections to the hypothalamus as the primary site of stress response regulation. These findings concur with postmortem findings of OFC structural deficits, OFC/sgACC-specific volumetric meta-analyses,, correlations between OFC thickness and cortisol levels and evidence of functional derangement of the sgACC in depression. Recently, right medial OFC thickness measured at baseline in healthy adolescent girls proved a strong predictor of the onset of depression in a multivariate model. The ventromedial PFC and OFC (including the sgACC) are critically involved in reinforcement learning, fear responsiveness and the adaptive control of emotions, which are disturbed in MDD, and have been associated with both a non-response to therapy, and a more unfavourable course of the illness. Distinct from our hippocampal volume finding, these effects were detectable already in first-episode patients with a medial OFC/ACC and insular focus, indifferent from recurrent patients who showed less widespread changes compared to controls. Further, no correlations with the number of episodes and no age-by-diagnosis effects were detected. Although these observations are based on cross-sectional data, we add to limited and conflicting reports of longitudinal volumetric changes in MDD, which suggest that progressive cortical abnormalities with growing disease load does not appear to be a general feature of depression.

23With regard to age at onset, no significant differences were found between adult patients with an adolescent-onset (⩽21 years) and controls. In contrast, adult-onset was associated with significant cortical thinning in numerous frontal, cingulate and temporal regions. Interestingly, our prior work showed hippocampal volume alterations in adolescent-onset but not adult-onset patients. This result may suggest differential effects of stress-related remodelling or interactions with brain maturational mechanisms at different periods of disease onset. Cortical structural deficits were not found in adolescent-onset adult patients. This, however, may in part be due to lower statistical power in the smaller adolescent-onset compared with the adult-onset patient samples (N=472 vs N=1214). In addition, the lack of effects could perhaps be explained by the fact that adolescent-onset patients were younger than the adult-onset groups. Hence, greater cortical thinning in MDD may be more pronounced in adult-onset patients if the disease effects interact with increased aging of the brain,, but see also Truong et al. Following this logic, we performed a post-hoc moderator analysis examining the effects of mean age of patients in each sample on cortical thickness differences between adolescent-onset (adult) patients and controls. Samples with a higher mean age of patients indeed showed greater cortical thinning in the adolescent-onset group compared with controls (Supplementary Figure S22). Though not robust to conservative correction for multiple comparisons (trend-level PFDR=0.09 for the left medial OFC), this pattern fits the lack of detected thickness differences in our adolescent MDD vs adolescent controls analysis. Prior studies have reported mixed results with regard to cortical abnormalities in adolescent MDD, showing increased,, decreased,, or no differences in cortical thickness. Cortical thickness decreases linearly during adolescence,,, owing to synaptic pruning, myelination and other remodelling effects. In adolescent MDD, anxious and depressed symptoms have been associated with greater cortical thickness. In contrast, our current results and prior reports,,,,, provide consistent evidence for cortical thinning in adult MDD. These opposite effects would suggest a delay in maturation (that is, delay in thinning) of cortical thickness in adolescent MDD, resulting in greater cortical thickness during various stages of brain maturation but thinner cortex eventually. A possible explanation for the lack of cortical thickness effects in the current study is that 70% of our adolescents were 18–21 years, perhaps older than the most sensitive period to detect maturation delays., Of note, although not significant, the left lateral OFC showed a medium effect size (d −0.31, percentage of difference −1.9%) for cortical thinning in adolescent MDD compared to controls, whereas cortical alterations in other regions were less clear.

24Adult MDD patients showed no surface area abnormalities compared to controls. However, adolescent patients revealed smaller left and right hemisphere total surface areas, reflecting a diffuse pattern of local surface area deficits (effect sizes d between −0.31 to −0.42, percentage of difference −3.3 to −5.9%). Similar to cortical thickness alterations in adult MDD we observed surface area deficits in medial OFC and superior frontal gyrus, but also in primary and higher order visual, somatosensory and motor areas. These deficits were observed in recurrent patients, suggesting a negative effect of multiple episodes.

25Cortical thinning starts from 2 to 4 years of age and continues across the lifespan, but overall cortical surface area follows a nonlinear and nonmonotonic developmental trajectory. The cortical surface expands until about 12 years, remains relatively stable and then decreases with age.,,, Development of cortical thickness and surface area are genetically independent and result from different neurobiological processes, representing distinct features of cortical development and aging. Cortical surface area abnormalities were not detected in our early-onset adult MDD patients, despite greater statistical power than for the adolescent analyses, so smaller cortical surface area in adolescent MDD may indicate delayed cortical maturation (that is, delayed expansion). Some regions with surface area abnormalities, including medial occipital regions (lingual gyrus), inferior parietal cortex, precentral gyrus, medial OFC and superior frontal gyrus, mature over a more prolonged time course during adolescence, and may be especially prone to a delay in maturation in adolescent MDD. Such delayed maturation may alter functional connections with other regions through decreases in growth and branching of dendritic trees and the number of synapses associated with gray matter volume, which may persist into adult MDD even if surface area measures normalize when transitioning into adulthood. The absence of cortical surface area abnormalities in the adult MDD patients with an early age of onset of depression could indicate such normalization; importantly, however, we still detected weak negative associations between severity of depressive symptoms and bilateral precuneus, left frontal pole and left postcentral gyrus surface area.

