
Initially described as early as the Seven Years War (1756-63), physicians have documented excessive physical exhaustion, anger, irritability, and depression, primarily among soldiers. Variously called shell shock, battle fatigue, and post-traumatic stress disorder (PTSD), this condition has come into the modern lexicon in the last decade or so. Its diagnostic description, separate from other anxiety disorders, was formalized in 2013. PTSD is most common after triggering traumatic events, impacting an estimated 6-7% of the civilian and 13-14% of the veteran population.
A variety of trauma-specific pharmacologic and non-pharmacologic therapies have been very effective in treating PTSD. Roughly 50% will respond to one of three non-pharmacologic therapies:
- Cognitive processing therapy: a form of treatment attempting to change thinking patterns by an individual understanding how they think about their trauma and its sequelae.
- Prolonged exposure therapy: listening to a patient’s narratives of their trauma in a “safe space” to let them gain control of their thoughts and feelings, making memories less fearful.
- Eye movement desensitization and reprocessing (EMDR): while talking about traumatic memories, people simultaneously focus on other stimuli, e.g., eye movement, hand taps, and sounds.
Forty percent of individuals respond to pharmacologic intervention, achieving remission. Unfortunately, a portion of these patients are resistant to either of these interventions, leaving them with marked disability in navigating life. Vagal nerve stimulation has been shown to be beneficial in these circumstances, and a study reported in Brain Stimulation provides proof-of-concept validation.
Proof of Concept
Proof-of-concept studies are designed to demonstrate the value of the therapy and identify any significant adverse risks. Given the small number of participants and the open-label nature of the study, the goal is to identify a feasible treatment.
This study combined a 12-session course of prolonged exposure therapy with short bursts of vagal nerve stimulation based on the belief that vagal stimulation enhances the remodeling of our thoughts. Nine individuals had a small device implanted around their vagus nerve, which could be stimulated during treatment as well as when doing their therapeutic “homework.” Participants had to meet the criteria for PTSD based on CAPS 5, an interview tool that ranks 20 symptoms on their frequency and severity. [1]
Of the 7 participants who completed therapy, all achieved remission for at least six months after the end of therapy (and the clinical trial). Across all the CAPS 5 domains, there was marked improvement. There were no serious device-related adverse events. The researchers conclude by noting that vagal stimulation in combination with guided psychotherapy results in,
“...adaptive changes in circuits associated with fear processing and …. [vagal stimulation] indirectly enhances plasticity via widespread neuromodulatory release.”
This promising synergy between prolonged exposure therapy and vagal nerve stimulation appears to tap into a deeper biological capacity, our brain’s ability to reshape itself. The improvements are not solely due to better coping mechanisms or emotional processing but from a fundamental rewiring of the brain's circuitry that enables us to adapt, reconfigure, and heal, even long after the trauma has been etched into memory.
Neuroplasticity
“Neuroplasticity can be viewed as a general umbrella term that refers to the brain’s ability to modify, change, and adapt both structure and function throughout life and in response to experience.”
We have discarded the belief that our brains, once past a “critical period,” most often associated with childhood and adolescent development, are fixed, only suffering the ravages of aging. As it turns out, while much of the brain’s structure and function does develop in that interval, there are multiple other “critical periods” in our lives. Episodes that initiate PTSD may be one of them.
Vagus, Latin for “wandering,” describes the vagus nerve’s course and extensive projections throughout the body, exiting the central nervous system through our skull rather than spinal cord. It provides motor pathways for most of our organs and feeds a wide range of sensory information to multiple areas of the brain, including the brainstem, which serves as a relay station for higher cortical activity. The connections with the brainstem are hypothesized as the pathway by which vagal stimulation influences a broad spectrum of neuromodulators.
The structure and functioning of our brain thrive on two opposing forces: stability and the ability to change over time. Plasticity is a shorthand for that dynamic opposition. The vagus nerve is one of several neuromodulator systems serving as critical plasticity gatekeepers, varying by age, gender, and disease states, including not only PTSD but tantalizingly dementia. Physiologically, plasticity is a balancing act between cholinergic, dopaminergic, noradrenergic, and GABAergic cellular networks.
