Posttraumatic Stress Disorder: Neurocircuitry and Implications for Potential Deep Brain Stimulation

Abstract

Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling psychiatric disorder that is notoriously difficult to treat. At some point in their lifetimes, 5-8% of men, 10-14% of women, and up to a quarter of combat veterans carry this diagnosis. Despite pharmacological and behavioral therapies, up to 30% of patients are still symptomatic 10 years after initial diagnosis. Recent advances in imaging have implicated changes in the limbic and autonomic corticostriatopallidothalamocortical (CSPTC) circuitry in the pathogenesis of this disease. Deep brain stimulation modulates CSPTC circuits in movement and other neuropsychiatric disorders. In this review, we discuss the salient clinical features and neurocircuitry of PTSD and propose a neuromodulation strategy for the disorder.

Deep brain stimulation of the basolateral amygdala for treatment-refractory combat post-traumatic stress disorder (PTSD): study protocol for a pilot randomized controlled trial with blinded, staggered onset of stimulation

“…We recognize that, as in other neuropsychiatric disorders associated with dysfunction in limbic circuitry, amygdala hyperactivation in PTSD is likely a node in an interconnected circuit, comprising at least the vmPFC, anterior insula, and extended amygdala, as well as the ventral striatum, with reciprocal connections to thalamus and hypothalamus, and output to brainstem nuclei that are also involved in the clinical phenomenology seen in the condition. While we thus agree with other investigators[146] that the BLn is not the only potentially valuable target for DBS in PTSD, we believe, based on the rationale described above, that it is the optimal target and it can be modulated safely with current technology.…”

“…Human functional neuroimaging findings are also strongly suggestive of amygdala hyperactivity as an underlying substrate of persistent PTSD, particularly the symptoms of stimulus-associated emotional and autonomic hyperarousal. While alternative targets for neuromodulation with DBS in PTSD have been proposed[146], our model, proposing high-frequency DBS of the bilateral BLn in treatment-refractory combat veterans, has the best overall support. It is feasible both from a technical neurosurgical perspective[147] and safe based on a recent clinical report of DBS with the same target for another treatment-refractory behavioral condition[142].…”

The application of deep brain stimulation in the treatment of psychiatric disorders

“…In addition, DBS increases serotonin levels in frontal areas and stabilizes dopamine levels in the striatum. DBS enhances extinction learning, suggesting it might be a promising treatment option for a variety of disorders with impaired fear extinction learning such as addiction and PTSD (Taghva, Oluigbo, Corrigan, & Rezai, 2013). Finally, DBS for OCD improves sensorimotor gating, a neurocognitive process that has been linked to several neuropsychiatric disorders with a presumed neurodevelopmental origin, such as autism and schizophrenia (Braff, Geyer, & Swerdlow, 2001).…”

“…PTSD has been associated with over-activity in the amygdalahippocampus axis, explaining excessive autonomic fear responses (Taghva et al, 2013). In addition, the ventro-medial PFC (vmPFC), responsible for inhibiting the amygdala, is generally under-active in PTSD and, therefore, failing to regulate amygdala over-activity and extinction learning.…”

A novel analytical brain block tool to enable functional annotation of discriminatory transcript biomarkers among discrete regions of the fronto-limbic circuit in primate brain

“…Consequently, it has been widely anticipated that analysis of changes in gene expression in cortical and subcortical brain regions of NHP, particularly those associated with executive function and emotional control in the fronto-limbic circuit, might yield mechanistic insights into many important human disorders. These disorders could include entities as diverse as posttraumatic stress disorder (PTSD) (Admon et al, 2013;Choi et al, 2011;Myers et al, 2013;Taghva et al, 2013), major depressive disorder (Badawy et al, 2013;Engel et al, 2013;Godsil et al, 2013;Lozano et al, 2008;Seminowicz et al, 2004;Sibille et al, 2004), autism spectrum disorders (Gotts et al, 2012), schizophrenia (GuillozetBongaarts et al, 2014;Lee, 2013;Penzes et al, 2013), and dementias associated with Alzheimer Disease (Grieve et al, 2005;Kensinger et al, 2002), Parkinson's Disease (Bonelli and Cummings, 2007;Ibarretxe-Bilbao et al, 2008), and cognitive decline (Arnsten et al, 1995). However, very little is known regarding the genomic and epigenomic signatures characterizing individual components of the healthy fronto-limbic circuit, and how they might change as a function of age.…”