The dysregulation of the default mode network (DMN), task-positive network (TPN), and salience network (SN) in depression arises from a complex interplay of biological, psychological, and environmental factors. Here's a synthesis of current research:

 Key Causes of Network Dysregulation in Depression

1. Chronic Stress and HPA Axis Dysfunction

• Prolonged stress activates the hypothalamic-pituitary-adrenal (HPA) axis, leading to elevated cortisol.

• This neuroendocrine disruption affects brain regions like the anterior cingulate cortex and insula (key nodes in the salience network), impairing their ability to regulate attention and emotion.

2. Rumination and Self-Referential Thought

• Depressed individuals often engage in persistent rumination—repetitive, negative self-focused thinking.

• This strengthens DMN connectivity, particularly between the medial prefrontal cortex and posterior cingulate cortex, reinforcing inward attention loops.

3. Reduced Neuroplasticity and Synaptic Efficiency

• Depression is associated with decreased levels of brain-derived neurotrophic factor (BDNF), which impairs synaptic plasticity.

• This affects the dynamic switching between networks, especially the salience network’s ability to recruit the TPN.

4. Functional Connectivity Imbalance

• Studies show hyperconnectivity within the DMN and hypoconnectivity between the DMN and TPN.

• The salience network, which normally toggles between internal and external focus, becomes biased toward internal negative stimuli, failing to activate task-oriented engagement.

5. Structural Brain Changes

• MRI studies reveal volume reductions in the anterior insula and dorsal anterior cingulate cortex—core regions of the salience network.

• These structural changes impair the network’s ability to detect and respond to salient external cues.

6. Genetic and Epigenetic Vulnerabilities

• Certain genetic polymorphisms (e.g., in serotonin transporters or BDNF) predispose individuals to altered network dynamics.

• Epigenetic modifications from early life stress can also prime the brain for maladaptive connectivity patterns.

Why This Matters

The triple network model (DMN, TPN, SN) offers a powerful framework for understanding depression not just as a chemical imbalance, but as a disrupted attentional architecture. The salience network’s failure to arbitrate between internal and external relevance traps the brain in a loop of self-referential negativity, preventing outward engagement and action.

This model also helps explain why interventions like mindfulness, psychedelics, and cognitive behavioral therapy—which recalibrate attention and salience—can restore healthier network dynamics.