Deep brain stimulation of the subgenual cingulum and uncinate fasciculus for the treatment of posttraumatic stress disorder

Abstract

Deep brain stimulation (DBS) has been investigated for neuropsychiatric disorders. In this phase 1 trial, we treated four posttraumatic stress disorder (PTSD) patients with DBS delivered to the subgenual cingulum and the uncinate fasciculus. In addition to validated clinical scales, patients underwent neuroimaging studies and psychophysiological assessments of fear conditioning, extinction, and recall. We show that the procedure is safe and potentially effective (55% reduction in Clinical Administered PTSD Scale scores). Posttreatment imaging data revealed metabolic activity changes in PTSD neurocircuits. During psychophysiological assessments, patients with PTSD had higher skin conductance responses when tested for recall compared to healthy controls. After DBS, this objectively measured variable was significantly reduced. Last, we found that a ratio between recall of extinguished and nonextinguished conditioned responses had a strong correlation with clinical outcome. As this variable was recorded at baseline, it may comprise a potential biomarker of treatment response.

A pilot study of closed-loop neuromodulation for treatment-resistant post-traumatic stress disorder

“…Moreover, we have shown that amygdala closed-loop neurostimulation leads to a decline in both PTSD symptomatology and amygdala reactivity to aversive stimuli, which may be due to neuroplasticity-related changes over time. These findings are consistent with our previous case report of reduced PTSD symptoms after open-loop deep brain stimulation (DBS) of the amygdala 24 and of the subgenual cingulum and uncinate fasciculus (which links the prefrontal cortex and amygdala via fiber tracts) 25 . Though prior work demonstrating that amygdala emotional responses are fairly stable across repeated exposures 26 suggests that reduced theta reactivity shown here is likely related to chronic neuromodulation, and not habituation, future non-invasive and invasive neurophysiological recording studies aimed to track the effect of repeated emotional paradigm exposure will be needed to corroborate this hypothesis.…”

“…Since clinical improvements in this study were accompanied by reduced amygdala theta reactivity towards aversive stimuli, closed-loop stimulation may contribute to a normalization of altered brain circuity in PTSD. Though we show that theta activity is modulated by valence separately in two TR-PTSD participants across three separate behavioral paradigms, future studies using larger sample sizes will be needed to generalize our findings to the larger TR-PTSD population, determine scalability of approach, and further characterize network-related changes during encoding of negative emotional valence and/or re-experiencing of trauma in PTSD – namely, interactions between the amygdala and other potentially involved brain structures such as the prefrontal cortex, hippocampus, subgenual cingulum and uncinate fasiculus 1 , 25 , 30 . Additionally, though we do not observe image valence-related changes in non-TR-PTSD participants across recording modalities, further investigation will be needed to corroborate our findings and investigate potential differences in valence-related oscillatory changes across different amygdala subregions in individuals without TR-PTSD.…”

A potential neuromodulation target for PTSD in Veterans derived from focal brain lesions

“…For instance, focal modulation of the amygdala with deep brain stimulation (DBS) 8 , laser ablation 10 , and responsive neurostimulation 11 has shown preliminary e cacy for PTSD in case reports, consistent with the nding that incidental lesions to the amygdala can reduce probability of PTSD 12 . Similar results have been seen with DBS to the uncinate fasciculus, which connects the amygdala to the ventromedial prefrontal cortex 13,14 . However, these invasive procedures may not be appropriate for many patients.…”

Regional associations of white matter integrity and neurological, post-traumatic stress disorder and autonomic symptoms in Veterans with and without history of loss of consciousness in mild TBI

“…It is notable that the strongest relationships between FA and stress measures (i.e., both global symptom severity and RSA/BRS difference scores) were found in the ATR and UNC across the full sample. Connecting orbitofrontal cortex to anterior temporal lobes, the UNC is particularly vulnerable to shearing injuries in TBI (Seo et al, 2012 ), and has been identified as a potential treatment target for deep brain stimulation treatment of PTSD (Hamani et al, 2022 ). The ATR, part of the anterior limb of the internal capsule, connects dorsolateral prefrontal cortex to the thalamus.…”