Biomarker of Depression? New Study Finds Neural Predictor of Depression

Depression is an extremely complicated disease and the leading treatment methods for depression have varying successes for different people. The first treatment options that people are offered are pharmacotherapy (medication) and psychotherapy (talk therapy), which are not always successful in relieving the symptoms of depression. When depression is resistant to the effects of medication and talk therapy, it is deemed “treatment resistant depression” and requires further forms of intervention. Some alternative options, such as electroconvulsive therapy (external electrical brain stimulation) are rather established and understood, while relatively newer treatment methods continue to evolve with recent discoveries. Deep Brain Stimulation (DBS) is a medical treatment technique that has historically been used to treat movement disorders such as Parkinson’s and dystonia. In recent history however, DBS’s application has broadened given its treatment potential in relation to mood disorders. Clinical research provides promising data supporting DBS’s effectiveness for treatment resistant depression, however further research seeks to refine delivery protocols to improve its efficacy.

DBS is a form of electrical stimulation that requires a minimally invasive neurosurgical procedure for implantation of electrodes into a specific region of the brain. This contrasts other electrical stimulation methods (such as electroconvulsive therapy) that are externally placed on the surface of the skin. DBS electrodes are connected to an implantable pulse generator (IPG), which is also placed inside of the head and serves as a power source that controls the stimulation of the DBS system. There are various implantation locations for DBS, depending on the desired effects. For example, to treat Parkinson’s disease, DBS electrodes are placed in brain regions that control movement (the globus pallidus interna and the subthalamic nucleus). Conversely, DBS electrodes for treatment resistant depression are typically implanted on the subcallosal cingulate (SCC) which regulates emotional behavior, particularly that which relates to sadness.

While DBS stimulation of the SCC has successfully offered lasting symptom relief for many patients, the treatment often requires frequent adjustments based on trial-and-error methods to meet the needs of each individual case. Individuals vary drastically in their responses to DBS and vigilant clinician monitoring of symptoms is needed to ensure success. The current methods of treatment monitoring rely on patient self-report surveys and clinician observations. Both of these are vulnerable to misinterpretation of mood fluctuations – it is hard to tell whether a mood shift indicates a need for treatment adjustment due to returning depression symptoms or if it is a regular, passing emotion. Therefore, an objective measure of depression recovery is key to properly administering and managing DBS treatment adjustments. Excitingly, research backed by the BRAIN initiative has recently revealed a biomarker that seems to monitor depression symptoms and identify the need for treatment adjustment before current methods (clinician intuition and self-report) are able to identify needs for treatment adjustments.

Alagapan et al. (2023) ran a 24-week clinical trial where they delivered DBS treatment to 10 patients via special implanted pulse generators (aforementioned electrical source of DBS), which not only powered the brain stimulation but also recorded the brain activity of the patients. To measure depression in the standard format (self-report), the researchers used the Hamilton Depression Rating Scale (HDRS). On this scale, scores below 8 represent a non-depressed state, scores between 17 and 23 represent moderate depression, and scores of 24 and above represent severe depression. The average HDRS score of the 10 person experimental group was 22.3 (moderate depression) before treatment and 7.3 (non-depressed state) after the 24-week treatment. This high success rate allowed the researchers to track biological features in their participants through their recoveries from “sick” to “stable”.

After completion of the study, researchers analyzed “local field potentials” which are the electric potentials of specific spaces in the brain. This electric measurement was taken by the implanted pulse generators. After this, a neural network classifier determined the differences in brain electric potential between “sick” and “stable” states in 5 of the participants. Data from all 5 participants were combined to create a representation of features that captured the differences between “sick” and “stable” states. This representation of important features is called the spectral discriminative component (the SDC). The SDC is the biomarker the researchers identified that seems capable of biologically tracking depression recovery and relapse.

Once the SDC was created, it was then tested on one of the participants whose data was not included in the creation of the model to see if it could recognize and predict that patient’s recovery tract. Notably, the test patient experienced a relapse in recovery during the trial. The SDC was successfully able to recognize the patient’s recovery patttern (aka correctly identify the patient’s “sick” and “stable” states based on the biomarker model). Its measurements were corroborated with the HDRS measurements of depression recovery about 90% of the time. The missing 10% is important, as it highlights the SDC’s unique capabilities to predict relapses before HDRS is able to recognize it. The SDC was one month quicker at recognizing the patient’s relapse than the HDRS. This means that the SDC biomarker identified changes in brain activity that predicted a relapse of depression symptoms one month before those symptoms were caught by HDRS and clinician evaluations.

The results found by Alagapan et al. (2023) have tremendous implications for future DBS treatment. The study not only found a biomarker that seems to successfully and objectively measure depression recovery, but the study also suggests that the SDC biomarker can predict the need for treatment adjustment before clinicians can. This is a major improvement to current methods because it flags regression in recovery before heavy symptoms appear whereas it is difficult for clinicians to recognize relapse states before symptoms are pronounced. This suggests that with SDC data, treatment can be updated and recovery can be more quickly restabilized – before significant return of depression symptoms. Another valuable aspect of the SDC is that it is common across patients, not individualized to each person. This means that the SDC tracks universal brain changes that occur during depression recovery. The subjectivity of current treatment options is a weakness as it allows for clinician error. Conversely, it seems that the universal features of the SDC biomarker are able to objectively measure symptoms for all patients.

In the arena of DBS treatment, current approaches are limited because they rely on clinician and self-report data to track recovery progress and adjustment needs. The SDC biomarker discovered through the BRAIN initiative suggests that an objective factor can be used to measure recovery, discriminate between “sick” and “stable” states, and identify need for treatment adjustment before relapse symptoms become severe. This new biomarker is extremely promising for DBS treatment, and in turn, very exciting for future treatment potentials of treatment resistant depression.

References: 

1. Alagapan, S, et al. (2023). Cingulate dynamics track depression recovery with deep brain stimulation. Nature, 622(1), 130-138. DOI: 10.1038/s41586-023-06541-3

2. “Brain Stimulation Therapies.” National Institute of Mental Health, U.S. Department of Health and Human Services, www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies. Accessed 9 Mar. 2024.

3. “Deep Brain Stimulation.” The Michael J. Fox Foundation for Parkinson’s Research | Parkinson’s Disease, www.michaeljfox.org/deep-brain-stimulation#:~:text=In%20DBS%20surgery%2C%20the%20surgeon,pallidus%20interna)%20that%20control%20movement. Accessed 9 Mar. 2024.

4. Delaloye, S., & Holtzheimer, P. E. (2014). Deep brain stimulation in the treatment of depression. Dialogues in Clinical Neuroscience, 16(1), 83-91. doi: 10.31887/DCNS.2014.16.1/sdelaloye

5. Dunlop et al. (2017) Functional connectivity of the subcallosal cingulate cortex identifies differential outcomes to treatment with cognitive behavior therapy or antidepressant medication for major depressive disorder. Am J Psychiatry, 174(6), 533-545. Doi: 10.1176/appi.ajp.2016.16050518