Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

To determine whether the characteristics of disease due to Toxoplasma gondii (toxoplasmosis) are dependent on the infecting strain, we have developed an enzyme-linked immunosorbent assay for typing strains that uses infection serum reacted against polymorphic peptides derived from Toxoplasma antigens SAG2A, GRA3, GRA6, and GRA7. Pilot studies with infected mice established the validity of the approach, which was then tested with human serum. In 8 patients who had Sabin-Feldman dye test titers >64 and for whom the infecting strain type was known, the peptides correctly distinguished type II from non-type II infections. ELISA analysis of a second group of 10 infected pregnant women from whom the parasite strain had not been isolated gave a clear prediction of the strain type causing infection. This method should allow statistically significant data to be obtained about whether different strain types cause disease with different characteristics.

Recent efforts to use fMRI to investigate the effects of acupuncture needle manipulation on the brain have yielded discrepant results. This study was designed to test the reliability of fMRI signal changes evoked by acupuncture stimulation. Six subjects participated in six identical scanning sessions consisting of four functional scans, one for each of the four conditions: electroacupuncture stimulation (2Hz) at GB 37, UB 60, non-acupoint (NP), and a control task of the finger-tapping. In the group analysis across all subjects and sessions, both the average ratings on a subjective acupuncture sensation scale and fMRI signal changes (increases and decreases) were similar for GB37, UB 60 and NP. Visual inspection of the activation maps from individual sessions and ICC analysis revealed that fMRI signal changes evoked by electroacupuncture stimulation were significantly more variable than those from the control finger-tapping task. The relatively large variability across different sessions within the same subject suggests multiple sessions should be used to accurately capture the activation patterns evoked by acupuncture stimulation at a particular point for a specific subject.

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The concept that specific acupuncture points have salubrious effects on distant target organ systems is a salient feature of Traditional Chinese Medicine (TCM). In this study, we used a multiple-session experiment to test whether electroacupuncture stimulation at two TCM vision related acupoints, UB 60 and GB 37, located on the leg, could produce fMRI signal changes in the occipital regions of the brain, and the specificity of this as compared with stimulation at an adjacent non-acupoint (NAP). Six normal, acupuncture naïve subjects completed the study. Each subject participated in six identical scanning sessions. Voxelwise group analysis showed that electroacupuncture stimulation at both vision related acupoints and the NAP produced modest, comparable fMRI signal decreases in the occipital cortex, including the bilateral cuneus, calcarine fissure and surrounding areas, lingual gyrus and lateral occipital gyrus. Further analysis of fMRI signal changes in occipital cortex showed no significant difference among the three points, UB 60, GB 37 and NAP. Our results thus do not support the view that acupuncture stimulation at vision-related acupoints induce acupoint specific fMRI BOLD signal changes in the occipital cortex. We speculate that cross modal inhibition, produced by needling-evoked somatosensory stimulation, may account for our finding of BOLD signal decreases in the occipital cortex. Given the complexity of acupuncture systems and brain activity, additional work is required to determine whether functional neuroanatomical correlates of acupoint specificity can be validated by means of brain imaging tools.