Cognitive deficits, such as memory and concentration difficulties and a general slowing of mental processing, are common in people with major depressive disorder (MDD). During acute depression, 94% of individuals experience cognitive deficits, which persist even after remission in 73% of individuals (Semkovska et al., 2019). These symptoms can have a considerable impact on an individual’s quality of life, but they are frequently overlooked as part of clinical treatment and tend to exacerbate with disease progression.
White matter is vital for information exchange between different brain regions and mainly consists of myelinated axons. However, the underlying biological mechanisms related to cognitive difficulties in MDD are poorly understood. Recent studies suggest that the brain’s white matter microstructure may contribute to their manifestation (van Velzen et al., 2020; Meinert et al., 2022), but these studies were cross-sectional in nature, and did not examine relationships between changes in white matter and cognitive symptoms in MDD over time.
Diffusion-weighted magnetic resonance imaging (dw-MRI) is a specialised MRI technique for examining changes in white matter at a microscopic level. Fractional anisotropy (FA) describes the directional coherence of diffusion (ranging from 0 to 1) and is a frequently used metric of white matter microstructure. Although there is a lack of specificity regarding what biological mechanisms are reflected by changes in FA, reductions in FA have previously been interpreted as a marker of degeneration of white matter – possibly reflecting demyelination or axonal damage or loss (Pasi et al., 2016).
Flinkenflügel et al. (2024) aimed to assess changes in cognitive performance and white matter microstructure in MDD after a 2-year interval using FA. The authors hypothesized that changes in white matter microstructure related to disease course may be linked with – or possibly even influence – cognitive decline in MDD.
During acute depression, up to 94% of individuals experience cognitive deficits, which persist even after remission in up to 73% of individuals.
Methods
This study is a subsample analysis of the Marburg-Münster Affective Disorders Cohort Study (MACS), an observational case-control study. Individuals aged 18-65 years of Caucasian ancestry and IQ>80 were eligible for inclusion. Individuals with MDD were recruited from local psychiatric hospitals in Germany and controls were recruited via newspaper advertisements. Psychiatric diagnosis of patients with MDD was confirmed using structured clinical interviews at baseline.
MRI scans and cognitive assessments were performed at baseline and after a two-year period. MDD disease course was documented using a “life-charting” approach (Post et al., 1988), in which participants recorded the number of episodes they experienced in the 2-year testing period. Changes in symptom severity were measured by administering the 21-item Hamilton Depression Rating Scale at both timepoints.
Results
The final sample included 881 participants (mean age = 36 years; SD = 13.5; 53% female). Sex and age were evenly matched between the control and MDD groups. The mean follow-up interval was 2.20 years. Of the MDD participants, 38% had acute MDD, 27% had partial remission and 35% were in full remission at baseline. At 2-year follow-up, 15% had acute MDD, 19% were partially remitted and 65% were fully remitted.
Cognitive performance
With regards to cognition, there were two main findings:
- The participants with major depressive disorder (MDD) exhibited worse cognitive performance compared to controls at both baseline and follow-up. This effect was primarily driven by individuals with acute MDD, but was also present in participants with partial or full remission.
- Cognitive performance for both groups appeared to improve over time, but this may have been driven by participants with MDD for whom severity of depression had decreased by follow-up.
Factional Anisotropy (FA)
The authors found a statistically significant interaction between diagnosis and time in the superior longitudinal fasciculus (SLF) – a tract associated with emotion regulation, executive function and language. There were no significant main effects of time or diagnosis. This means that MDD patients showed a greater decline in FA over time in this specific white matter tract at follow-up compared to control participants.
However, when examining differences in FA between healthy controls and MDD patients, no significant differences were found at either timepoint. Only individuals with acute MDD had significantly lower FA compared with controls. This suggests that differences in FA are difficult to detect in MDD and may only be detectable when observed over time in specific white matter tracts. It further suggests that changes in FA may only become apparent in the acute stage of MDD when compared with healthy controls.
Disease course, FA, and cognitive performance
The main focus of this study was to investigate the relationships between disease course, white matter microstructure (measured using FA) and cognitive decline in MDD over time. The authors found that:
- Across both healthy and MDD participants, cognitive performance decline was associated with a decline in FA over time, suggesting cognitive performance may be linked with white matter microstructure regardless of diagnosis.
- Course of illness was not associated with change in FA, meaning that adverse disease course in MDD was not found to be related to changes in white matter microstructure over time.
