Deep brain stimulation of the amygdala for treatment-resistant combat post-traumatic stress disorder: Long-term results

Abstract

Deep brain stimulation (DBS) holds promise for neuropsychiatric conditions where imbalance in network activity contributes to symptoms. Treatment-resistant Combat post-traumatic stress disorder (TR-PTSD) is a highly morbid condition and 50% of PTSD sufferers fail to recover despite psychotherapy or pharmacotherapy. Reminder-triggered symptoms may arise from inadequate top-down ventromedial prefrontal cortex (vmPFC) control of amygdala reactivity. Here, we report long-term data on two TR-PTSD participants from an investigation utilizing high-frequency amygdala DBS. The two combat veterans were implanted bilaterally with quadripolar electrodes targeting the basolateral amygdala. Following a randomized staggered onset, patients received stimulation with adjustments based on PTSD symptom severity for four years while psychiatric and neuropsychiatric symptoms, neuropsychological performance, and electroencephalography were systematically monitored. Evaluation of vmPFC-Amygdala network engagement was assessed with ¹⁸FDG positron emission tomography (PET). CAPS-IV scores varied over time, but improved 55% from 119 at baseline to 53 at 4-year study endpoint in participant 1; and 44%, from 68 to 38 in participant 2. Thereafter, during 5 and 1.5 years of subsequent clinical care respectively, long-term bilateral amygdala DBS was associated with additional, clinically significant symptomatic and functional improvement. There were no serious stimulation-related adverse psychiatric, neuropsychiatric, neuropsychological, neurological, or neurosurgical effects. In one subject, symptomatic improvement was associated with an intensity-dependent reduction in amygdala theta frequency power. In our two participants, FDG-PET findings were inconclusive regarding the hypothesized mechanism of suppression of amygdala hyperactivity. Our findings encourage further research to confirm and extend our preliminary observations.

Keywords: Amygdala; Case studies; Longitudinal study; Neuromodulation; Post-traumatic stress disorder; Treatment-resistance.

Figure 1. Amygdala DBS for PTSD: CAPS Scores and Stimulation Adjustments

Bilateral, continuous Deep Brain Stimulation of the basolateral amygdala (BLA), targeting either right (R) or left (L) dorsal (dBLA) or ventral (vBLA) contacts located within that structure. Stimulation intensity is shown in volts. Frequency was kept at 160Hz except for a 1-month unsuccessful trial of 100 Hz at month 25 in participant 1. Pulse width was kept at 60us, except for a 1-month trial from Month 0 to Month 1 in participant 2 during the double-blind period (see text). Stimulation was monopolar with case (+). B = Baseline, with 3 CAPS-IV¹⁹ measures over 3 months in participant 1 and 4 measures over 6-months (due to delay in surgery scheduling availability) in participant 2: participant 1 CAPS-IV mean 119 (s.d. 2.5); participant 2, CAPS-IV mean 68 (s.d. 4.9) prior to surgery. Months on X-Axis are from date of surgery, with “Month 0,” being 1-month after surgery, when double-blind active-vs-sham stimulation began. Some dates of CAPS assessment occurred at intervals other than monthly due to scheduling difficulty, and some stimulation intensity changes occurred between months for the same reason. A 30% reduction in CAPS-IV total score was the a priori designation of responder status, based on data available at time of study initiation. Beginning at month 49, patients were seen for clinical care and subsequently symptom measurement was not systematic. The last recorded CAPS-IV rating in participant 1 was at month 83. Thereafter, only the CAPS-5 was used. Clinicians for participant 2 did not record symptom measures for over a year after study completion. Beginning at month 103 in participant 1, and 63 in participant 2, CAPS-5 scores were recorded prospectively. To permit comparison of symptom severity across the entire period of observation, CAPS-5 scores were converted to imputed CAPS-IV scores by multiplying the 17 items both scales have in common by two (see Supplementary data.doc for reference). Participant 1 had Medtronic^R Activa PC^R pulse generator battery replacement at month 55. Participant 2 had Medtronic^R Activa PC^R pulse generator replaced with Medtronic^R Percept^™ at month 45.5. Participant 1 had Medtronic^R Percept^™ placed at Month 93. During month 107 in participant 1, L vBLA was added inadvertently for 3 weeks, without exacerbation of PTSD.

Figure 2. Participant 2 Anger Events

See text for definition of the three types of anger events. Events were determined from review of records and interviews of participant, family members, and treating clinicians for the 28-month period prior to enrollment, and thereafter, monitored prospectively. (The veteran had dropped out of care for over a year prior to returning, 28 months prior to enrollment).

Figure 3.. Volume of Tissue Activated (VTA) Tractography

A and B, Patient-specific amygdala segmentations in patient 1 (A) and 2 (B) showed that the VTA of the stimulation parameters at last follow-up (Patient 1: 1.4 v left and 4.3 v right; Patient 2: 3 mA; 160 hz, 60 us) involves mainly the basal segment and the most medial part of the lateral segment of the basolateral complex (bilateral arrows in C and D). L, left. R, right. S, superior. I, inferior. C, Normative tractography shows connections between the area stimulated in both patients with the hippocampus and the mPFC. D, The specific areas of the mPFC are connected with the amygdala through the uncinate fasciculus to Brodmann area 11/12 (black arrow) and through the ventral amygdalofugal pathway to the Brodmann area 25 (white arrow).