Unilateral amygdala ablation: a potential treatment option for severe chronic post-traumatic stress disorder (PTSD)?

KEYWORDS:

• amygdala
• PTSD
• neuromodulation
• magnetic resonance imaging (MRI)
• psychophysiology
• neurosurgery
• fear neurocircuitry
• hippocampus

1. Introduction

Post-traumatic stress disorder (PTSD) is a debilitating disorder that occurs when psychiatric symptoms, such as flashbacks, nightmares, and hyperarousal, develop after exposure to a traumatic event. Unfortunately, PTSD diagnoses and trauma exposure are prevalent in many communities today. About 70% of adults have experienced a traumatic event at least once, and lifetime PTSD estimates range between 6% and 9%, with even higher levels reported in at-risk or low-resourced populations [1–3]. Data shows that the increasing rates of PTSD in our communities constitute a public health crisis that warrants more attention, research, and better treatment. Although the recommended PTSD treatments, such as trauma-focused therapy, with or without medication, are successful for some patients, studies have found that about 30–50% of PTSD patients do not respond to current treatment options [4], which illustrates the importance of developing new methods and ways of treating this disorder.

Interestingly, functional magnetic resonance imaging (fMRI) studies have shown that the amygdala could be a determining factor behind PTSD treatment non-response [5]. The amygdala is a brain structure involved in emotion processing and associative fear learning. The amygdala has many essential activation centers for common PTSD symptoms, such as the feeling of fear, the fight/flight response, and hyperarousal (for example, being on guard). We and others have found that amygdala hyper-reactivity, particularly in the right brain hemisphere, predicts PTSD symptom development, severity, and treatment non-response [5–9]. Whether these findings indicate a causal role of amygdala hyper-reactivity in PTSD symptom maintenance and treatment non-response is less understood.

In promising news, however, a significant development in our current understanding of the link between the amygdala and PTSD was found in a case series we published in 2020. In this series, ablating the right amygdala along with an epileptic hippocampus was associated with unambiguous improvements in PTSD symptoms [10]. Two patients with medically refractory medial temporal lobe epilepsy with comorbid PTSD underwent amygdala ablation, a procedure in which the right amygdala is destroyed by laser interstitial thermal therapy. In this surgery, the neurosurgeon uses real-time MRI thermography to guide the probe and laser heat to irreversibly ablate part of the medial temporal lobe, specifically including the unilateral amygdala and anterior hippocampus. After ablation, the patients’ seizure frequencies decreased, but they also reported greater tolerance of events that had previously triggered their PTSD symptoms. We also observed changes in their fMRI results (including reduced threat reactivity in brain areas remote from the ablation, such as contralateral amygdala as well as the dorsal anterior cingulate cortex, and increase in ventromedial prefrontal cortex threat reactivity), psychophysiological responses to fear, and ability to distinguish danger and safety. Our prior findings therefore suggest that reducing or eliminating amygdala function could improve chronic PTSD symptoms and treatment response.

These findings have generated patient and clinician interest in the possibility of using amygdala ablation as a treatment for severe, chronic, refractory PTSD. The feasibility of ablating the brain region so causally associated with PTSD is potentially appealing and may be a welcome and more direct and definitive treatment for patients with PTSD who have exhausted other options. Despite this promise, however, several caveats are essential to consider in the context of its future potential treatment for severe, chronic, treatment-resistant PTSD.

Our published results to date, while suggestive, are nevertheless preliminary. First, we made observations only in patients suffering from both right medial temporal lobe epilepsy and PTSD, which may undermine the generalizability to patients with PTSD alone. Second, we observed the effects of combined right amygdala and anterior hippocampus ablation. While the amygdala has been directly implicated in PTSD by other studies, lending face validity to the amygdala’s causal role, our preliminary results do not formally dissect the benefits of isolated amygdala ablation. Third, there are case reports suggesting development or worsening of PTSD symptoms after left amygdala-hippocampectomy [11] or left amygdalotomy [12], as well as a case report of development of PTSD after right temporal lobe ablation that included the right amygdala, hippocampus and temporal pole [13], which suggests that specificity of hemisphere and regions for ablation is critical and warrants further investigation. Fourth, our small, open-label, uncontrolled, prospective, observational case series does not constitute a formal clinical trial of a design that would maximize the quality of the results. Randomized controlled trials (RCT) comparing the safety and effectiveness of the investigation intervention to standard of care therapy (medication and cognitive-behavioral therapy), and ideally utilizing blinding and even sham surgery control (when ethical to perform a sham surgery and feasible), are the preferred approach. While the necessity of alternative clinical trial designs for novel surgical therapies is increasingly recognized, the fraught history of psychosurgery in the middle of the last century demands the highest level of attention to ethical oversight to guarantee informed consent and appropriate trial design for surgery for psychiatric indications.

Safety and effectiveness, including recovery duration and treatment longevity, of amygdala ablation for treating PTSD, remain key questions. In our case series, we observed that patients did not completely recover from all PTSD-related symptoms after ablation; however, they did recover sufficiently such that they no longer met the clinical criteria for PTSD. One of the patients in our case series reported that six months after surgery, she was still checking for danger but not feeling the fear she used to feel. By 12 months post-surgery, she no longer reported these behaviors. These findings may indicate bottom-up learning, which eventually overrides previously learned behaviors. If persistently heightened amygdala reactivity prevents extinction learning, ablation may allow a break in this cycle and permit a return to a more adaptive state of extinction learning. What we also have yet to investigate is the effects of potential retraumatization after amygdala ablation. Notably, a study by Koenigs et al. in 2007 [14] suggested that individuals with brain damage to areas including the amygdala and the ventromedial prefrontal cortex (vmPFC) did not develop PTSD compared to control subjects with injuries to other brain regions. Their data suggested that PTSD is associated with the overactivation of the amygdala, with correlations to a lack of inhibition by vmPFC and decreased hippocampal function, which again indicates the importance of the amygdala.