Four Chemical Systems Drive Neuroplasticity
Four critical neurotransmitter systems —norepinephrine, acetylcholine, GABA, and dopamine —choreograph both maintenance, the ongoing repair of the brain, and compensation, “the cognition-enhancing recruitment of neural resources in response to relatively high cognitive demand.”
- Norepinephrine, like a double expresso, powers up attention, arousal, and readiness to learn. It plays a vital role in tuning the brain’s response to sensory inputs, reshaping our sensory maps —the guides to what we experience —by enhancing the signal-to-noise ratio, which helps distinguish relevant stimuli from background chatter. Vagal stimulation appears to provide a norepinephrine-mediated increase in neural excitability, thereby improving memory and attention.
- Acetylcholine acts through areas of the brain to enhance the encoding of new information. When we speak of neurons “that fire together, wire together,” we are referring to acetylcholine’s role in reinforcing relevant patterns while pruning the noise. It appears to act synergistically with norepinephrine in critical periods. Its production and efficacy decline with age, leading to memory lapses, reduced learning capacity, and perceptual dulling. Vagal stimulation acting on an area of the brainstem is believed to enhance acetylcholine production.
- Dopamine plays a crucial behind-the-scenes role as the engine of motivation and reward, setting the tone for learning by reinforcing behaviors that lead to desired outcomes. Additionally, dopamine, like norepinephrine, modulates the signal-to-noise ratio in cortical circuits, enabling the brain to discern “what matters.” Vagal stimulation working through a “relay station” within our brainstem indirectly enhances dopamine production.
- GABA (gamma-aminobutyric acid) applies the brakes on the excitation provided by the other three neurotransmission systems, creating the stability that maintenance requires. As the brain’s primary inhibitory neurotransmitter, GABA is essential for coordinating the timing and precision of neural firing. Rather than stifling plasticity, it defines boundaries, locking in stable circuits once learning has occurred. Vagal stimulation, acting through the brainstem, increases the inhibitory tone of the brain.
The vagus nerve also plays a role in inflammation regulation and sleep modulation. Acting through the stimulation of acetylcholine’s anti-inflammatory pathway, vagal signals suppress cytokines, reducing peripheral inflammation. Vagal pathways also downregulate our pituitary-adrenal axis, reducing stress-related inflammation. The enhanced parasympathetic tone induced by vagal stimulation can improve the onset of sleep and deepen non-rapid eye movement (non-REM) sleep, facilitating restorative rest.
The science behind vagal nerve stimulation in PTSD treatment represents a hopeful shift in how we approach psychological trauma and other mental health conditions, tantalizingly dementia, another disorder deeply embedded in the brain’s structure and function. By leveraging the body’s neuromodulation and the natural dynamics of neuroplasticity, we open the door to therapies that not only manage symptoms but also catalyze recovery at a cellular level. While these findings remain preliminary, they underscore a potential for “holistic” interventions to restore agency and quality of life to individuals once considered treatment-resistant.
[1] At a minimum, participants were required to have one symptom that intruded on their thoughts, one symptom of avoidance, two symptoms indicating clinically significant changes in cognition and mood, and two symptoms of hyperarousal. Scores rank from 0-80, and the research excluded participants who scored higher than 46, indicating severe PTSD.
Sources: Vagus Nerve Stimulation Therapy For Treatment-Resistant PTSD Brain Stimulation DOI: 10.1016/j.brs.2025.03.007
Dynamic Brains and the Changing Rules of Neuroplasticity: Implications for Learning and Recovery Frontiers in Psychology DOI: 10.3389/fpsyg.2017.01657
Impact Of Transcutaneous Vagus Nerve Stimulation On Healthy Cognitive And Brain Aging Frontiers in Neuroscience DOI: 10.3389/fnins.2023.1184051