The duration of depression may influence how severely the disease alters the brain

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Researchers from the universities of São Paulo and Oxford show that the duration of the disorder and severity of symptoms are associated with differences in functional brain connections, which may pave the way for personalized treatments.

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An article signed by Maria Fernanda Ziegler from Agência FAPESP explained that depression affects about 5.8% of the Brazilian population and presents a wide range of symptoms, intensities, and durations. A study published in Scientific Reports involving patients with major depressive disorder demonstrated that the severity of symptoms, as measured by the Hamilton Depression Scale, and the length of time a person remains depressed (chronicity), are both associated with changes in brain function.

For the study, researchers from the University of São Paulo (USP) in Brazil and the University of Oxford in the United Kingdom analyzed brain images from 46 patients with major depression. The results suggest that the duration of depressive episodes is associated with differences in functional brain connectivity. However, they do not allow for the differentiation or diagnosis of individual cases on their own.

“Major depression can alter brain function compared to people without the disorder. In this study, however, we identified that chronic patients [those with depression for more than 24 months] and non-chronic patients exhibit distinct patterns of connection between two important functional networks: the Central Executive Network [CEN], focused on executive control, and the Default Mode Network [DMN], associated with introspective thoughts and self-reflection,” said Tamires Zanão, a FAPESP fellowship recipient and first author of the study.

The researcher explained that the CEN and the DMN are two major brain systems with complementary functions. The CEN involves brain regions such as the dorsolateral prefrontal cortex and the parietal cortex. It is associated with the executive control required for goal-oriented tasks. The DMN, on the other hand, is diffuse and includes areas such as the medial prefrontal cortex, the precuneus, and the hippocampus. It is related to internal processes such as self-reflection, autobiographical memory, and spontaneous thoughts. Due to its complexity, the DMN is often divided into subnetworks, such as those involving the precuneus.

“More detailed models of brain network organization suggest that the precuneus doesn’t act solely within the DMN, but also connects to subnetworks related to the CEN. For that reason, that region is considered a point of integration between different brain systems, functioning as a sort of ‘bridge’ between processes oriented toward the ‘internal world’ and cognitive control,” she said.

Typically, both networks exhibit coordinated dynamics with the participation of the salience network, which is involved in switching focus between the external environment and internal processes. In depression, however, these dynamics may be altered, which has been associated with symptoms such as rumination and difficulty concentrating. “That misalignment between those networks may favor the predominance of introspective and self-referential thoughts, often with a negative bias. That helps explain why people with depression tend to get stuck in negative thoughts and have difficulty directing their attention to the environment when necessary,” Zanão explained to Agência FAPESP.

In the study, the researchers observed that the duration of depression appears to be associated with the dynamics of these two networks. In people with more recent episodes, the functional connection between the CEN and precuneal regions in the DMN decreases as symptoms worsen. In contrast, patients with long-term depression exhibited an opposite pattern: the greater the severity, the stronger the connectivity between these networks.

Other studies using large population databases, such as the UK Biobank, have demonstrated a positive correlation between CEN activity and precuneus regions in the DMN in healthy individuals. In the USP study conducted with the University of Oxford, although there was no direct comparison with healthy individuals, patients with non-chronic depression, especially those with fewer symptoms, exhibited connectivity patterns closer to the typical profile.

“The results are consistent with the hypothesis that changes in brain connectivity in depression may evolve over time. Previous research indicates that, in initial episodes, there may be a reduction in connectivity between certain networks, while in recurrent or more prolonged cases, changes in functional connectivity emerge,” explained Zanão.

Another finding from the study indicated an association between the severity of depressive symptoms and gray matter volume in two specific brain regions: the anterior cingulate cortex and the right dorsolateral prefrontal cortex. These regions have both been extensively linked to the disorder in previous studies.

“The anterior cingulate cortex, for example, has connections with areas involved in both emotional regulation and cognitive functions, playing an important role in integrating emotion and thought. Changes in that region have often been associated with the intensity of depressive symptoms. Although, in some contexts, greater gray matter volume is interpreted as indicative of better cognitive functioning, the results in the literature on depression are mixed. Previous studies have reported both reductions and increases in volume in those regions. Part of that discrepancy may be related to the use of antidepressants, as there’s evidence that medication can influence structural measures of the brain,” Zanão stated.

Because the current study included patients who were not taking antidepressants at the time of analysis, the authors suggest that the findings may more accurately reflect changes associated with depression itself rather than the effects of treatment.

Evidence from techniques such as tomography and transcranial magnetic stimulation suggests that depression may involve an imbalance in prefrontal cortex activity, with lower activity on the left side and higher activity on the right.

“According to that hypothesis, the left hemisphere would be more closely related to processing positive emotions, while the right hemisphere would be more involved with negative emotions. In this context, the finding of increased volume in the right dorsolateral prefrontal cortex observed in the study is consistent with that theoretical model, although its functional significance isn’t yet fully understood,” she said.

The researcher explained that these findings could aid in developing more personalized depression treatments in the future.

“Although guided by clinical evidence, the choice of treatment for depression still involves adjustments over time, as the response can vary from person to person. Studies like this one contribute to advancing our understanding of the disease, but more data is needed before this information can guide individualized clinical decisions,” Zanão added.

The brain imaging data from the 46 patients diagnosed with depression are part of a larger clinical trial coordinated by Professor André Brunoni from USP and currently at the University of Texas Southwestern Medical Center. Zanão analyzed the data for this study during his postdoctoral fellowship at the University of Oxford with support from FAPESP. FAPESP also funded the research through projects 12/20911-5, 22/03266-0, and 23/13893-5.

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The article “Chronicity moderates the impact of severity on central executive-default mode network functional interactions in depression” can be read at Nature Communications. Authors: Tamires Zanao, Piergiorgio Salvan, Lais B. Razza, Pedro Henrique Rodrigues da Silva, Andre R. Brunoni & Jacinta O’Shea
The article The duration of depression may influence how severely the disease alters the brain signed by Maria Fernanda Ziegler was published on Agência FAPESP