Exploring Closed-Loop Amygdala Neurostimulation as a Breakthrough Approach for Treatment-Resistant Post-traumatic Stress Disorder

Published in Neuroscience
Exploring Closed-Loop Amygdala Neurostimulation as a Breakthrough Approach for Treatment-Resistant Post-traumatic Stress Disorder
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In a novel pilot study, we investigated the neurophysiological processes in the human amygdala related to post-traumatic stress disorder (PTSD). We closely monitored intracranial electroencephalographic activity over one year in two individuals with implanted amygdala electrodes for the management of treatment-resistant PTSD. We observed specific increases in low-frequency brain activity in the amygdala during aversive experiences. Subsequent utilization of elevated low-frequency power as a trigger for closed-loop neuromodulation resulted in significant reductions in PTSD symptoms following one year of treatment. Additionally, we observed decreased amygdala theta activity associated with aversive experiences along with clinical improvements. These early findings suggest that targeting elevated amygdala theta activity during negative emotional states may hold promise for future closed-loop neuromodulation therapies in PTSD.

The Idea: Functional Neurosurgery for Post-traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) has been a prominent issue at the Departments of Defense and Veterans Affairs especially since the conflicts in Iraq and Afghanistan. Although most patients improve through the application of psychotherapy and medication, there remains a significant subset (roughly 30% of individuals) who continue to suffer1. Given the severity of the issue, our research group became intrigued by the potential of neuromodulation as a therapeutic avenue for those resistant to conventional treatments. Drawing from our collective clinical experience, we recognized that deep brain stimulation (DBS) mimics a functional inactivation of the area targeted in movement disorder. This notion was further reinforced by the groundbreaking work of Helen Mayberg and Andres Lozano2, who have previously employed DBS to target a specific brain region that exhibited heightened activity during episodes of depressive symptoms. Remarkably, their patients exhibited notable improvements, suggesting that DBS could also be effective in alleviating emotional symptoms by modulating hyperactive brain regions. Functional neuroimaging studies have consistently revealed hyperactivity in the amygdala during periods of symptomatic episodes in patients with PTSD3. Consequently, it appeared plausible that DBS neuromodulation could be applied to regulate amygdala activity and, in turn, ameliorate the symptoms associated with PTSD.

Bridging the Gap: From Rodents to Humans

In our initial pre-clinical investigation, we embarked on a study utilizing rodents as a model for PTSD4. The animals were subjected to foot shock while in the presence of a small tennis ball, and a week later, they were reintroduced to the ball. Notably, the group of animals treated with DBS exhibited playful behavior towards the ball, whereas the untreated group displayed symptoms akin to PTSD, such as hiding the ball under the bedding. This observation indicated that DBS treatment had a normalizing effect on the behavior of the treated rats within this PTSD model. Encouraged by these findings, we formulated a hypothesis that humans suffering from treatment-resistant PTSD could potentially benefit from amygdala DBS as a novel therapeutic approach. Building upon this pre-clinical evidence, we proposed a clinical trial5 involving patients with treatment-resistant PTSD to further investigate the efficacy of DBS. Two patients underwent the surgical procedure, and the outcomes have been highly promising. The first patient achieved clinical remission, experiencing an impressive 80% reduction in symptoms. The second patient continues to exhibit improvement, with an initial 30% reduction in symptoms. These results underscore the potential of amygdala DBS as a viable treatment option for individuals who have not responded to conventional therapies. In light of these findings and inspired by the success of responsive neurostimulation in treating epilepsy, we recognized the benefits that a closed-loop strategy could offer over an open-loop system. Consequently, our efforts have focused on identifying specific neural substrates associated with PTSD symptoms, aiming to establish a neural signature that can trigger on-demand stimulation.

Closed-loop Amygdala Neurostimulation as a Breakthrough Approach for Treatment-resistant PTSD

In our recent pilot study, our research group utilized intracranial electroencephalography (iEEG) to directly collect data from the amygdala over a one-year period. The study involved two male combat veterans with treatment-resistant PTSD (TR-PTSD) who had implanted electrodes in their amygdala. Brain activity was assessed during exposure to aversive stimuli in three difference paradigms, including exposure to negative emotional images (Fig. 1a), listening to personalized trauma-related memories, and self-reporting of symptom exacerbation in daily life. Our findings revealed a significant increase in amygdala theta activity (brain waves with frequencies between 5 and 9 Hz) during aversive periods compared to positive or neutral stimuli across tasks (Fig. 1b, left panel). This increase in theta activity was specifically observed in our TR-PTSD participants and absent in a group of epilepsy participants without TR-PTSD (Fig. 1b, right panel). To explore potential therapeutic interventions, we used the neural signature of elevated theta activity to introduce closed-loop neuromodulation therapy. The implanted device was programmed such that stimulation was automatically triggered upon elevations in amygdala low-frequency activity. Remarkably, in the course of 11 months of closed-loop stimulation, both participants (TR-PTSD 1 and TR-PTSD 2) experienced meaningful reductions in their PTSD symptoms as measured by clinician-rated and patient-rated assessments along with increases in daily therapy stimulation counts (Fig. 1 c and d). 

Figure 1: a, Emotional Image Task showing illustrative neutral, positive, and negative images. b, Norm. amygdala theta (5-9 Hz) bandpower in TR-PTSD participants (squares = TR-PTSD 1, triangles = TR-PTSD 2) but not epilepsy (non-TR-PTSD) was significantly increased during the presentation of negative (red) compared to pos/neu (blue) images. ** = p < 0.01. c, Changes in CAPS-5 scores (gray) for TR-PTSD 1 during pre-stimulation (Pre-Stim) periods (baseline 1, 2, and month 1) and post-stimulation periods (Month 2-12) along with changes in mean (± s.e.m.) daily therapy (stimulation) counts (orange) over the same time period. Gray * = reliable change in CAPS-5 relative to Pre-Stim periods. d, Same as c but for TR-PTSD 2.

Interestingly, the initial differentiation in amygdala theta power between aversive and positive/neutral stimuli during exposure to images and personalized trauma reminders in individuals with TR-PTSD was no longer observed after 11 months of closed-loop neurostimulation. Our findings provide preliminary evidence supporting the effectiveness of closed-loop neuromodulation therapy as a potential avenue for addressing elevated amygdala theta activity in patients with TR-PTSD and for improving PTSD symptoms that were not treatable before. By employing this pioneering approach, our objective is to enhance the precision and effectiveness of responsive neurostimulation in alleviating PTSD symptoms, thereby paving the way for more targeted and personalized treatments for PTSD in the future. 

References:

  1. Jonas, D. E. et al. Psychological and Pharmacological Treatments for Adults With Posttraumatic Stress Disorder (PTSD). (Agency for Healthcare Research and Quality (US), 2013).
  2. Mayberg, H. S. et al. Deep Brain Stimulation for Treatment-Resistant Depression. Neuron 45, 651–660 (2005).
  3. Etkin, A. & Wager, T. D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 164, 1476–1488 (2007).
  4. Langevin, J.-P., De Salles, A. A. F., Kosoyan, H. P. & Krahl, S. E. Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. Journal of Psychiatric Research 44, 1241–1245 (2010).
  5. Langevin, J.-P. et al. Deep Brain Stimulation of the Basolateral Amygdala for Treatment-Refractory Posttraumatic Stress Disorder. Biological Psychiatry 79, e82–e84 (2016).

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