This brain surgery shows potential to treat epilepsy, PTSD and even fear

The mother-of-three suffers from a rare condition called Urbach-Wiethe disease, which has caused certain parts of her brain to waste away, resulting in focal bilateral amygdala lesions. The resulting damage has severely damaged her amygdala, which helps to process and regulate emotion, especially fear and threatening stimuli. The amygdala plays a vital role in activating appropriate fear-related behaviors in response to threatening or dangerous stimuli - including the so-called fight or flight response.

According to The human amygdala and the induction and experience of fear, published by Justin Feinstein, Ralph Adolphs, Antonio Damasio, and Daniel Tranel (who worked with S.M. for more than a decade), the amygdala is involved in various facets of fear processing, ranging from fear conditioning to the modulation of attention and memory for fear-related stimuli, fear recognition, and the induction of fear-related behaviors. 

While patient S.M. had a rare disease, in 2018, Jody Smith from New York felt that surgery was the only option to prevent his epileptic seizures from getting worse. Diagnosed with epilepsy at the age of 26, he would experience intense but brief emotional sensations that gave him a feeling that something terrible was about to happen, triggering a "fight-or-flight response". 

During the surgery, doctors removed the front half of the right temporal lobe, the right amygdala, and the right hippocampus. Weeks later, Smith noticed that his abiding fear had dissolved, along with the accompanying anxiety and loss of mental energy, Vice News. A few situations, such as remaining nonchalant when a spider bit him, made him realize that his two invasive brain surgeries had made him almost entirely fearless. 

We caught up with Dr. Sanne J.H. Van Rooij, an assistant professor in Psychiatry and Behavioral Sciences at Georgia’s Emory University, who has been studying amygdala ablation for years, to tell us about this intriguing procedure and its potential effects on post-traumatic stress disorder (PTSD) and the treatment of other disorders. 

Does the amygdala brain region control all types of fear?

"The amygdala does not exactly control fear, it is the region that processes sensory and contextual information and triggers the fear response (fight/flight/freeze). When a fear response would not be appropriate because of the context, for example when seeing a bear in a zoo, other regions are part of the fear circuitry that is responsible for controlling the fear response. The hippocampus provides contextual information (“you are in a zoo”) and the ventromedial prefrontal cortex is responsible for downregulating/dampening the amygdala to control the fear response," Van Rooij explained.

All the above are the regions of the brain that play a vital role in fear learning and extinction processes. "This circuit is responsible for all types of fear, but it is more complex than described here," she said.

"The amygdala is thought of as the emotion or fear center of the brain and shown to be hyperresponsive in PTSD. Moreover, hyperresponsivity of the amygdala was found to predict the development of PTSD and treatment non-response. Because of that, I have been very interested in the amygdala and its role in stress/trauma/PTSD and recovery from PTSD," she told us.

According to Van Rooij, studying amygdala ablation is a unique approach to investigating this in humans. 

Can I have my amygdala removed?

The procedure is not minor. Those who learn of the surgery are often immediately fascinated - can they really become fearless? But the procedure, though well-known, isn't used simply to reduce anxiety or fear. "At this point, the amygdala will only be removed for treatment-refractory epilepsy where, after careful evaluation, the amygdala is determined responsible for the onset of seizures. It is also important to note that it only involved unilateral (one-sided) ablation," said Van Rooij.

And because amygdala ablation is an invasive procedure that is only used for treatment-refractory epilepsy at this moment, Van Rooij and colleagues are now investigating an indirect manipulation of the amygdala as a treatment for PTSD. "I received a grant for a clinical trial to investigate brain stimulation (transcranial magnetic stimulation, TMS) as a treatment for PTSD," she said.

However, the amygdala is a deep structure that cannot be reached directly with non-invasive brain stimulation.

"We, therefore, use a novel approach using a (functional magnetic resonance imaging) brain scan to define the area within the right dorsolateral prefrontal cortex (control center of the brain) that communicates (is most strongly functionally connected) with the right amygdala. We then stimulate this area for 30 minutes, twice a day for 10 days. Another brain scan is collected after the two weeks of treatment to measure the effects of this 10-day TMS treatment on brain function," she explained. 

Post ablation saw a reduction in fear and PTSD effects

In 2020, Van Rooij and colleagues studied two patients diagnosed with comorbid PTSD, characterized by heightened fear responses to things that reminded them of their trauma. 

"Both patients then underwent surgery of the right amygdala (and some other temporal lobe structures including the hippocampus) for their treatment-refractory epilepsy. The surgery was performed as usual for their treatment-refractory epilepsy and was not altered because of the research," said Van Rooij.

Following the laser surgery, the first patient reported a loss of his previous PTSD symptoms.

"For the second patient, we collected neuroimaging, psychophysiological and clinical data before and six and 12 months after their surgery. She also did no longer meet the diagnostic criteria for PTSD. Specifically, our findings indicated an improvement in the hyperarousal symptoms, which includes greater startle response/jumpiness, hypervigilance, and is most closely related to the fear response the patient in the case describes," notes Van Rooij.

Furthermore, the second patient's startle response, which directly measures the fear response triggered by the amygdala, was lower after surgery, "though the patient was still able to differentiate fear and danger signals, in fact, even better than before surgery. We also observed an improvement in activation of the ventromedial prefrontal cortex, which directly regulates the amygdala during fear processing," she said.

"It was a very intriguing observation that made a lot of sense given what we know about the amygdala and PTSD," said Rooij.

Is the loss of fear and anxiety a worrying outcome?

"Learning fear is critical for survival, and removing both sides of the amygdala could likely be dangerous and could result in abnormalities in memory, social and sexual functioning (Kluver-Bucy syndrome)," said Van Rooij. Hence, only the right and not the left amygdala was removed in the patients in their case series. "The protocol is to not remove bilateral temporal lobe structures."

"That being said, overreacting to stimuli related to a stressful event while not actually being in a life-threatening situation (a reminder of trauma in a safe environment) could be very disabling, and this continuous process of overreacting to trauma reminders is a key impairment in PTSD," said Van Rooij.

Their research suggests that ablating the right side of the amygdala could help the patient not to be on constant alert. It could also reduce or eliminate PTSD symptoms. "In those situations, the benefits of ablation could outweigh the potential risks, especially given our finding that the patient could still learn to differentiate danger from safety after right ablation, likely because only the right amygdala was ablated," she said.

Does the removal of the amygdala have any collateral effects?

"It could impact emotional or neurocognitive functioning and there are researchers including at Emory (Dr. Daniel Drane) studying the effects of the ablation on neurocognitive and emotional functioning," Van Rooij said.

She said that her studies did not observe a negative effect on fear learning or emotional memory. In anything, they saw improvements.

"It is also good to keep in mind that the brain structures of patients with severe treatment-refractory epilepsy may not function appropriately prior to surgery, and the treatment team, including neurosurgeons, neurologists, and neuropsychologists always make a balanced decision weighing risks and benefits," added Van Rooij.