Probing the Dorsolateral Prefrontal Cortex and Central Executive Network for Improving Neuromodulation in Depression

There is a critical need for more effective treatments for depression, which currently affect 20% of Americans during our lifetimes. Brain stimulation treatments, including repetitive transcranial magnetic stimulation (rTMS), represent the front line of innovative approaches by directly targeting and correcting specific dysfunctional brain networks. A core dysfunctional network in major depressive disorder is the fronto-parietal central executive network (CEN), a network critical for decision making and cognitive control. The CEN includes the dorsolateral prefrontal cortex (dlPFC), the target of FDA-cleared rTMS treatment for depression. rTMS to the dlPFC is thought to improve depression by modulating local dlPFC excitability and enhancing downstream CEN connectivity. However, our ability to probe the CEN and study this potential mechanism on an individual basis is critically lacking, likely contributing to suboptimal rTMS remission rates (20-40%). We hypothesize that the CEN connectivity is weakened in depression and can be maximally modulated by individualizing localization.

To test this hypothesis, a single rTMS 'dose,' prospective, randomized, double-blind, cross-over design with 50 depressed patients was conducted to characterize the effects of intermittent theta burst stimulation (iTBS) on frontoparietal network excitability. Participants were 18-65 years old and screened to exclude psychiatric or neurological disorders, including moderate or greater depressive symptoms.

Participants first underwent MRI scanning to obtain structural brain data for neuronavigation. During the experimental session, intermittent theta burst stimulation (iTBS) was applied to the dlPFC to modulate the CEN. Two stimulation conditions were administered in randomized order: real iTBS and sham iTBS. To probe network-level changes, single-pulse TMS (spTMS) was applied to both the dlPFC and posterior parietal cortex (PPC) before and after iTBS. These probes were interleaved with iTBS in alternating blocks, allowing for repeated assessments of cortical excitability and connectivity across time. TMS-evoked potentials (TEPs) were recorded using EEG to quantify changes in both local (dlPFC) and downstream (parietal cortex) responses. The primary outcome was the change in TMS-evoked EEG responses (e.g., early TEP components) following iTBS.

This study design enables characterization of the temporal dynamics and dose-dependent effects of iTBS on human brain networks. Findings from this work provide insight into mechanisms of noninvasive brain stimulation and may inform future efforts to optimize personalized neuromodulation strategies for neuropsychiatric disorders.

Inclusion criteria

• Men and women, ages 18 to 65
• Depression assessed through in-depth Structured Clinical Interview for DMS-5 (SCID-I)
• PHQ9 > 10 for disease severity
• Must comprehend English well to ensure adequate comprehension of the EEG and TMS instructions, and of clinical scales
• Right-handed
• No current or history of neurological disorders
• No seizure disorder or risk of seizures
• No use of PRN medication within 24 hours of the scheduled study appointment

Exclusion criteria

• Those with a contraindication for MRIs (e.g. implanted metal)
• Any unstable medical condition
• History of head trauma with loss of consciousness
• History of seizures
• Neurological or uncontrolled medical disease
• Active substance abuse
• Diagnosis of psychotic or bipolar disorder
• A prior history of ECT or rTMS failure
• Currently taking medications that substantially reduce seizure threshold (e.g., olanzapine, chlorpromazine, lithium)
• Currently pregnant or breastfeeding