- For the MDD group, poorer disease course during the two-year interval predicted worse cognitive deficits at follow up.
Taken together, this means that poorer disease course may lead to worse cognitive performance, but is not necessarily related to white matter microstructure in MDD. Furthermore, changes in white matter microstructure did not influence (mediate) the relationship between disease course and cognitive performance.
Finally, there was a statistically significant interaction between general cognitive performance and time in a large bilateral cluster comprising the corpus callosum, corona radiata and superior longitudinal fasciculus – tracts important for higher cognitive functions and motor control. This means that decline in cognitive performance was associated with loss of FA over time across both groups.
Statistical checks of other potential moderating factors showed a small association between current medication intake and cognitive performance decline but no associations with FA. Moreover, neither medication nor psychiatric comorbidity was found to affect the overall pattern of results.
Within the MDD group, decline in white matter microstructure and adverse course of depressive symptoms independently predicted lower cognitive performance at follow-up.
Conclusions
There are four main takeaways from this study:
- Major depressive disorder (MDD) patients (across acute, partially and fully remitted patients) showed worse cognitive performance than controls at both timepoints.
- Both groups exhibited a decrease in fractional anisotropy (FA) over time suggesting decline in white matter microstructure, but MDD patients showed a steeper decrease in certain structures.
- Participants across both groups who showed a greater decline in white matter microstructure had greater decline in cognitive performance over time.
- Within the MDD group, decline in white matter microstructure and adverse course of depressive symptoms independently predicted lower cognitive performance at follow-up.
However, contrary to the hypothesis, changes in FA were not found to mediate the link between disease course and cognitive symptoms in MDD. This suggests that further research is needed to explore the relationships between disease course, underlying microstructure and cognitive abilities in MDD.
Depressed patients (across acute, partially and fully remitted patients) showed worse cognitive performance and a steeper decrease in select white matter structures than controls.
Strengths and limitations
This is the first study to explore the relationship between cognition and white matter microstructure in MDD over time. It is a well-powered study which provides valuable information about the effect of MDD on cognition using a comprehensive battery of assessments, encompassing adults aged 18 to 65 years, with patient and control groups that are evenly matched for age and sex.
Several measures were taken to reduce the risk of bias in this study. For instance, robustness checks were carried out to assess the effects of outliers, analysis strategy or sociodemographic or clinical characteristics of participants (e.g., medication or comorbidities) on the results. The hypotheses and analyses were preregistered in May 2023 on the OSF registry, although baseline data collection was carried out between September 2014 and June 2019.
However, there are also some limitations to this study. Firstly, the use of retrospective reports to capture disease course may have been biased by current depressive symptoms. Secondly, because data were collected at two separate locations (Marlburg and Münster), there may have been confounding effects of site or scanner, although the authors attempted to minimise this risk by controlling for location in the statistical models. Other relevant covariates previously been shown to influence white matter microstructure and cognition (Farokhian et al., 2017; Lövdén et al. 2020), such as sex and years of education, could have been included. Only Caucasian individuals were eligible for the study, which limits generalisability of the findings. Moreover, only individuals with complete datasets were included, suggesting that participants with poorer clinical outcomes may not have been included in the analyses. Further, no individuals with lived experience were involved in the research or writing process. The inclusion of perspectives from individuals with lived experience may offer a more nuanced understanding of aspects of MDD and can provide valuable insights into the interpretation of findings.
It should also be noted that the primary outcome measure for white matter microstructure used in this study, fractional anisotropy (FA), is a proxy measure of neural microstructure. FA is sensitive to changes in white matter organisation but it does not provide specific information about changes to white matter tissue such as axonal loss or myelin degradation. Increases in other diffusion tensor imaging (DTI) metrics (mean, radial and axial diffusivity) for the MDD group are reported in the supplementary material, which suggest there may be more widespread white matter degeneration, but future studies making use of recent advances in diffusion MRI, aimed at addressing the limitations of traditional DTI, will be needed to provide information about specific biological changes.
This study is the first to explore the relationship between cognition and white matter microstructure in MDD over time, but DTI metrics are proxy measures of microstructure, and so further research is needed to examine the biological processes which lead to neural degeneration in MDD.
Implications for practice
This study draws attention to the importance of viewing major depressive disorder (MDD) not only as a mood disorder, but as a condition with significant neurocognitive implications in acute, partially and fully remitted stages. Although MDD participants showed a small increase in cognitive performance over time, potentially due to improvement in disease course, scores were still worse than controls at follow-up.