Regarding the issue of generalizability of our prior observations, epilepsy patients have brain alterations that lead to seizure activity, meaning the ablated tissue is pathological. In these cases, even though ablation of medial temporal lobe structures for treatment-resistant epilepsy is associated with some measurable adverse effects on spatial recall and pattern recognition [9], the benefits of controlling the seizures outweighed the risks of treatment. The risk versus benefits assessment may be different in a non-epileptic brain. Importantly, amygdala alation is a surgical procedure that may have unforeseen irreversible effects in individuals who do not have epilepsy. Currently, there is no data on the potential impact of amygdala ablation on emotional, cognitive, or other clinical outcomes in non-epileptic patients. Extrapolating available data on these outcomes in epilepsy patients suggests an optimistic picture [15], but for serious consideration of this treatment, data in non-epilepsy patients is needed. An obvious next step is more research into this area in PTSD patients without epilepsy, but the same uncertainties and risks would still apply. The challenge for researchers now is how to effectively translate what we have learned about the relationships between the amygdala and PTSD from epileptic patients with PTSD to a patient population without epilepsy.

There is an exciting discussion to explore between the optimism for the future application of ablation from a clinical perspective, in contrast to the cautious views from the viewpoint of researchers. From a research perspective, there is not enough data to support amygdala ablation treatment for clinical use, and even the initiation of a clinical trial is restricted at this moment. However, a team of interdisciplinary specialists, including neurosurgeons, psychiatrists, neurologists, and psychologists, could deliberate the use of ablation when carefully considering all treatment options that a patient may have exhausted and then balance the risk associated with treatment versus no treatment. There is much work to be done before concluding that amygdala ablation would significantly benefit certain patients with PTSD, but our early results suggest the feasibility of such clinical studies.

Finally, investigations in patients undergoing amygdala ablation, essentially a form of lesion-symptom mapping that remains a cornerstone of clinical neuroscience, may be relevant to developing nondestructive or neuromodulatory approaches to treating PTSD. Learning more about the effects of ablation on PTSD symptoms contributes to an understanding of the interaction among different brain regions involved in the development and maintenance of PTSD symptoms, which themselves may be therapeutic targets.

2. Expert opinion

Focal ablative neurosurgical approaches have shown promise in clinical applications. For example, Albazron et al. [16] used lesion-symptom mapping to identify mood-regulating brain regions and found significant improvement in average mood ratings after amygdala resection. Laser interstitial thermal therapy and MRI-guided ultrasound procedures have also been correlated with improvement in symptom severity for refractory obsessive-compulsive disorder [17,18]. These findings highlight the potential of utilizing neurosurgical approaches in mapping and modulating specific brain circuits implicated in psychiatric conditions. Although neurosurgical treatments of PTSD remain investigational, and widespread clinical use would be premature, early results suggest that amygdala ablation in select individuals might provide a dramatic improvement in severe, disabling symptoms. Such validation of a causal role of the amygdala in PTSD symptoms and treatment failure informs ongoing efforts to refine hypotheses about how the pathological network nodes that mediate PTSD may be both invasively and non-invasively targeted.

Another elective surgical treatment is Deep Brain Stimulation (DBS) which implanting electrodes that can regulate irregular brain activity and can correct for pathological brain activity or chemistry associated with a variety of conditions. DBS to the amygdala or other network nodes mediating PTSD is feasible but investigational. In preliminary evidence from a small ongoing clinical trial, amygdala DBS may lessen hyperarousal symptoms and the underlying anxiety associated with PTSD [19].

Although noninvasive treatments cannot currently target a hyperactive amygdala directly, surface-applied stimulation techniques are being investigated as a method for indirectly targeting downstream targets such as the amygdala. For instance, Transcranial Magnetic Stimulation (TMS) could treat PTSD patients non-invasively with magnetic fields to stimulate areas of the brain. Current TMS research in our lab is focused on building from the insights gained from the ablation study. 1 Hz TMS to the rDLPFC has been shown to be effective for PTSD [20]. Given the reciprocal relation between the DLPFC and amygdala in emotion processing [21], we work under the premise that DLPFC stimulation may improve regulation of the amygdala. We use functional neuronavigation to individualize the TMS treatment target, for which we use resting state functional connectivity (RSFC) to define the area in the right dorsolateral prefrontal cortex with the strongest positive functional connectivity with the right amygdala and treat this area for 10 days. The amygdala’s causal role, as shown in prior work, is presumed as we investigate the effects of TMS treatment on PTSD biomarkers.

For most patients, an effective nondestructive therapeutic option, such as TMS, is obviously preferred over an invasive approach. Nevertheless, for those with severe and debilitating PTSD refractory to medications, trauma-focused therapy, and noninvasive neuromodulation, neurosurgical therapies such as DBS or focal amygdala ablation hold promise for this debilitating condition.

Declaration of interest

JT Willie has received research support from and/or has served as a paid consultant from: Medtronic (for consulting and research support), Neuropace (for consulting and research support), ClearPoint/MRI Interventions (for consulting), and AiM Medical (for consulting). The terms of this arrangement have been reviewed and approved by Washington University in accordance with conflict-of-interest policies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

SJH van Rooij is funded by the Brain and Behavior Research Foundation National Alliance for Research on Schizophrenia & Depression Young Investigator Award and National Institutes of Mental Health grant K01 MH121653. JT Willie is supported by National Institutes of Mental Health grant R01 MH120194.