Biomarkers in Major Depressive Disorder – 2

Biomarkers in the Diagnosis of Major Depression – Magnetic Resonance Imaging Studies: Previously on the article series concerning the Biomarkers in Major Depressive Disorder, the topics mentioned included what biomarkers are, as well as why and how they are used in the diagnosis of depression and in the prediction of response to treatment. This chapter of the series will analyze the biomarkers, which are obtained by means of magnetic resonance imaging methods in order to diagnose major depression.

Magnetic Resonance Imaging (MRI)

This is a noninvasive imaging technique that displays the anatomic structures of the body in a magnetic field, using radio waves. Though a costly method, it can be safely used on pregnant women and children as it does not involve the use of radiation. The studies conducted on Major Depressive Disorder through the MRI method includes the gray matter volume (GMV) in the brain, the cortical thickness, the micro-integrity of the white matter areas, and other parameters of the structures of the brain. For instance,

• The changes in the gray matter volume in bilateral anterior cingulate cortex (ACC) were revealed by a meta-analysis of the gray matter volume studies in MDD (Lai, 2013). The stress-related reduction of the gray matter volume in ACC indicates that this can potentially be a biomarker.
• The fact that the white matter micro-integrity could potentially be a biomarker in major depression was set forth by the changes observed in the MDD regarding the micro-integrity of a region (superior longitudinal fasciculus), which links frontal regions to limbic and temporal regions (Lai and Wu, 2014; Lai and Wu, 2016).
• A compilation study on MRI put forward that, in major depression, convergent abnormalities in hippocampus, amygdala and putamen, as well as in ACC, could be peculiar to depression (Gray et al., 2020).

Functional Magnetic Resonance Imaging (fMRI)

Providing information on the brain function by utilizing the changes in the blood flow and oxygen levels in the brain tissue, fMRI is a method highly-used in the diagnosis and treatment of disorders. fMRI can be divided into two types, which are task-based (task-fMRI) and resting-state fMRI (rs-fMRI). Brain imaging is performed while the patient is given specific tasks, such as emotion, cognition or reward tasks, in order to have the fMRI task reveal a certain model of change in MDD. The resting-state is obtained without the fMRI having a specific task.

Studies on the Resting-State fMRI

• The stress-related cortisol hormone spikes based on the state after awakening. Cortisol Awakening Response: The changes in the cortisol awakening response are closely correlated with the balancing of the Hypothalamus-Pituitary-Adrenal Axis, which regulates the reaction given by the body when under stress, and it is one of the most reliable biomarkers in predicting depression. The resting-state and task-based fMRI studies (Boehringer et al., 2015) revealed that the individual differences in the cortisol awakening response are correlated with the reduction of the gray matter volume in anterior cingulate cortex (ACC) in the brain, and that the brain activity increases in the ACC regions of people under stress.
• High fluctuations were observed in the resting-state brain activities in subgenual ACCs of major depression patients receiving Electroconvulsive Therapy (ECT) (Argyelan et al., 2016).
• Another study on the resting-state fMRI demonstrated that the connections between fronto-limbic regions, such as ACC, amygdala and hippocampus, are correlated with the severity of major depression.
• In addition to the resting-state brain activities of major depression patients, the therapeutic effect, which is created by the treatment received by them, also provides information about the pathophysiology of major depression. In a resting-state fMRI study (Brakowski et al., 2017), the major depression patients receiving pharmacotherapy were observed to have had changes in their functional connections in the fronto-limbic, default mode network and parieto-temporal, while changes were observed in the fronto-limbic circuit in the patients receiving psychotherapy; and in the ACC, dorsolateral prefrontal cortex (DLPFC) and Default Mode Network connections in the depression patients receiving ECT and transcranial magnetic stimulation (TMS).

fMRI studies involving tasks

When compared to the resting-state fMRI studies, the biomarkers in task-based fMRI studies would technically depend on the characteristics of the tasks in the fMRI design. These studies found out the following:

• Emotion recognition task: The change between the default mode network, amygdala-visual connections (Tozzi et al., 2017)
• Administrative functions task (the do/don’t task): Reduced activity in ACC and insula (Miller et al., 2015)
• Working memory (the n-back test): The inadequacy compared to the control group in terms of activating the medial frontal cortex, which takes part in the working memory while both depression patients and bipolar depression patients carry out the n-back test (Rodrigez-Cano et al., 2017)
• Voluntary attention task: hyper-connectivity between the default mode network and task-based circuit (Tozzi et al., 2017)
• Monetary incentive delay (learning through extrinsic reward): A correlation between reward and the weakening of the ability to learn following the reduction of the functional connection between the ventral tegmental area (VTA), which is located in the reward center circuit of the brain, and striatum in depression patients (Kumar et al., 2018).

Magnetic Resonance Spectroscopy (MRS)

Magnetic resonance spectroscopy (MRS) is a noninvasive technique, which can be used to complete the magnetic resonance imaging (MRI) in the tissue characterization and which can reliably measure the neural metabolites in a specific brain region. The following results were found in the studies conducted with the MRS method in Major Depressive Disorder:

• The choline/creatine ratio in the anterior cingulate cortex (ACC) increased in major depression patients; this was considered a biomarker that would help diagnose major depression (Shi et al., 2014).
• Higher levels of choline in the frontal lobe can be an indicator peculiar to the MDD pathophysiology (Riley and Renshaw, 2018).
• The comparison of major depression patients to healthy control elements yielded significant differences in the correlation between the glutamate levels in the medial frontal regions and the white matter micro-integrity of the pathways interconnecting the ACC and amygdala (Nugent et al., 2019).
• A study on melancholic depression in adolescence showed that the connection between the tryptophan metabolites and neurotoxic metabolites in limbic regions, such as striatal areas, is a potential biomarker (Gabbay et al., 2010).
• Reduced glutamate levels were observed in the ventromedial prefrontal cortex in patients going through major depression for the very first time, which can represent a potential biological marker (Draganov et al., 2020).

As to the biomarkers in major depressive disorder, the MRS studies revealed the correlation between the structural changes in fronto-limbic regions, such as frontal regions, ACC and striatum, and the metabolites with changing levels (choline/creatine, glutamate, tryptophan). Consequently, studies on magnetic imaging resonance show that functional abnormalities can also be the biomarkers of the diagnosis of depression, along with the anatomic and chemical changes in fronto-limbic regions in major depression.

REFERENCES:
– The studies mentioned in the article are included in Dr. Lai’s compilation of articles titled “Fronto-limbic neuroimaging biomarkers for diagnosis and prediction of treatment responses in major depressive disorder” (2021).
– Lai, C. H. (2021). Fronto-limbic neuroimaging biomarkers for diagnosis and prediction of treatment responses in major depressive disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 107, 110234.