What is Major Depressive Disorder (MDD)?
MDD is one of the most common psychiatric disorders, affecting at least five percent of the world’s population4,5. Individuals suffering from MDD experience persistently low moods, feelings of hopelessness, and anhedonia, also known as the inability to feel pleasure4,5. Nearly two-thirds of people with MDD have suicidal ideation, and roughly 15% of those affected die by suicide4.
The symptoms of MDD disrupt one’s ability to carry out their day-to-day responsibilities and place undue strain on relationships and career performance. Worryingly, MDD carries high comorbidities with developing substance use disorders, obsessive-compulsive disorder, bipolar disorder, and anxiety4.
Depression as a Personalized Disorder
Research has confirmed a long-suspected idea about depression—it isn’t a single disorder, but many4.
Drysdale et al. investigated nearly 1,200 depression patients, and successfully identified four distinct subtypes based upon connectivity alterations in the limbic system and frontostriatal pathways (subcortical pathways which feed into the default mode, salience, and central executive networks)11,12. By clustering subjects based upon network abnormalities, researchers developed sensitive, highly-specific neuroimaging biomarkers to differentiate depression subtypes11.
In another paper, resting-state fMRI revealed that patients with treatment-resistant depression had more localized network alterations than those patients who responded to treatment8. While both groups had disruptions to prefrontal-limbic-thalamic connectivity, treatment-resistant depression was characterized by stark alterations to prefrontal-limbic connectivity13.
Future work could provide psychiatrists and psychologists with the information they need to treat the patient’s depression subtype rather than the current generalized approach. In addition, identifying abnormal network connectivity could provide targets for neurostimulation techniques like TMS.
Brain Networks Associated with Depression
Research has associated depression with significant disruptions to connectivity in many key brain networks—tightly coupled brain regions that fluctuate in activity together during a task or at rest.
These networks and their contributions to depressive symptoms are:
- The salience network undergoes structural changes during depression, reducing in volume and increasing in coupling with the Default Mode Network, likely underpinning the characteristic changes in mood during MDD18.
- The sensorimotor network which demonstrates altered functional connectivity which scales with Depression intensity, and manifests feelings of fatigue, heaviness of limbs, and body and chest discomfort19.
- The visual system receives and processes visual stimuli. In MDD, retinal input to the visual system is compromised, causing deficiencies in contrast interpretation, and perceptual loss of complex visual information20.
- The limbic system, the core network for emotion, reactions to new stimuli, and memory - during depression induces feelings of detachment from self and others, as well as emotional reactivity21.
- The default mode network (DMN) which has reliably demonstrated heightened functional connectivity in MDD, relating directly to the severity and length of depressive episodes. The DMN additionally encodes self-referential thought, future thinking, and autobiographical memory, functions which become compromised in MDD22.
Identifying and characterizing alterations in these important brain networks is the first step to advancing our understanding of depression.
Figure 2. The salience network is one of many networks associated with symptoms of depression
The Future: Depression Therapy with Connectomics
Recently, connectomics has been used to explore the heterogeneity of depression. Siddiqi et al identified that independent depressive symptoms and their severity are driven by different connections between the major brain networks which underpin the disorder. Namely, anxiogenic symptoms were driven by connections from the Default Mode Network, whereas dysphoric symptoms - such as sadness and anhedonia - were driven by connections arising from the salience network23.
Figure 3. Color map of brain areas responsible for Anxiosomatic vs. Dysphoric symptoms of depression - adapted from Siddiqi et al., 2020
Moreover, evaluating an individual’s unique depression via their own brain connectivity enabled these researchers to adopt a more personalized neurostimulatory approach to effectively treat their patients symptoms. Another study, the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), adopted a similar approach, targeting unique brain regions with TMS based on their patients' underlying functional connectivity. This study found that 90.5% of the MDD patients investigated met remission criteria after five days of treatment, demonstrating the time-saving and effective response of leveraging connectomics to treat MDD24.
Connectomics is an exciting tool for studying depression, and it is clear that the human connectome plays an important role in the symptoms which define it. As the field of connectomics continues to progress, future individualized treatments may soon be uncovered.