A personalized functional (f)MRI-guided transcranial magnetic stimulation (TMS) that focuses on threat neurocircuitry lowers amygdala threat reactivity and alleviates long-term symptoms of post-traumatic stress disorder (PTSD), reports a study.
“The positive results show the promise of personalized circuit-based TMS for PTSD and contribute to advancing precision psychiatry,” the researchers said.
Fifty adults with PTSD participated in this double-blind clinical trial and were randomly allocated to receive 10 twice-daily sessions of either 1-Hz TMS or sham TMS. TMS was delivered to an fMRI-guided target within the right dorsolateral prefrontal cortex (PFC) with the strongest functional connection to the right amygdala.
Active TMS resulted in a significant decrease in right amygdala threat reactivity (β, −0.09, 95 percent confidence interval [CI], −0.18 to −0.01; p=0.035) relative to sham TMS, but no significant effect was seen on skin conductance reactivity (β, 0.27, 95 percent CI, −0.43 to 0.97; p=0.4). [Am J Psychiatry 2026;183:343-354]
Significant reductions from pre- to post-TMS were observed in hyperarousal and total PTSD symptoms across groups (β, 0.27, 95 percent CI, −0.43 to 0.97; p=0.4), with no significant differences between groups. Active TMS also reduced hyperarousal (β, −3.59, 95 percent CI, −6.62 to −0.66; p=0.018) and total PTSD (β, −11.91, 95 percent CI, −20.82 to −3.01; p=0.010) from pre-TMS to follow-up.
“Clinical findings were found to be robust in sensitivity analyses,” the researchers said.
“These findings suggest the potential for a personalized approach to neuromodulation in individuals with PTSD,” they added.
Neurostimulation therapy
Neuroscience-guided approaches to neurostimulation therapy have also demonstrated potential in other psychiatric disorders. Moreover, the first personalized fMRI-guided TMS protocol for depression received FDA approval following the success of a clinical trial. However, the same strategy for PTSD is lacking. [Nat Mental Health 2023;1:1033-1042; Am J Psychiatry 2022;179:132-141]
Even in psychiatric disorders with more extensive neuromodulation research, few investigators have explored the mechanisms of TMS by measuring long-term neuroimaging outcomes, according to the researchers. [JAMA Psychiatry 2019; 76:71-78; Mol Psychiatry 2024;29:2678-2688]
“The findings of our neuroscience-guided clinical trial offer an important addition to ongoing efforts by other groups to optimize TMS for PTSD by defining neuroimaging predictors, (eg, greater ventromedial PFC–amygdala functional connectivity) and identifying neuroscience-guided targets,” they said. [Biol Psychiatry 2018;83:263-272; Nat Neurosci 2024;27:2231-2239; Am J Psychiatry 2019;176:939-948]
Ventromedial PFC
A key regulator in the threat circuit, the ventromedial PFC had dense projections to the amygdala, and high-frequency stimulation to a ventromedial PFC target “anticorrelated with the amygdala” is a potential treatment strategy to PTSD. [Nat Neurosci 2024;27:2231-2239]
“However, the location of the ventromedial PFC and choice of high-frequency stimulation could hinder tolerability, especially in a population with trauma exposure,” according to the researchers. “Our study was the first to use a personalized and accelerated approach, and … [w]e demonstrated that the amygdala can be modulated through low-frequency right dorsolateral PFC stimulation.”
In the current study, the dorsolateral PCS was “broadly defined to allow for the possibility that the strongest positive functional connections were observed in more medial regions. Further research on personalized TMS is needed to determine efficacy, feasibility, and tolerability,” the researchers said.