Mechanisms of non-pharmacological interventions: Linking research with clinical practice

Dr Gerard Farrell

About this programme of work

This programme of work started with my PhD, which explored the mechanisms of cervical spine manual therapy on the autonomic nervous system and endocrine system, specifically the hypothalamic pituitary adrenal-axis (HPA-axis), in people with persistent post-concussion symptoms. From this body of work, we expanded this line of research into investigating the underlying pain mechanisms of manual therapy in people with chronic lower back pain and developed a clinical service (dysautonomia service).

Where have we come from? Endocrine and autonomic nervous system mechanisms of manual therapy

Manual therapy is a common and effective treatment for concussion symptoms and many other neck-related conditions such as cervicogenic headache or dizziness. While we know it works, we don’t fully understand why. My PhD set out to answer this question by investigating the endocrine and autonomic nervous system mechanisms of cervical spine manual therapy in both healthy people and in people with persistent post-concussion symptoms.

Collectively, the endocrine system (specifically the HPA-axis), and the autonomic nervous system, make up the peripheral stress response. The focus of this thesis was on the stress response, which are the changes that happen in your body when you’re under pressure, like giving a speech in front of a big audience. For some people, this stress response can be too strong; for others, it may be too weak. When it doesn’t work properly, or if its baseline activation is too much or too little, it can lead to ongoing symptoms or illness.

Could mobilising (a form of manual therapy involving gentle oscillations of the joints in the cervical spine) the joints of the upper versus lower cervical spine selectively module the stress response? That’s what we set out to discover.

What we found

Study one: Healthy participants

Our first study looked at whether mobilising the upper or lower cervical spine selectively modulated the endocrine system, specifically the HPA-axis releasing the stress hormone cortisol, and/or the autonomic nervous system, specifically the parasympathetic nervous system, in healthy males.

Here’s what we found:

• Cortisol concentration decreased 30 minutes after mobilising the lower cervical spine.
• Interestingly, there was also a trend for cortisol concentration to increase the night after lower cervical spine mobilisation.

This finding was interesting because people with conditions like persistent concussion symptoms or long-COVID often have low cortisol levels. Could lower cervical spine mobilisation be a novel way to increase cortisol concentration in people who need it?

Study two: Participants with persistent concussion symptoms

Next, we repeated the study with people who had ongoing concussion symptoms, such as headaches, dizziness, or fatigue.

Here’s what we found:

• Cortisol concentration decreased 30 minutes after mobilising the lower cervical spine.
• Overnight, cortisol concentration increased after lower cervical spine mobilisation but decreased after upper cervical spine mobilisation.
• Parasympathetic nervous system activity (the “rest and digest” system or vagal system) increased after upper cervical spine mobilisation.

What does this mean?

• Mobilising the lower cervical spine might help boost the stress response in people who have a weakened one, by increasing cortisol concentration the night after the intervention.
• Mobilising the upper cervical spine might help calm the stress response in people who have a heightened one, by decreasing cortisol concentration the night after the intervention.

These findings open the door to potentially using targeted manual therapy techniques to help people with conditions like postural orthostatic tahycardia syndrome (POTS) or Ehlers-Danlos Syndrome, who often have a dysregulated stress response. This might be someone else's PhD.....

This research was supported by the Stanley Paris PhD Fellowship and the University of Otago Doctoral Scholarship.

What we’re working on now

Lumbar spine manipulation study

We are currently investigating the physiological pain mechanisms (via substance P from saliva) and clinical outcomes in people with chronic low back pain receiving one of three types of lumbar spine manipulation (specific, non-specific, or sham manipulation). This study, funded through the Stanley Paris Fellowship, directly builds on my PhD, which sparked a strong interest in uncovering the underlying mechanisms of manual therapy. My clinical practice has further shaped this interest by focusing on how these mechanisms connect to real-world patient outcomes.

The importance of this work lies in its integration of physiological and clinical perspectives, an area with surprisingly little existing research. We are combining what we observe in the clinic every day, changes in people’s pain, with what is happening “under the hood”. By examining internal physiological responses, such as biomarkers in saliva, we aim to better understand why pain changes after spinal manipulation and how these mechanisms translate into meaningful clinical outcomes.

Following a very efficient recruitment process and treatment phase (thank you to our participants and clinicians!), this project has now completed recruitment and its treatment phpase, and the data has been forwarded to our biostatistician. We anticipate completing the manuscript by mid‑2026.

This research was supported by the Stanley Paris Fellowship.

