Deep brain stimulation of the periaqueductal gray for treatment of nociceptive pain: tryptophan loading and the serotonergic circuit of pain

Abstract

Background: Pain and pain-related diseases pose a major treatment challenge. Current medical treatments frequently provide inadequate pain control to patients, or cause dependence and other unwanted side-effects. Despite initial failures of open-label trials to show efficacy in the use of deep brain stimulation (DBS) for pain, several groups have reported utility of this modality on carefully selected patients. There are several characterized pain pathways in operation in the human brain. A common theme to the pathways thus far identified is their dependence on the neurotransmitter serotonin for modulation of pain. Deep brain stimulation for pain may well activate one of the serotonin-dependent pathways to stimulate relief. Greater experience, and improvements in both technology and patient selection, has paved the way for the potential use of electrical stimulation of subcortical structures to manage intractable and nociceptive pain syndromes and also for the mechanistic study of the pathways involved in the symptomatic relief of pain caused by stimulation. Methods: We preoperatively loaded four patients with 4 grams of L-tryptophan, and implanted DBS electrodes in the periaqueductal gray (PAG). Results: Upon loading the patients with 4 grams of L-tryptophan two weeks preoperatively and the continual use of tryptophan at doses greater than 2.5 grams, we note a significant improvement in the pain symptoms of all of our patients implanted at the PAG. Upon decrease in L-tryptophan dose below 2.5 grams, every patient experienced return of their pain symptoms despite PAG stimulation. The average length of followup is 9.75 months with a range of three to 14. Conclusions: Tryptophan loading of the patient prior to PAG electrode placement, and the continued use of tryptophan postoperatively correlates with better outcomes and more significant pain reduction. Tryptophan probably increases serotonin levels and results in activation of anti-nociceptive pain pathways at the PAG.

Neuromodulation for Pain: A Comprehensive Survey and Systematic Review of Clinical Trials and Connectomic Analysis of Brain Targets

“…To permit connectomic network mapping, seeds were created for the following DBS targets: the posterior floor of the third ventricle; left side centromedian intralaminar parafascicular complex, nucleus accumbens, PAG, periventricular gray region (PVG), posterior limb of the internal capsule, posteroinferior hypothalamus, ventral posterolateral (VPL) nucleus; bilateral ACC, and ventral striatum/anterior limb of the internal capsule [24][25][26][27][28][29][30][31][32][33]. Cortical stimulation seeds were created for the subgenual ACC; left DLPFC, dorsal ACC, PMC, and PSC [34][35][36][37][38].…”