Psychoneuroimmunology as a framework for studying the effects of complementary healthcare (CHC) in clinical populations: a pragmatic, stepwise approach to clinical trial development

Project Background
Psychoneuroimmunology (PNI) is a relatively recent field of study which integrates the disciplines of psychology, neuroscience, and immunology to probe the interactions between behavior, the nervous system, and the immune system. Opposing a reductionist design that limits the observation of effects to a single paradigm, the PNI approach respects the multi-system evolutionary development of the organism (1). Thus, insight relative to the mechanisms of action and effects of an intervention are expanded. Importantly, aberrations in all three PNI domains (i.e., psychological, neurological, immunological) are known to be associated with numerous health related conditions (2).

The first key aspect of the PNI framework involves psychology. The psychological domain can be conceptualized as a combination of several interrelated components including mental health, emotional health, and beliefs & expectations (3). Interestingly, a recently published clinical trial on military service members suggests that chiropractic may have a positive impact on various aspects of psychological functioning including depression and anxiety (4).

The second integral aspect of the PNI paradigm is the neurological domain. Within this domain lies the autonomic nervous system (ANS). The ANS governs internal physiological processes such as heart rate and has two primary branches that have direct neural connections to the central nervous system (CNS): the parasympathetic nervous system (PSNS) and the sympathetic nervous system (SNS) (5). Generally, the PSNS is associated with “rest & digest” functions while the SNS is associated with a state of stress-induced “fight-or-flight” responses (6). Notably, increasing evidence suggests that chiropractic adjustments can modulate the activity of the ANS (7, 8). There is also some evidence that chiropractic may influence lower extremity, somatomotor function (9) which has implications for gait and fall risk. Further, limited data suggests that spinal adjustments may modulate the activity of the prefrontal cortex (10) hinting at the potential for effects on other clinically relevant, neurologically mediated processes such as executive functioning.

The third PNI domain is immunological functioning. The immune system’s primary role is in defense of the organism against a broad array of microbes and other potential pathogens (11). There are a handful of studies in relatively healthy populations that have evaluated chiropractic’s impact on immune-related biomarkers (12) including a recently published observational study which suggests that chiropractic may modulate the levels of secretory immunoglobulin A (sIgA), an antibody released by the mucosa providing nonspecific, first-line defense against pathogens (13).

All that said, comprehensive and robust assessments of chiropractic’s impact on PNI-associated endpoints have yet to be performed in clinical populations.

Based on the promising evidence to date, it is plausible that multiple, clinically important, PNI-related dysfunctions (e.g., heightened stress levels, executive function impairments, autonomic dysfunction, immune dysregulation) could be ameliorated via complementary healthcare (CHC) approaches such as chiropractic. If shown to exhibit efficacy in clinical populations across the PNI spectrum, CHC may offer a viable solution to soaring healthcare costs (14).

 Project Description & Objectives
Life University’s Center for Chiropractic Research (CCR) seeks to employ effectiveness-implementation (E-I) hybrid designs (15) in a stepwise manner within a rigorous clinical trial framework. More specifically, in the initial phase of each trial (year 1), we will utilize an E-I hybrid design type 3 whereby a small, single-arm trial is run with the primary aims centering around implementation outcomes (e.g., how acceptable are our testing & intervention protocols in this clinical population?). Informed by the initial phase, the next phase (year 2) will utilize an E-I hybrid type 2 design which recruits a larger sample for a randomized, controlled trial (RCT) with a more balanced focus on implementation outcomes (e.g., how good is retention within a given control arm?) and intervention outcomes (i.e., how effective are our interventions in this clinical population?). The final phase (year 3+) will incorporate an E-I hybrid type 1 design with a large, fully powered RCT focusing predominantly on intervention outcomes for a given clinical population. Importantly, in line with recommendations for more patient-centric clinical trials (16, 17), we aim to involve patients and clinicians directly in the trial design process to 1) ensure that patient-centered outcomes are at the forefront, 2) improve recruitment and retention efforts, and 3) enhance the uptake and impact of the findings.

Regarding testing, the CCR has developed a novel and comprehensive assessment battery to evaluate a core set of clinically relevant, PNI-related outcomes. This core set is designed to be applicable across conditions and complement validated, condition-specific clinical endpoints. Currently, core psychological measures include patient reported outcomes (i.e., 29-item Patient Reported Outcome Measurement Information System (PROMIS-29); Perceived Stress Scale (PSS)) endorsed by the National Institutes Health (NIH) which track an array of psychology-related metrics including levels of depression, anxiety, and stress. Within the neurological domain, both objective (e.g., electroencephalography (EEG); electrocardiography (ECG); impedance cardiography (ICG); electromyography (EMG)) and subjective (i.e., 8-item PROMIS cognitive function (PROMIS Cog-8); 31-item Composite Autonomic Symptoms Score (COMPASS-31)) outcomes are evaluated. Finally, immunological health is measured via validated biomarkers including levels of salivary secretory immunoglobulin A (sIgA), an antibody released by the mucosa providing nonspecific, first-line defense against pathogens (13). With respect to the delivery of the trial intervention, we are leading with a pragmatic approach whereby we enlist volunteer clinicians within the local community to deliver “real-world” (i.e., personalized) care in a “real-world” (i.e., clinic) setting. Introducing pragmatic elements into modern trial designs has been increasingly advocated in recent years to provide more “real-world” evidence that enhances the external validity (i.e., generalizability) of trial results (18).

Project Alignment
Ultimately, we believe our model can serve as a template to develop efficient, evidence-informed, transdiagnostic assessment protocols and intervention strategies that can be readily deployed in community based CHC settings with clinically relevant outcomes that are of primary interest to the patients they serve.

Budget
We are seeking a USD $591,020.00 grant to assist with participant compensation, consumables, trial clinicians’ fees, publication fees, graduate research assistant stipends, a post-doctoral research position, and statistician contracting over three years. A yearly budget allocation is provided for review.