The results highlight the importance of designing holistic treatment strategies aimed at mitigating potential effects of cognitive symptoms on other important aspects of life. Cognitive symptoms such as brain fog and memory difficulties may negatively impact one’s ability to effectively adhere to treatment plans. If an individual’s organisational abilities are impacted, measures need be put in place to ensure medication is taken as prescribed and clinical appointments are attended to avoid exacerbation of other symptoms.
The importance of prioritising early detection is also stressed. A depression diagnosis is associated with an increased risk of developing dementia in later life (Alzheimer’s Society, 2024). Long-term monitoring of cognitive function in patients with recurrent or chronic depression is needed, as they may be at higher risk of progressive changes. Preventative strategies and routine cognitive assessments in MDD patients could help detect early signs of cognitive decline, prompting timely interventions.
Although the study did not find a mediation effect of white matter microstructure on the relationship between disease course and cognition, both FA and cognitive function were most impacted in participants with acute MDD. Specifically, decline in tracts involved in higher cognitive abilities like attention, working memory, language and emotional regulation (Koshiyama et al., 2020), were associated with poorer cognitive performance at follow-up for both groups. It is possible that these tracts are most vulnerable to neurotoxic effects of stress. Clinical management of MDD could focus on treatment strategies which have shown promise in supporting white matter microstructure in general, such as exercise or meditation-based programmes which may increase FA across different white matter tracts, and improve cognitive function (Jemni et al., 2023), but more research is needed specifically in the context of MDD.
The findings draw attention to the importance of viewing MDD not only as a mood disorder, but as a condition with significant neurocognitive implications in acute, partially and fully remitted stages.
Statement of interests
Fionnuala declares no known competing financial interests or personal relationships that may have influenced this blog.
Links
Primary paper
Flinkenflügel, K., Meinert, S., Hirtsiefer, C., Grotegerd, D., Gruber, M., Goltermann, J., Winter, N.R., Stein, F., Brosch, K., Leehr. E.J., Böhnlein, J., Dohm, K., Bauer, J., Redlich, R., Hahn, T., Repple, J., Opel, N., Nitsch, R., Jamalabadi, H., Straube, B., Alexander, N., Jansen, A., Nenadić, I., van den Heuvel, M. P., Kircher, T. & Dannlowski, U. (2024). Associations between white matter microstructure and cognitive decline in major depressive disorder versus controls in Germany: a prospective case-control cohort study. The Lancet Psychiatry, 11(11), 899-909.
Other references
Alzheimer’s Society (August 2024). Depression and Dementia Risk. https://www.alzheimers.org.uk/about-dementia/managing-the-risk-of-dementia/reduce-your-risk-of-dementia/depression
Jemni, M., Zaman, R., Carrick, F. R., Clarke, N. D., Marina, M., Bottoms, L., … & Konukman, F. (2023). Exercise improves depression through positive modulation of brain-derived neurotrophic factor (BDNF). A review based on 100 manuscripts over 20 years. Frontiers in Physiology, 14, 1102526.
Koshiyama, D., Fukunaga, M., Okada, N., Morita, K., Nemoto, K., Yamashita, F., … & Hashimoto, R. (2020). Association between the superior longitudinal fasciculus and perceptual organization and working memory: A diffusion tensor imaging study. Neuroscience Letters, 738, 135349.
Lövdén, M., Fratiglioni, L., Glymour, M. M., Lindenberger, U., & Tucker-Drob, E. M. (2020). Education and cognitive functioning across the life span. Psychological science in the public interest, 21(1), 6-41.
Meinert, S., Leehr, E. J., Grotegerd, D., Repple, J., Förster, K., Winter, N. R., … & Dannlowski, U. (2022). White matter fiber microstructure is associated with prior hospitalizations rather than acute symptomatology in major depressive disorder. Psychological Medicine, 52(6), 1166-1174.
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Post, R. M., Roy-Byrne, P. P., & Uhde, T. W. (1988). Graphic representation of the life course of illness in patients with affective disorder. The American journal of psychiatry, 145(7), 844-848.
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Van Velzen, L. S., Kelly, S., Isaev, D., Aleman, A., Aftanas, L. I., Bauer, J., … & Schmaal, L. (2020). White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group. Molecular psychiatry, 25(7), 1511-1525.
