In Reply: Case Series: Unilateral Amygdala Ablation Ameliorates Post-Traumatic Stress Disorder Symptoms and Biomarkers

To the Editor:

We are grateful to the authors¹ for their thoughtful letter regarding our report² of 2 patients with right medial temporal lobe epilepsy (MTLE) in whom well-defined comorbid post-traumatic stress disorder (PTSD) benefited greatly from right laser ablation of the amygdala and hippocampus (stereotactic laser amygdalohippocampotomy [SLAH]). Both patients suffered refractory PTSD for years or decades prior to onset of seizures. These 2 patients were distinct in several demographic and clinical respects: one was a Caucasian male and the second an African-American female; one suffered combat-related PTSD following a blast-related traumatic brain injury and the other had noncombatant civilian PTSD without head trauma. One was cured of epilepsy by right SLAH, while the second was not. Despite such differences, both achieved early and lasting remission of PTSD as determined from a combination of patient reports, objective clinical indices, and validated physiological and functional imaging biomarkers. Our case series represents early experience prospectively characterizing effects of epilepsy surgery on comorbid PTSD with a hypothesis that right amygdala plays a critical role in maintaining PTSD. These studies were made possible by carefully documented observations and a sustained proactive collaboration of a neurosurgeon with psychologists, psychiatrists, and neuroscientists. While case reports such as these should be viewed as preliminary results, they can provide critical insights and hypotheses that lay the groundwork for rigorous work to follow.

Are PTSD and epilepsy more comorbid than typically appreciated? Can there be common pathophysiological links between PTSD and MTLE? Does the amygdala of the right/nondominant hemisphere play a more important role in PTSD than the left? Would unilateral ablation of amygdala and hippocampus be required to achieve benefits for PTSD? What is the role of the temporal pole and other structures often impacted in epilepsy surgery? Such questions are raised by this study and would have potential therapeutic implications. Indeed, a few retrospective uncontrolled single-case reports might suggest that while right amygdalohippocampectomy could ameliorate PTSD, left amygdalohippocampotomy does not protect against developing PTSD.^3-5

The authors¹ rightly question whether the combination of hippocampotomy and amygdalotomy may account for some of the benefits we report. Indeed, the observations in our original report do not strictly parse potential roles of amygdala and hippocampus in maintaining PTSD. A recent case report observed perioperative emergence of PTSD symptoms from a remote childhood trauma after right hippocampectomy sparing the amygdala—and presumably its ascending connections.⁶ We likewise have recently prospectively examined another patient case in whom PTSD emerged several years after an open right hippocampectomy sparing the amygdala, but in whom PTSD was subsequently ameliorated yet again by ipsilateral amygdalotomy (J.T.W. and S.J.H.v.R., unpublished observations). Thus, right hippocampal function may protect in part against the development of PTSD, while right amygdala promotes and maintains PTSD. The hippocampus is essential for safety learning, and functional neuroimaging studies suggest that intact hippocampal functioning is associated with resilience and lower PTSD risk in both recently and chronically traumatized civilians.^7,8 It is therefore entirely possible that unilateral nondominant amygdalotomy alone would be even more effective for PTSD, but this important question is difficult to address in epilepsy patients since MTLE is rarely addressed by amygdalotomy alone.

While our study² highlights the importance of directly targeting the amygdala, other brain structures may be amenable to less or noninvasive neuromodulatory interventions. For instance, while the amygdala is likely not accessible to transcranial magnetic stimulation (TMS), it is possible that the TMS of dorsolateral or ventromedial prefrontal cortices could be used to indirectly downregulate the functionally connected amygdala.

When all else fails, would psychiatrists and patients consider a surgical therapy for refractory PTSD? Like the growing investigational uses of deep brain stimulation (DBS) to treat obsessive compulsive disorder and major depressive disorder, at least one other ongoing neurosurgical effort is investigating bilateral amygdala DBS for PTSD.⁹ While DBS therapy generally carries advantages of programmability and reversibility, our study also supports the viability, simplicity, and potential definitiveness of a unilateral lesional approach.

The need is great: 30% to 50% of PTSD patients fail to respond to the current gold-standard trauma-focused cognitive therapies,¹⁰ leaving a large swath of patients to carry the burden of chronic PTSD. This burden may be even higher in the epilepsy population.¹¹ Studies of invasive interventions for PTSD remain scarce. Neuromodulation and ablation both deserve further investigation within the context of coordinated multidisciplinary care of neurosurgeons, psychiatrists, and psychologists.

Funding

The current study was supported by a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation to SJHvR, an Emory University Research Committee pilot grant to KRB, and funding from the National Institutes of Health (NIH), National Center for Advancing Translational Sciences (NCATS) to KRB (UL1TR002378; KL2TR002381), National Institute of Neurological Disorders and Stroke (NINDS) to KRB/JTW (R21 NS104953), and the National Institute of Mental Health (NIMH) to KRB (K01 MH116364).

Disclosures

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Dr Willie serves as a consultant for Medtronic Inc, MRI Interventions Inc, and NeuroPace Inc. All other authors declare no conflicts of interest exist.