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Depressive disorders are a group of mental health conditions characterized by pervasive feelings of sadness, diminished pleasure in life, and a significant impact on daily functioning. These conditions are most prevalent in individuals during their 30s and affect women at twice the rate of men. Contrary to popular belief, younger individuals are generally more susceptible to these disorders than older adults. Two key types of depressive disorders include Major Depressive Disorder (MDD) and...
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Differences in High-Frequency Connectivity Among Large-Scale Functional Networks Linked to Major Depressive Disorder

Ty Lees1,2, Sarah E Woronko1, Mohan Li1

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|October 17, 2025
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Major depressive disorder (MDD) and treatment-resistant depression (TRD) show distinct neural connectivity patterns. TRD exhibits increased connectivity within the default mode network (DMN) and between the DMN, frontoparietal network (FPN), and salience network (SN) in beta frequency bands.

Keywords:
EEGElectroencephalographyFunctional connectivityLORETAResting-state

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Area of Science:

  • Neuroscience
  • Psychiatry
  • Brain Imaging

Background:

  • Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD) are associated with altered neural connectivity.
  • The triple network model, involving the Default Mode Network (DMN), Frontoparietal Network (FPN), and Salience Network (SN), is central to understanding these alterations.
  • The precise nature and specificity of these connectivity changes in MDD versus TRD remain unclear.

Purpose of the Study:

  • To compare high-frequency resting-state functional connectivity (rsFC) within and between the DMN, FPN, and SN.
  • To investigate differences in rsFC between healthy controls (HC), individuals with MDD, and individuals with TRD.
  • To elucidate the neural mechanisms underlying treatment resistance in depression.

Main Methods:

  • Resting-state electroencephalogram (EEG) data were collected from 34 MDD, 24 TRD, and 34 HC participants.
  • Exact low-resolution electromagnetic tomography was employed to estimate theta and beta rsFC.
  • Connectivity was analyzed within and between the DMN, FPN, and SN.

Main Results:

  • Individuals with depression (MDD and TRD pooled) exhibited enhanced within-DMN beta1 connectivity compared to controls.
  • Participants with TRD showed significantly increased within-DMN, DMN-to-FPN, and FPN-to-SN beta3 connectivity compared to MDD participants.
  • These connectivity differences persisted even after controlling for current depressive symptom severity.

Conclusions:

  • High-frequency rsFC differences, particularly in beta bands, within and between the DMN, FPN, and SN may underlie treatment resistance in depression.
  • Further research is needed to explore the impact of heterogeneity factors like medication, age of onset, and episode history.
  • Understanding the temporal dynamics of depressive episodes is crucial for a comprehensive view of neural connectivity changes.