Can brain wiring predict who benefits from TMS under stress?
Frontal magnetic stimulation did not lower the stress-hormone response on average, but women whose left prefrontal cortex was more strongly anti-coupled with the caudal anterior cingulate at rest showed a smaller cortisol rise after real stimulation.
Source
Individual resting-state frontocingular functional connectivity predicts the intermittent theta burst stimulation response to stress in healthy female volunteers
Study at a glance
- Design
- Human experiment — Randomised, sham-controlled within-subject crossover: resting-state fMRI at baseline, then on two days a Trier Social Stress Test followed by active or sham intermittent theta burst stimulation (iTBS) to the left DLPFC, at least a week apart.
- N
- N=34 · Four of the recruited women were excluded for incomplete scans or missing cortisol data, leaving 34 for the connectivity and cortisol analyses; 33 for the mood analyses.
- Population
- Healthy right-handed young women aged 18 to 27 using hormonal contraceptives, recruited at Ghent University
- Outcome
- Salivary cortisol after stress (area under the curve relative to increase and to ground) as a function of stimulation type and baseline DLPFC-to-ACC resting-state connectivity; mood ratings
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What they did
Healthy young women first had a resting-state fMRI scan to measure how the left dorsolateral prefrontal cortex (DLPFC), the usual TMS target in depression, was connected to five subregions of the anterior cingulate cortex (ACC). On two later days they underwent the Trier Social Stress Test (a mock job speech and mental arithmetic in front of a hidden jury) and then received two sessions of either real or sham intermittent theta burst stimulation over their individually located left DLPFC. Saliva cortisol was sampled repeatedly after the stressor.
What they found
The stress test raised cortisol on both days, but active stimulation did not change the cortisol response compared with sham. However, connectivity between the left DLPFC and the left caudal ACC interacted with stimulation: the more negative (anticorrelated) this baseline connection, the smaller the cortisol increase after active, but not sham, stimulation (a moderate positive correlation with active stimulation and none with sham). Connectivity with the subgenual ACC, a well-known predictor of TMS response in depressed patients, did not predict the effect.
The limits
What it doesn't show
Only healthy young women on hormonal contraceptives were tested, so the results cannot be generalised to men or to people with depression. The key result is an individual-difference correlation within one sample of 34 and needs replication; ten connectivity measures were tested, although a Bonferroni correction was applied. Stimulation came right after the stressor, so effects on the stress peak and on recovery cannot be separated, and the 5-minute gap between sessions is shorter than in most protocols. There was no separate measure of subjective stress beyond mood scales.
Key terms
- Intermittent theta burst stimulation (iTBS)
- A fast form of repetitive TMS delivering bursts of pulses in a theta rhythm, generally thought to increase excitability in the stimulated cortex.
- Resting-state functional connectivity
- The correlation between spontaneous BOLD signal fluctuations in two brain regions while a person rests; a negative value is called an anticorrelation.
- HPA axis
- The hypothalamic-pituitary-adrenal system that releases the stress hormone cortisol and normally switches itself off by negative feedback.
- Trier Social Stress Test (TSST)
- A standard lab stressor combining a public speech and mental arithmetic in front of an evaluating panel, reliably raising cortisol.
- Area under the curve with respect to increase (AUCi)
- A summary of cortisol samples that captures how much levels rose above the first measurement, indexing HPA-axis sensitivity.
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Quiz yourself
What was the average effect of active versus sham iTBS on post-stress cortisol?
Common questions
If active stimulation did nothing on average, why is the result interesting?
Because the effect depended on each person's brain connectivity; averaging over people who respond and people who don't can hide a real effect, which matches the large individual variability seen in clinical TMS.
Why stimulate the dorsolateral prefrontal cortex to change stress hormones?
TMS cannot reach deep limbic structures directly, so it targets an accessible cortical hub that is connected to regions such as the anterior cingulate that help regulate stress and mood.
Why was a sham coil used?
The sham coil looks and sounds like the real one but delivers no effective stimulation, so any difference between days can be attributed to the magnetic stimulation rather than expectations.
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