Building on the lumbar spine manipulation study

Following our research into lumbar spine manipulation, we plan to apply for further funding to study other physiological biomarkers following lumbar spine manipulation in chronic lower back pain.

Our focus will be on measuring:

• Inflammatory biomarkers
• Autonomic nervous system biomarkers
• Endocrine system biomarkers

Manual therapy is widely recognised as an evidence-informed intervention for chronic low back pain, but we still don’t fully understand why it helps. By uncovering the underlying mechanisms, we can better identify when and for whom it works best, leading to more targeted treatments and, ultimately, better outcomes for patients. Building on this work, our goal is to apply for funding for a fully powered trial that rigorously links physiological responses with clinical outcomes, providing the evidence base needed to refine practice and improve patient care.

Autonomic nervous system and cardiovascular mechanisms of cold‑water exposure

Building on our broader programme of work investigating the mechanisms of non‑pharmacological interventions, this year we are supervising an honors student examining the autonomic and cardiovascular mechanisms of cold versus lukewarm water showers in healthy individuals.

There is existing literature supporting cold‑water immersion (i.e. cold baths, plunge pools, or taking a dip in the ocean) as a means of regulating autonomic nervous system function. However, access to these modalities is not feasible for everyone, and many individuals are unable to tolerate full cold‑water immersion.

Anecdotally, in my clinical practice I have been using cold or lukewarm water exposure administered via showers with positive effect as a management strategy to support autonomic regulation. This appears particularly beneficial for people living with myalgic encephalomyelitis/chronic fatigue syndrome, long COVID, and persistent post‑concussion symptoms.

This project aims to explore the autonomic and cardiovascular system mechanisms underpinning this approach and to determine whether shower‑based exposure could represent a more accessible and tolerable alternative to traditional cold‑water immersion.

Watch this space - we will be seeking participants for this project in the very near future.

Bringing research into clinical practice: Dysautonomia service

Another key outcome from my PhD was setting up a dysautonomia service, where research findings are directly integrated into clinical care.

My PhD helped shape my special interest in managing conditions linked to dysautonomia (also called autonomic dysfunction or stress response dysfunction).

These conditions include:

• Postural Orthostatic Tachycardia Syndrome (POTS)
• Ehlers-Danlos Syndrome (EDS)
• Hypermobility Spectrum Disorders (HSD)
• ME/Chronic Fatigue Syndrome

Our approach always starts with understanding the person first and foremost-this is their story. We then link this to their condition and its underlying physiology, so we can tailor interventions to their individual needs.

Read news story about my work setting up a new dysautonomia service

Where we are going: Intertwining research with clinical practice

The next step in this programme of research is to further develop the dysautonomia service. At present, I am mentoring other physiotherapists in our clinic to support people with these complex conditions. To make the service more accessible, we offer telehealth, reducing barriers for people who cannot travel, who live outside Dunedin, or whose health conditions make in-person visits too difficult.

Through this service, we are learning a great deal from the people we see. Many have shared experiences of stigma and of the lack of awareness within the healthcare system regarding conditions involving dysautonomia. These stories highlight the urgent need for more equitable, informed, and compassionate care across Aotearoa New Zealand. At the same time, we have identified that many healthcare professionals are not adequately trained or aware of how to manage these complex conditions.

Future research will build directly on these clinical insights. In addition to quantitative investigations of treatment mechanisms and outcomes, I plan to use qualitative approaches to better understand how people navigate the health system with dysautonomia, as well as to identify what healthcare professionals know, and don’t know, about these conditions and their management. This will allow us to co-design training and resources that are targeted, relevant, and responsive to both patient and clinician needs. Ultimately, this integrated co-designed approach will improve clinical care, expand professional knowledge, and contribute to building fairer healthcare pathways.

Acknowledgements

I want to take this opportunity to thank everyone who has supported my PhD and fellowship in any way. Your encouragement, guidance, and expertise have been invaluable.

A special thanks goes to all the participants in my studies. Each of you generously gave up your time, and you are the reason this research was possible. Without your willingness to be involved, these studies simply could not have happened.

The team (past and present)

• Study lead: Dr. Gerard Farrell (Lead Investigator and Senior Professional Practice Fellow at the School of Physiotherapy Clinics)
  Email gerard.farrell@otago.ac.nz
• Associate Professor Steve Tumilty (primary supervisor of my PhD)
• Professor Chad Cook
• Associate Professor Cathy Chapple
• Dr. Jimmy Zheng
• Associate Professor Kesava Sampath
• Dr Angela Gisselman
• Professor Rajesh Katare
• Dr Ewan Kennedy