Young adults with major depressive disorder show distinct metabolic signals in two brain regions, and the pattern differs between those who struggle on thinking tasks and those who do not. In a new study published in the Journal of Affective Disorders, researchers found that patients whose test scores indicated cognitive impairment had more choline relative to creatine in a part of the frontal midline called the anterior cingulate cortex, while all patients—impaired or not—had an elevated choline‑to‑creatine ratio in the putamen, a deep structure involved in motivation and learning. The ratio in the putamen also rose in step with the number of past depressive episodes among the impaired patients.
While many studies have examined mood-related symptoms of depression, less is known about the biological basis of cognitive changes in this condition, especially in younger adults. Prior research suggested that metabolic changes in the brain might be linked to these symptoms, but the specific patterns and brain regions involved remained unclear.
To investigate this, the researchers recruited 105 right-handed young adults between the ages of 18 and 35 who had recently been diagnosed with major depressive disorder but had not yet received treatment. They also included a control group of 68 healthy young adults matched for age and demographic factors. All participants completed a widely used cognitive test battery, known as the MATRICS Consensus Cognitive Battery, which measures skills like memory, attention, and processing speed.
Based on test results, the depressed participants were divided into two groups: those with cognitive impairment and those without. A person was considered to have cognitive impairment if they scored at least 1.5 standard deviations below the average in two or more areas of the test. Using this standard, 39 of the 105 depressed participants were classified as having cognitive impairment, while the remaining 66 did not meet this threshold.
In addition to the cognitive testing, participants underwent a brain scan known as proton magnetic resonance spectroscopy. This imaging technique measures the concentration of certain chemicals in specific brain regions. The researchers focused on two areas: the anterior cingulate gyrus and the putamen. These regions are involved in emotional regulation, attention, memory, and motivation—all of which are often affected in depression.
The scans looked at the levels of choline-containing compounds (a marker related to cell membrane turnover and inflammation), creatine (a marker of energy metabolism), and N-acetylaspartate (a marker of neuronal health). The researchers then calculated the ratio of choline to creatine (Cho/Cr) and N-acetylaspartate to creatine (NAA/Cr) in both brain regions.
The results revealed several key differences. Participants with both depression and cognitive impairment had significantly higher Cho/Cr ratios in the right anterior cingulate gyrus compared to both healthy controls and depressed individuals without cognitive impairment. This suggests a possible link between changes in this region’s chemistry and the presence of cognitive difficulties.
Additionally, both depressed groups—those with and without cognitive impairment—showed elevated Cho/Cr ratios in the left putamen when compared to the control group. This finding implies that metabolic changes in the putamen may be common among people with depression, even if cognitive performance is relatively preserved.
The study also found a correlation between the number of depressive episodes and higher Cho/Cr levels in the left putamen among those with cognitive impairment. In other words, people with more frequent depressive episodes tended to show greater chemical changes in this brain region, which might suggest that these alterations accumulate over time.
Interestingly, the researchers did not find any significant differences between the groups in terms of NAA/Cr ratios, which are thought to reflect overall neuronal integrity. This might mean that the observed differences in choline levels are more reflective of inflammation, cell membrane activity, or changes in glial cells rather than outright neuron loss.
The anterior cingulate gyrus has long been thought to play a key role in balancing emotional and cognitive processes. It helps regulate attention, monitors performance, and contributes to learning and adapting to new rules. Previous studies have shown that people with depression often have disrupted connectivity in this area, especially in parts that coordinate with other brain regions involved in mood and cognition. The higher choline levels seen in the right anterior cingulate among cognitively impaired patients could reflect inflammation or other stress-related cellular changes that interfere with its normal functioning.
The putamen, on the other hand, is part of the striatum and is typically associated with motivation, reward processing, and motor control. In depression, this area has been linked to symptoms such as low motivation and reduced pleasure. Changes in the putamen’s chemistry, as seen in this study, could be part of the broader brain dysfunction that contributes to these symptoms.
Importantly, the study emphasizes that not all individuals with depression show cognitive impairment, and the biological changes associated with these impairments may be distinct from those linked to mood symptoms. While both depressed groups had some abnormalities in the putamen, only those with cognitive impairment showed the additional changes in the anterior cingulate.
This distinction could help explain why some patients respond well to antidepressants while others continue to struggle with concentration, memory, or other cognitive functions. Understanding these differences may help guide more personalized treatment approaches in the future, such as combining standard antidepressants with cognitive interventions or anti-inflammatory treatments for those with cognitive symptoms.
Despite its strengths, the study has some limitations. The sample size, while relatively large for a brain imaging study, was still limited to young adults from a single hospital. The findings may not generalize to older adults, who may have different patterns of brain aging or inflammation. The researchers also focused only on two brain regions, so it’s possible that other areas involved in cognition may show relevant changes as well. Additionally, the study only measured metabolites at one point in time, so it cannot determine whether the observed changes preceded or followed the onset of cognitive problems.
The authors suggest that future research should explore a broader range of brain regions, examine how these changes evolve over time, and include inflammatory markers like C-reactive protein to further investigate the potential role of immune system activity. They also highlight the need to investigate sex differences and the effects of treatments on brain chemistry and cognitive function.
The study, “The abnormal choline to creatine ratio of the right anterior cingulate gyrus is linked to cognitive impairment in youth with major depressive disorder,” was authored by Shijie Luo, Shunkai Lai, Linna Chu, Ying Wang, Pan Chen, Xiaojie Ye, Jinping Zhuo, Munila Abula, Yikun Liang, Dongxue Wei, Meiqi Zhang, Jie Yin, Xiaodan Lu, Jianzhao Zhang, Yiliang Zhang, Shuming Zhong, and Yanbin Jia.