26To our knowledge, alterations in cortical surface area abnormalities have not been evaluated in adolescents with MDD. Surface area deficits of the ventromedial PFC and precuneus in children and adolescents have been associated with higher anxiety, of the lingual and temporal gyri in children with childhood maltreatment, of prefrontal regions in children experiencing early life adversity and of the OFC in adolescents with conduct disorder. Importantly, early life stress, symptoms of anxiety and externalizing problems in childhood and early adolescence are all risk factors for early-onset MDD.,

27Cortical thickness and surface area abnormalities were mainly observed in first-episode MDD and adolescent MDD, respectively; this may indicate that cortical alterations are a feature of more heterogeneous MDD samples, including adolescent and first-episode adult MDD individuals who may go on to other outcomes, including bipolar or psychotic disorders, instead of adult MDD samples with a more 'pure' depressive phenotype (in our study characterized by recurrent MDD and adult MDD with an adolescent-onset of depression in whom the illness is confirmed over time). Indeed, lower surface areas in many of the same regions we observed in adolescent MDD in the current study were prospectively predictive of poor functional outcomes in young people with a clinically defined risk of developing psychosis. Similar analyses currently underway in the ENIGMA Schizophrenia and ENIGMA Bipolar Disorder working groups may clarify whether regional cortical surface area and thickness are altered to a greater extent in individuals with schizophrenia and bipolar disorder than the alterations we observed in (adult) MDD. Nonetheless, prospective studies are needed to confirm this heterogeneity hypothesis.

28We did not adjust the regional comparisons for average thickness or total surface, respectively, as our main question was directed towards regional MDD-related changes instead of identifying regional effects that exceed a global effect. In contrast to surface area measures, which are highly associated with global measures of the brain (for example, intracranial volume, as a proxy for overall brain size), cortical thickness does not scale proportionately with brain size. In the current study, global deficits in cortical surface area (indicated by smaller left and right total surface area) were observed in adolescents with MDD. Therefore, our surface area results need to be interpreted as a diffuse, global surface deficit in adolescent MDD, with potential additional regional accentuation.

29Furthermore, we used a ⩽21-year cutoff for adolescent vs adult MDD (cf. 'Introduction' section) consistent with our previous work. Definitions of adolescent MDD in the literature are not consistent, so alternative definitions might yield different results. Ideally, age and age of onset effects on brain abnormalities in MDD should be examined using a dimensional approach. However, in the current meta-analysis the statistical analyses were performed within each site, precluding this approach as few samples covered the entire lifespan. In addition, the age distribution of the adolescents (9% between 12 and 16 years, 21% between 16 and 18 years, 70% ⩾18 years) and the limited adolescent sample size (while larger than prior reports) may not be ideally sensitive to detect age-by-diagnosis interaction and cortical thickness effects. Future addition of more adolescent MDD samples to reflect a balanced age distribution may aid in detecting cortical changes associated with MDD at different stages of brain development.

30In addition, when combining already collected data across worldwide samples, data collection protocols are not prospectively harmonized. Imaging acquisition protocols and clinical assessments therefore differed across studies, which limits analysis of sources of heterogeneity. The current study did not allow a reliable investigation of antidepressant medication effects on cortical structure because of its cross-sectional design and lack of detailed information on history, duration and type and dosage of antidepressant treatment. Still, in Supplementary Information SI1 we report on comparisons between patients taking antidepressant, antidepressant-free patients and controls. Adult patients using antidepressants showed robust and widespread effects of cortical thinning, whereas non-users showed cortical thinning only in the left medial OFC. However, this cross-sectional finding should not be interpreted as contradicting generally observed neuroprotective effects of antidepressants. It is likely confounded by clinical standards recommending antidepressant use mainly for severe or chronic MDD. In adolescent MDD patients, surface area deficits were observed in antidepressant-free patients and not in adolescents taking antidepressants. Clearly, intervention studies with preantidepressant and postantidepressant treatment comparisons of antidepressants are required to draw valid conclusions on the impact of antidepressant use on cortical structure.

31Cortical structure is abnormal in numerous brain regions in adult and adolescent MDD. Medial OFC was consistently implicated across analyses—in adults, adolescents and analyses of clinical correlations. This finding reinforces the hypothesized prominent role of this region in depression throughout life. Other than subcortical volumetric effects, cortical thickness changes were robustly detectable in adult patients at their first episode. MDD may dynamically impact cortical development, and vice versa, with different patterns of alterations at different stages of life. Cortical thickness measurements showed greater differences than surface area measures in adult MDD, but consistent surface area deficits were found in adolescent MDD. Cortical thickness and surface area represent distinct morphometric features of the cortex and may be differentially affected by depression at various stages of life. Future (longitudinal) studies are needed to examine dynamic changes in the cortical regions we examined here and to relate such changes to symptom profiles, outcomes and treatment responses in MDD.