In the current study, we sought to determine whether MDD was associated with differences in subcortical grey matter volume or white matter integrity in a large imaging dataset from a single scanner of more than 8000 people, and among them over 1000 were included as cases and controls in the analyses for the present study. The sample sizes of MDD cases and controls included in the analysis of white matter integrity is by far the largest to our knowledge. Also, the present study considered two important brain structural modalities in two highly overlapping samples. Whilst we did not find any statistically significant subcortical volumetric differences between unaffected participants and individuals with probable MDD (using any of the definitions with increasing severity), we did find substantial evidence of reduced white matter integrity in MDD. This was seen globally, in two of the three categories of tracts (association/commissural fibres and thalamic radiation tracts), and in individual tracts (bilateral superior thalamic radiation, forceps major and left superior longitudinal fasciculus). Similar patterns of findings were seen for both principal and recurrent definition of depression with generally greater effect sizes in recurrent cases, with the exception of the localised differences in the superior thalamic radiation and forceps major.

Our study notably did not find evidence for bilateral hippocampal volume reduction as previously reported in the large collaborative meta-analysis of MDD19. We also did not find evidence of reductions in hippocampal volume when looking at recurrent MDD as published in the same study. The lack of subcortical volumetric differences associated with probable MDD diagnoses in the current study therefore does not support the widely held belief that there are subcortical volumetric changes associated with the disorder. There are several potential explanations for this. Firstly, the UK Biobank dataset included only community-dwelling, ambulant individuals who could independently complete the health and cognitive assessments, and attend the follow-up imaging assessments. This approach arguably selected MDD groups that were more well/better functioning but equally more representative of the general population than purely clinically ascertained samples. We also used a composite ‘probable’ MDD diagnosis that was based on self-report symptoms and hospital admission statistics, and the cases were selected based on self-report lifetime experience of probable depression. In contrast, many other studies previously used a structured clinical interview schedule, such as the Structured Clinical Interview for DSM-IV (SCID), to define MDD according to standard criteria. Some studies have specifically studied people who were certainly experiencing depression at the time of imaging assessment33. Whilst the probable MDD definitions used in the current paper were not based on an interview, they showed many of the same epidemiological and risk-factor associations as clinically defined cases22, 34.

Although we do not report subcortical volume differences, we did find substantive evidence for robust deficits in both global and local white matter integrity. We found that MDD patients had global loss of FA which was also found to be reduced in association and commissural fibres as well as in thalamic radiations, but not in projection fibres. FA in these structures was also more severely reduced in the recurrent MDD patients. The above results indeed reflect findings from previous small-sample and meta-analytic studies17, 35, 36, while extending them to a more generalizable population-based cohort excluding potential methodological confounds as associated with the previous studies. A previous meta-analytic study that compared 231 MDD patients with 261 healthy participants found reduced FA in inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, posterior thalamic radiation and corpus callosum, which belong to the association/commissural fibres and thalamic radiations17. Following the above study, another two recent meta-analyses found integrity reductions in the same categories, i.e. dorsal lateral PFC area, commissural fibres35, 37. The global loss of FA in these regions could be the result of general neurodevelopmental alterations in MDD patients38, and findings within defined subsets of white matter tracts could reflect the neurological basis of MDD as a disconnection within an integrated network of cortex-cortex and cortical-limbic pathways39. The general FA reductions in groups of tracts is also consistent with findings from resting-state fMRI studies, which reported abnormalities in MDD populations in regional networks rather than just individual regions or structures6, 40. The networks that derive from prefrontal cortex and thalamus has been found largely contribute to emotional and social cognition processes38. The reduced integrity in these groups of tracts may therefore reflect the repeatedly found impairment of emotion regulation41, 42, reward processing43 and executive control44 in MDD populations.

In the tests of single white matter tracts, we found significantly altered integrity in left superior longitudinal fasciculus and superior thalamic radiation both in the overall MDD population and recurrent MDD patients. Reduction of left superior longitudinal fasciculus was notably larger in recurrent MDD patients. Reduction of integrity in forceps major was also found in MDD compared with healthy subjects, however showed no specific change of FA in recurrent MDD.

Superior longitudinal fasciculus, as a part of association fibres, connects prefrontal cortex and other lobes45. Small-sample studies have specifically reported reduced integrity in superior longitudinal fasciculus in various depressive samples, including elderly patients with depression38, 46, depressive adolescents47 and adolescents with familial risk for depression45, compared with controls. Meta-analytic studies35, 48 and a review36 also ascertained that the reduction of white matter integrity specifically in superior longitudinal fasciculus may be an important biomarker of the presence of depression. A recent study combined genetic and neuroimaging techniques found that people with higher polygenic risk of depression have greater loss of FA in superior longitudinal fasciculus49, suggesting that it may also therefore be a useful trait-related marker of risk. Loss of integrity in superior longitudinal fasciculus has also previously been reported to be associated with various cognitive dysfunctions, like working memory50 and attention48. Severity of depressive symptoms was also found correlate with FA loss in superior longitudinal fasciculus51. There is increasingly convincing evidence therefore that reduced integrity in superior longitudinal fasciculus might be an important feature of the neurobiology of MDD and may underlie impaired emotional process and cognitive abilities in MDD population18.

Another strength of the present study is that cross-modality assessment was conducted on both subcortical volumes and white matter integrity. Though the findings were largely found in white matter integrity instead of subcortical volumes, this is consistent with another cross-modality study by Sexton et al.16, which presented that no significant group difference was found between late-life depression and healthy control, whereas white matter integrity was reduced in many regions16. Another study on 358 people similarly found that depressive symptoms of elderly subjects also showed significant deficit in white matter, but not in grey matter measures52. The age range for the present study is from 40 to 70, which covers a notable range of elderly participants. This feature of our sample could be the reason why it showed similar contrast of findings between white matter and grey matter measurements.

Potential limitations of the current study should be considered, these include the absence of a face-to-face structured diagnostic interview schedule and the lack of hospital-based sampling. The large sample size may, however, overcome some of these difficulties and community based population sampling may yield more generalizable findings than those based on clinically ascertained samples alone8, 53. The current investigation, by avoiding the combination of clinically and methodologically diverse samples, may also have ameliorated several important confounds such as differences due to different healthcare systems and illness related conditions including age of onset and duration of illness. Another factor of interest for future studies is the effect of hospital treatment. As studies have reported changes of depressive symptoms caused by medication or cognitive treatment3, investigates on the neurological effect of treatment should be conducted. The prevalence of the present study is lower than 10%, which is less than the prevalence of ~20% in overall sample of the cohort in the study by Smith et al.22. This was mainly due to the difference of sizes between the two samples. There were ~5500 participants in the sample with T1-weighted/DTI data, whereas over 30 times of people were included in the full cohort (N = 172,751). This difference therefore supports the necessity of studying MDD in a large sample to minimise the bias of selecting study sample. A further potential limitation is that for the volumetric analysis we only focused on the subcortical volumes in the current study. We can therefore not exclude the possibility of cortical differences in MDD, including regional volume differences, as well as measures of cortical thickness and gyrification for example.

Our study presents a comprehensive comparison of brain structural changes related to MDD using the largest single sample available to date from a single scanner with uniform methodologies for clinical categorisation and scanning. We mainly report reductions of white matter FA in general latent measures of association and commissural fibres as well as thalamic radiations, and in left superior longitudinal fasciculus both in MDD and recurrent MDD. Future work would be potentially focusing on structural changes in cortical areas as well as richer stratification of MDD into informative biologically-based subgroups.