Researchers pinpoint brain lesions that reduce PTSD symptoms in veterans, showing that targeting the PTSD circuit with TMS could lead to a breakthrough in noninvasive treatments for trauma survivors.
Study: A potential target for noninvasive neuromodulation of PTSD symptoms derived from focal brain lesions in veterans. Image Credit: Andrew Angelov / Shutterstock.com
A recent Nature Neuroscience study explores the optimal neuroanatomical target to treat post-traumatic stress disorder (PTSD) in veterans.
Neuromodulation and PTSD
Approximately 30% of military combat veterans and trauma survivors develop PTSD, a condition that is characterized by depression, suicidal tendencies, and substance use. Existing PTSD therapies include medications and psychotherapy, both of which are moderately effective; therefore, there remains an urgent need to develop more effective treatments for PTSD.
Neuromodulation is a powerful technique that activates or inhibits brain circuits associated with a given symptom or disorder. Preliminary assessments have shown that focal modulation of the amygdala with deep brain stimulation (DBS), responsive neurostimulation, and laser ablation are effective for managing PTSD.
Non-invasive techniques like transcranial magnetic stimulation (TMS) cannot directly access deep targets within the brain, particularly the amygdala. Nevertheless, this approach can target the dorsolateral prefrontal cortex (DLPFC), which has been shown to alleviate major depression.
Importantly, two multi-center clinical trials have indicated that effective antidepressant targets may adversely affect PTSD, thus emphasizing the importance of developing targeted treatments specific to PTSD.
About the study
Based on a previous causal lesion-derived circuit model of PTSD, the current study identified TMS targets associated with PTSD symptoms independent of depression. All relevant data were obtained from the Vietnam Head Injury Study (VHIS).
Participants who suffered severe traumatic injuries during the Vietnam War were recruited for the study, 197 of whom had a history of penetrating head injury that caused a focal brain lesion. Fifty-five study participants sustained non-neurological injuries of comparable severity and were considered controls.
The boundaries of each lesion were identified through head computed tomography (CT) scans. Study participants with incomplete data were excluded from the analysis.
The Structured Clinical Interview for DSM-IV-TR Axis I disorders, Non-Patient Edition (SCID) was considered as the primary outcome. To determine whether a particular brain lesion influenced PTSD symptoms, an unpaired t-test was performed to compare PTSD scores between the brain lesion and control groups. Voxel lesion-symptom mapping (VLSM) was used to determine specific voxels associated with PTSD.
The resting-state functional connectivity (rsFC) between each lesion location and all other brain voxels was estimated using a normative human connectome database. This approach created a whole brain “connectivity map” for each participant.
A total of 193 military veterans with penetrating traumatic brain injury (TBI) were considered to assess whether brain connectivity influences PTSD. Furthermore, 20 veterans were selected to determine whether TMS-induced change in this circuit improves PTSD severity.
Study findings
Patients with amygdala lesions had lower PTSD scores than those with other lesions, whereas most patients without PTSD symptoms developed lesions outside the amygdala.
Brain lesions that were associated with lower PTSD incidence included the medial prefrontal cortex (mPFC), medial temporal lobe, and anterolateral temporal lobe, which were collectively referred to as the “PTSD circuit.” Within the PTSD circuit, the tapetum of the corpus callosum, which connects both medial temporal lobes together, was identified as the peak region. The PTSD circuit was not associated with comorbidities like anxiety, alcoholism, or cognitive impairment.
When a whole-brain analysis was conducted using the VLSM map, no individual locations associated with PTSD were identified.
To clarify the generalizability of the circuit, the lesion-derived PTSD circuit was compared with a map of published PTSD-related neuroimaging findings. To this end, the previously published neuroimaging correlates of PTSD were consistent with the lesion-based PTSD circuit identified in the current study.
The researchers also conducted a connectome-wide association study (CWAS), which indicated that PTSD-associated voxels were more likely to be present inside of the PTSD circuit. The default mode network (DMN), which refers to regions of the brain that are active during self-directed thought, contained a significant proportion of PTSD-associated voxels, though to a lesser extent than the voxel density present within the lesion-based PTSD circuit.
Targeting the PTSD circuit with TMS
Previous studies involving targeted TMS indicate that this treatment induced increased changes in fear when the PTSD circuit was targeted. Additional studies were also reviewed and found to confirm the researchers’ hypothesis that inhibitory TMS reduces fear conditioning, thereby increasing the effects of a traumatic event in the affected individual, whereas excitatory TMS to the PTSD circuit may improve fear.
In the current study, the researchers treated a 62-year-old man with treatment-resistant PTSD due to childhood physical abuse with TMS targeted to the PTSD circuit. The patient underwent a total of 50 sessions of accelerated intermittent theta burst stimulation (iTBS) over a seven-day period, following which the patient reported sustained improvements in his PTSD symptom severity for four weeks.
The peak superficial node in the PTSD circuit, the medial prefrontal cortex, may serve as a promising TMS target for PTSD.”
Journal reference:
- Siddiqi, S. H., Philip, N. S., Palm, S., et al. (2024) A potential target for noninvasive neuromodulation of PTSD symptoms derived from focal brain lesions in veterans. Nature Neuroscience 1-9. doi:10.1038/s41593-024-01772-7