A recent study has revealed new insights into the neural mechanisms underlying treatment-resistant depression. By recording stereotactic electroencephalography (sEEG) signals from patients’ brains, the team identified specific abnormalities in the way depressed individuals process emotional information. This study, published in Natural mental healthrepresents a promising step toward understanding and potentially treating this challenging disease.
Depression is a common but serious mental health disorder characterized by persistent feelings of sadness, hopelessness, and a lack of interest or pleasure in daily activities. It affects millions of people worldwide and can significantly impair a person’s ability to function at work, school, and in personal relationships.
Although many people with depression respond well to standard treatments, such as medications and psychotherapy, a significant subset of patients do not experience sufficient relief from these approaches. This condition is known as treatment-resistant depression. It is defined as the inability to respond to at least two different antidepressant treatments administered at adequate doses and durations.
The new study by Baylor College of Medicine researchers aimed to explore the neural basis of an emotion processing bias observed in people with depression. This bias leads to a stronger response to negative information than to positive information, which exacerbates depressive symptoms. Understanding the neural mechanisms underlying this bias is crucial to developing targeted interventions that can better address the unique challenges of treatment-resistant depression.
“There has been a big question in the field as to whether there was a physiological abnormality that we could measure related to depression, because people had historically viewed it as a disorder of the ‘mind’ rather than a disorder of the “brain” and its cells. In this study, we were able to capture highly sensitive data from awake and behavioral human subjects that demonstrate a physiological basis for treatment-resistant depression,” the authors said. study Kelly Bijanki, associate professor, and Xiaoxu Fan, postdoctoral researcher.
For the study, sEEG electrodes were implanted in specific regions of the participants’ brains, specifically the amygdala and prefrontal cortex (PFC). These regions were chosen because of their known roles in emotion processing and regulation. The electrodes provided high spatial and temporal resolution recordings of brain activity, allowing researchers to observe detailed neural responses to emotional stimuli.
The study included 12 patients with epilepsy and 5 patients diagnosed with treatment-resistant depression. Epileptic patients served as a control group since they were already undergoing stereotactic electroencephalography (EEG) monitoring for seizure localization. Treatment-resistant depressed patients had failed to respond to at least four different antidepressant treatments and were recruited as part of an initial feasibility trial.
Participants were asked to rate the emotional intensity of photographs of human faces displaying various expressions, ranging from very sad to very happy. This task was designed to evoke and measure their neural responses to positive and negative emotional stimuli. Ratings of emotional intensity were recorded using a computer interface, ensuring precise synchronization with brain activity data captured by the sEEG electrodes.
The researchers found that people with treatment-resistant depression had an increased and prolonged amygdala response when looking at sad faces compared to the control group. This increased activity began approximately 300 milliseconds after presentation of the sad faces, indicating a hyperactive bottom-up processing system.
The group with treatment-resistant depression also showed a reduced amygdala response to happy faces at a later stage (around 600 milliseconds). This finding suggests a diminished ability to process positive emotional stimuli, which may play a role in the persistent low mood characteristic of depression.
The researchers observed an increase in alpha band power in the prefrontal cortex of treatment-resistant depressed patients during the final stage of processing happy faces. Alpha band power is thought to reflect inhibitory processes in the brain.
Additionally, there was enhanced alpha band synchronization between the prefrontal cortex and the amygdala, indicating stronger top-down regulation of the amygdala by the prefrontal cortex in these patients. This suggests that the prefrontal cortex may overly inhibit the amygdala, thereby contributing to a reduced emotional response to positive stimuli.
“sEEG can provide data with high temporal resolution and reliable anatomical precision of signal sources,” Bijanki and Fan told PsyPost. “With the help of sEEG, our results clearly revealed that different neural mechanisms are responsible for the biased processing of negative and positive emotions in TRD patients.
The study also explored the effects of deep brain stimulation on neuronal responses in treatment-resistant depressed patients. After deep brain stimulation was delivered to the cingulate and ventral subcallosal regions of the ventral capsule/striatum, the neuronal responses to emotional stimuli in patients showed significant changes.
The amygdala response to sad and happy faces increased and alpha band power in the prefrontal cortex decreased during processing of happy faces. Additionally, alpha band synchronization between the prefrontal cortex and amygdala during processing of happy faces was reduced, bringing neural activity patterns closer to those observed in the control group.
“Treatment-resistant depression has a signature in the activation pattern of neurons in the brain, particularly during an emotional task,” Bijanki and Fan explained. “We find that the brain may be overly sensitive to negative emotional information in depressed patients, and we see evidence of increased top-down inhibition from a moderating brain region that may explain the abnormality. Furthermore, we find that after therapeutic brain stimulation, this pattern is normalized. We hope that with further study, this signal can help clarify the mechanism of depression and suggest potential new treatments.
The small sample size limits the ability to generalize the results. Additionally, the use of epilepsy patients as controls, who themselves may have different levels of depressive symptoms, could affect the comparison. Future research should aim to include larger and more diverse samples to validate these findings.
The researchers also plan to explore how these neural markers can be used to assess the effectiveness of treatments for depression. “We hope to use the biased signature of emotional processing as a biomarker to evaluate the effects of treatments for depression and as an indicator of the severity of depression symptoms in future patients,” the researchers said.
The study titled “Brain Mechanisms Underlying Emotion Processing Bias in Treatment-Resistant Depression” was authored by Xiaoxu Fan, Madaline Mocchi, Bailey Pascuzzi, Jiayang Xiao, Brian A. Metzger, Raissa K. Mathura, Carl Hacker, Joshua A. Adkinson. , Eleonora Bartoli, Salma Elhassa, Andrew J. Watrous, Yue Zhang, Anusha Allawala, Victoria Pirtle, Sanjay J. Mathew, Wayne Goodman, Nader Pouratian and Kelly R. Bijanki.