The Cingulate–Mitochondrial–Resonome Axis (CMRA) Series — Part I
About This Series
This article is part of a six-part series designed to make the Cingulate–Mitochondrial–Resonome Axis (CMRA) framework accessible to pet owners, veterinarians, rehabilitation professionals, and students. Each article explores one aspect of the science behind chronic pain, rehabilitation, and whole-body physiology using clear, practical language while remaining grounded in peer-reviewed scientific evidence.
About the Author
Dr. Holly Pollard-Wright is a veterinarian and post-doctoral researcher with advanced certifications in canine rehabilitation (CCRP), veterinary acupuncture (CVA), and small animal myofascial therapy (CSMP). Her peer-reviewed manuscript describing the CMRA framework was published in Frontiers in Pain Research. This educational series translates that scientific work into language that is accessible to a broader audience.
Pain Is Not Only a Joint Problem
When a dog develops osteoarthritis, spinal instability, tendinopathy, or chronic myofascial restriction, our attention naturally focuses on the affected structure.
We assess:
- Joint range of motion
- Muscle symmetry
- Inflammation
- Imaging findings (radiographs, MRI, or CT)
These factors matter.
However, chronic musculoskeletal dysfunction not only alters tissues. It alters how the brain interprets signals from those tissues.
The important takeaway: Pain is interpreted and integrated in the brain (1). Rather than simply originating in a joint or tissue, pain reflects the brain’s response to signals it interprets as a potential threat. These signals can arise from real physical problems such as joint inflammation, instability, or restricted soft tissue. The brain then processes this information — along with past experience and context — to determine how much pain is experienced.
The Brain’s Integration Role
The brain contains specialized regions that process and integrate bodily information.
One of these regions is the cingulate cortex.
A little brain anatomy helps explain why:
- The brain is divided into regions with distinct functional roles.
- The outer layer is called the cortex.
- The cingulate cortex sits near the midline and helps integrate emotion, motivation, signals from the body, and movement decisions (2, 3).
Importantly, this region does not simply register pain intensity. It helps determine:
- How unpleasant something feels
- Whether a movement is worth the effort
- Whether the body feels safe or threatened
- How much energy to allocate to action
In other words, it helps connect what’s happening inside the body to behavior.
Visual Overview
Figure: Pain and Personality Change. Conceptual illustration of how musculoskeletal dysfunction generates repeated sensory input that is integrated within the cingulate cortex, influencing movement, emotion, and observable behavior. This schematic aligns with the integrative framework described in the CMRA model (6).
Why Chronic Pain Changes Behavior
Chronic pain is associated with measurable changes in brain structure and connectivity, particularly in regions including the cingulate cortex (1, 4).
When musculoskeletal tissues send repeated stress signals to the brain, adaptive neural changes occur.
Over time, this may influence:
- Willingness to engage in movement
- Gait confidence
- Frustration tolerance
- Social interaction
- Autonomic tone (stress versus calm balance)
Behavioral shifts linked to chronic pain are increasingly recognized in both humans and companion animals (5).
These changes are not personality flaws.
They may reflect adaptive changes in how the brain integrates ongoing bodily signals, pain, emotion, and movement.
The Gap in Traditional Models
Conventional rehabilitation appropriately focuses on:
- Reducing inflammation
- Improving joint mechanics
- Strengthening muscle
- Restoring mobility
However, neuroscience literature demonstrates that chronic pain involves central nervous system reorganization in addition to peripheral pathology (1, 4).
There remains a mechanistic gap between tissue-level dysfunction and observable behavioral change.
A recently published theoretical framework, the Cingulate–Mitochondrial–Resonome Axis (CMRA), proposes that rehabilitation-associated restoration of interoceptive coherence may serve as a candidate process linking changes in peripheral tissues with affective, autonomic, nociceptive, and motor adaptation in the brain (6).
This framework does not replace biomechanical understanding. It extends it.
Why This Matters Clinically
If behavior and motivation are partly shaped by how the brain interprets bodily signals, then rehabilitation has implications beyond joint mechanics.
When we improve the quality and predictability of signals coming from musculoskeletal tissues, we may observe broader integrative effects.
Clinical Translation
When signal quality improves, we may observe:
- Reduced maladaptive vigilance → The brain feels less persistently on guard.
- Improved motor confidence → Movement feels safer and more predictable.
- Stabilized autonomic tone → Stress and calm systems return toward balance.
- Supported affective regulation → Emotional responses become steadier.
Rehabilitation may therefore act both peripherally and centrally (6).
Looking Ahead
In the next article, we’ll explore where these bodily threat signals originate. The story begins deep inside the cell — within mitochondria, the microscopic organelles best known for producing cellular energy.
Growing evidence suggests that mitochondria do much more than produce energy. They also help sense cellular stress, influence inflammation, and shape the signals that ultimately travel through the nervous system to the brain.
Next in the CMRA Series:
References
1. Apkarian, A. V., Baliki, M. N., & Geha, P. Y. (2009). Towards a theory of chronic pain. Progress in Neurobiology, 87(2), 81–97.
2. Bush, G., Luu, P., & Posner, M. I. (2000). Cognitive and emotional influences in anterior cingulate cortex. Trends in Cognitive Sciences, 4(6), 215–222.
3. Shackman, A. J., Salomons, T. V., Slagter, H. A., Fox, A. S., Winter, J. J., & Davidson, R. J. (2011). The integration of negative affect, pain, and cognitive control in the cingulate cortex. Nature Reviews Neuroscience, 12(3), 154–167.
4. Baliki, M. N., Petre, B., Torbey, S., Herrmann, K. M., Huang, L., Schnitzer, T. J., Fields, H. L., & Apkarian, A. V. (2012). Corticostriatal functional connectivity predicts transition to chronic back pain. Nature Neuroscience, 15(8), 1117–1119.
5. Mills, D. S., Demontigny-Bédard, I., Gruen, M., Klinck, M. P., McPeake, K. J., Barcelos, A. M., et al. (2020). Pain and problem behavior in cats and dogs. Animals, 10(2), Article 318.
6. Pollard-Wright H and Klomhaus A (2026) The cingulate–mitochondrial–resonome axis: a conceptual framework integrating rehabilitation, interoception, and affective–motor processing in canine chronic pain. Front. Pain Res. 7:1807872. doi: 10.3389/fpain.2026.1807872