One Depression, Many Networks: A Symptom-Dimensional Systematic Review of Functional Connectivity

Rama M. Abbadi, Nanda B. Gopan, Spencer Eiting, Rachel Johnson, Ziad Nahas

DOI: Pending DOI

Synopsis

Depression is not one illness, and its neural underpinnings are not one problem. This systematic review linked brain network dysfunction to specific symptom dimensions in depression: rumination, anhedonia, anxiety, cognitive fatigue, and impaired emotion regulation. Across 58 studies, each dimension mapped onto a partially distinct network signature. Rumination involved failure of frontoparietal control over default mode network activity. Anhedonia involved disrupted reward circuit connectivity with the default mode network. Anxiety involved trait-level salience network hyperactivation. These patterns argue for symptom-level rather than diagnosis-level targeting in neuromodulation and motivate symptom-stratified target selection as a testable hypothesis for interventional trials.

Background

Depression is clinically heterogeneous, and attempts to map connectivity patterns onto diagnostic categories have produced inconsistent results. Subtype models suggest that network-level dysfunction cuts across DSM boundaries rather than tracking diagnosis (1), which raises a more fundamental question: what are these networks doing, and which symptoms do they regulate? Large-scale cortical networks, including the default mode network (DMN), salience network (SN), frontoparietal network (FPN), and cingulo-opercular (CO) network, offer a framework for answering that question (2). The SN gates switching between the internally-directed processing of the DMN and the externally-directed processing of the FPN (3), and its failure to do so cleanly has consequences across multiple symptom domains. Depression disrupts this architecture at multiple levels, altering within-DMN connectivity, DMN-FPN interactions, and SN function in ways that vary considerably across patients and bear little consistent relationship to total severity scores (2,4).
This review organizes the functional connectivity literature around five symptom dimensions: rumination, anhedonia, interoceptive distress, cognitive fatigue, and impaired cognitive reappraisal. We consider both static connectivity and dynamic approaches, since depression appears to involve not just abnormal connectivity strength but reduced flexibility and prolonged trapping in maladaptive network states (4, 5). Where available, we incorporate causal evidence from neuromodulation. The goal is to clarify which network dysfunction patterns drive which symptoms, and what that means for individualized target selection in interventional psychiatry (6).

Methods

PubMed was searched in March 2026 using a structured query combining terms for depressive disorders (major depressive disorder [MDD], treatment-resistant depression [TRD], bipolar depression, depressive episode), large-scale cortical networks and their canonical nodes (default mode network [DMN], salience network [SN], frontoparietal network [FPN], cingulo-opercular network [CO], medial prefrontal cortex [mPFC], posterior cingulate cortex [PCC], dorsolateral prefrontal cortex [DLPFC], anterior insula, dorsal anterior cingulate cortex [dACC]), functional connectivity [FC] methodology (resting-state fMRI, effective connectivity, dynamic connectivity), and symptom dimensions of interest (rumination, anhedonia, interoception, anxiety, cognitive fatigue, cognitive reappraisal). The search yielded 751 records.
Two reviewers independently screened all titles and abstracts against a five-step decision tree requiring: adult samples with confirmed depressive episodes (MDD, TRD, or bipolar depression), network-level connectivity focus, connectivity-based methodology, and direct linking of network findings to at least one target symptom dimension. Reviews, non-human studies, and pediatric samples were excluded. Inter-rater agreement was high across 751 screened records, with 36 conflicts adjudicated by a third independent reviewer. Of these, 145 advanced to full-text review, and 58 studies were included in the final synthesis following structured data extraction and quality assessment.

Results

58 studies met inclusion criteria: 39 resting-state fMRI, 8 task-based fMRI, 6 EEG, 3 MEG, and 1 fNIRS. Sample sizes ranged from 17 to 887. Most studies examined unipolar MDD (n=46); the remainder included TRD (n=7), bipolar depression during depressive episodes (n=2), and transdiagnostic samples (n=2). Interventions spanned ketamine, rTMS, ECT, ezogabine, MBCT, neurofeedback, transcutaneous vagus nerve stimulation, and antidepressants. Findings are summarized in Figure 1 (symptom-to-network mapping matrix; cell color encodes evidence strength from strong to indirect/absent).
Rumination (k=20). Reduced DMN-FPN anticorrelation and DMN hyperintegration were the most consistent findings, particularly in relation to brooding. Notably, dynamic FC outperformed static FC across multiple studies, with dmPFC temporal variability, MPFC-insula coupling dynamics, and posterior DMN-FPN co-activation patterns each predicting rumination severity where static models failed. SN connectivity during induced ruminative states tracked disengagement difficulty rather than thought content, dissociating SN and DMN contributions to the rumination phenotype. The closest thing to causal evidence in this dimension came from neurofeedback normalization of DLPFC-PCC anticorrelation, which reduced brooding specifically while leaving anxiety unchanged. Brooding and reflection mapped onto distinct DMN subsystem pairs across several independent samples.
Anhedonia (k=19). The most reproducible treatment-related finding was reward-DMN decoupling: striatal connectivity to PCC and sgACC connectivity to pgACC and ventral striatum tracked anhedonia improvement with both ketamine and ezogabine. The anticipatory-consummatory dissociation, where sgACC-striatal FC predicted anticipatory but not consummatory anhedonia, replicated across two drugs, two methodologies, and two diagnostic groups, suggesting some robustness to this specific dissociation Cross-modal support came from EEG, where DMN-FPN alpha hyperconnectivity correlated with SHAPS scores but not with total depression severity.
Anxiety and Interoception (k=14). SN hyperactivation, including amygdala-SN coupling and insula-cerebellar hyperconnectivity, appeared as a trait feature present even in remitted MDD. A multimodal study found that cortisol failed to engage adaptive FPN-threat network coupling in both current and remitted depression, while rACC GABAergic tone modulated DMN-SN connectivity under stress only in healthy controls, pointing to a neurochemical basis for why stress reliably triggers rumination in depression but not in health.
Preliminary Signals in Underrepresented Dimensions:
Cognitive Fatigue (k=6, preliminary). Reduced DMN and FPN flexibility, prolonged dwell time in hypoconnected states, and CCN-somatomotor hyperconnectivity each predicted fatigue severity independently of total depression scores, with the CCN-fatigue link specifically demonstrated in older adults.
Cognitive Reappraisal (k=5, preliminary). FPN hypoamplitude was a trait-level finding in lifetime MDD, present regardless of current symptom state. Insula subdivision analyses dissociated emotion processing from regulation impairments, with dlPFC connectivity implicated specifically in reappraisal capacity rather than emotional reactivity.
Across all five dimensions, dimensional instruments revealed connectivity patterns that total severity scores consistently missed.

Discussion

This review demonstrates that organizing the functional connectivity literature around symptom dimensions rather than diagnostic categories reveals coherent network-symptom relationships that total severity approaches obscure. Across 58 studies, each dimension mapped onto a partially distinct network signature: DMN-FPN anticorrelation loss and SN disengagement failure for rumination (4,7, 8, 9), reward-DMN decoupling for anhedonia (10, 11), SN trait hyperactivation for anxiety and interoception (12), and FPN flexibility deficits for cognitive fatigue (13, 14). These patterns were detectable only when studies used validated dimensional instruments, reinforcing the argument that total severity scores are insufficient for network-level mechanistic inference.
The clinical implication is direct. If rumination and anhedonia involve partially dissociable circuits, neuromodulation target selection should reflect that dissociation. The anticipatory-consummatory anhedonia finding, replicated across two drugs and two methodologies (10, 11), and the brooding-specific response to DLPFC-PCC neurofeedback (9) both suggest that symptom-level precision in target selection is not only possible but necessary.
Several limitations warrant acknowledgment. The review draws from a single database, introducing potential selection bias. Cognitive fatigue (k=6) and cognitive reappraisal (k=5) remain underrepresented relative to rumination and anhedonia, and most included studies are cross-sectional, limiting causal inference. Future work should prioritize longitudinal designs, dynamic connectivity methods, and dimensional outcome measurement.

Disclosures

Nothing to disclose by any author(s).

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