The framework, called the Cingulate–Mitochondrial–Resonome Axis (CMRA), was introduced in a Hypothesis and Theory article published in Frontiers in Pain Research. It represents a deliberate departure from conventional structure-centered rehabilitation models. Rather than viewing rehabilitation as a purely peripheral intervention that mechanically restores damaged tissue, the CMRA proposes that therapeutic exercise, manual therapy, and movement re-education act in part by restoring the coherence and organization of interoceptive signaling — the body’s vast, distributed system for sensing its own internal state. This internal sensing network, which the authors refer to as the resonome, encompasses signals arising from connective tissue, autonomic pathways, sensorimotor feedback loops, and cellular bioenergetic processes, particularly those governed by mitochondria.

The cingulate cortex, a region of the brain nestled above the corpus callosum, sits at the center of this framework for good reason. It is one of the most densely connected hubs in the mammalian brain, integrating information about pain, emotion, autonomic state, and motor planning. In chronic pain conditions, the cingulate cortex undergoes functional reorganization, becoming hyperactive and increasingly coupled to networks that amplify suffering and reduce motivation for movement. The CMRA framework proposes that when interoceptive signals from the periphery become disorganized — as occurs with chronic inflammation, sustained biomechanical dysfunction, or autonomic imbalance — the cingulate cortex receives noisy, incoherent input. This noisy input, in turn, drives maladaptive affective and motor responses: increased pain perception, reduced willingness to move, heightened sympathetic arousal, and a downward spiral of deconditioning and suffering.

Rehabilitation, in this light, is not simply a mechanical fix. It is a form of interoceptive re-education. When a dog performs controlled, progressive exercise, receives manual therapy, or engages in structured movement, the peripheral tissues generate new patterns of afferent signaling — proprioceptive feedback, autonomic tone shifts, inflammatory resolution signals, and bioenergetic cues from muscle mitochondria. These signals, according to the CMRA, gradually restore coherence to the resonome. The cingulate cortex, receiving cleaner and more organized input, can then recalibrate its output: reducing pain amplification, normalizing autonomic tone, and facilitating more confident, fluid movement. The result is a positive feedback loop in which improved interoceptive signaling leads to better central regulation, which in turn enables more effective rehabilitation participation.

Building conceptually upon the Feelings of Knowing–Fundamental Interoceptive Patterns (FoK–FIP) theory, the CMRA framework integrates insights from interoceptive neuroscience, autonomic physiology, mitochondrial biology, and affective-motor processing into a unified model. The FoK–FIP theory posits that the brain continuously generates predictions about the body’s internal state based on prior interoceptive patterns, and that chronic pain represents a state in which these predictions have become locked into maladaptive configurations. Rehabilitation, from this perspective, works not by directly repairing tissue but by providing the nervous system with new interoceptive evidence that gradually updates these predictive models, allowing the brain to reframe its interpretation of bodily signals and reduce the affective burden of chronic pain.

One of the most provocative aspects of the CMRA framework is its explicit acknowledgment that functional improvements can occur despite persistent structural pathology. This observation, long noted by rehabilitation clinicians, has been difficult to reconcile with purely biomechanical models. A dog with radiographic evidence of severe osteoarthritis may show dramatic functional gains after a rehabilitation program, even though the underlying joint damage remains unchanged. The CMRA framework offers a potential explanation: the rehabilitation intervention may have restored interoceptive coherence, allowing the cingulate cortex and associated networks to reduce pain amplification and normalize motor output, independent of any change in tissue structure. This prediction distinguishes the CMRA from conventional models and generates experimentally testable hypotheses about the relationship between interoceptive organization, central neurocognitive change, and behavioral outcomes.

The framework also incorporates mitochondrial bioenergetics as a critical component of the axis. Mitochondria, the energy-producing organelles within cells, are not merely metabolic workhorses. They are dynamic signaling platforms that communicate with the nucleus, modulate inflammatory responses, and influence neural excitability. In chronic pain states, mitochondrial dysfunction in muscle, peripheral nerves, and even central neurons may contribute to sustained nociceptive signaling and reduced capacity for tissue adaptation. The CMRA proposes that rehabilitation-induced improvements in mitochondrial function — driven by the metabolic demands of progressive exercise — may generate bioenergetic signals that contribute to the restoration of interoceptive coherence, linking cellular energy status to whole-organism pain adaptation through the cingulate-mediated regulatory network.

To make this framework scientifically useful rather than merely speculative, the authors propose that rehabilitation-associated physiological changes may be reflected by multimodal measures including infrared thermography, quantitative gait analysis, and validated behavioral assessments. Infrared thermography can capture changes in autonomic tone and peripheral blood flow, providing a non-invasive window into sympathetic and parasympathetic regulation. Quantitative gait analysis can detect subtle improvements in movement symmetry, cadence, and weight distribution that may reflect both biomechanical restoration and central motor reorganization. Behavioral assessments, validated for canine chronic pain, can quantify changes in activity, affect, and pain-related behavior. The framework predicts that these measures will show coordinated changes across multiple domains, consistent with improved interoceptive organization, rather than isolated improvements in any single metric.

Importantly, the authors are careful to note that these multimodal measures are not specific to the CMRA framework. Changes in thermography, gait, and behavior may also reflect established mechanisms such as altered biomechanics, reduced inflammation, central sensitization, or predictive processing updates. The framework’s value lies not in replacing these mechanisms but in proposing a higher-order organizing principle: that coordinated, cross-domain changes are the signature of restored interoceptive coherence, and that this coherence serves as a candidate mediating variable linking peripheral rehabilitation interventions to central neurocognitive and behavioral change. This framing generates falsifiable predictions that can be tested in future studies, distinguishing the CMRA from purely descriptive accounts of rehabilitation success.

The authors also acknowledge that one component of the framework — the proposed role of large-scale endogenous electromagnetic organization — remains speculative and incompletely validated. This aspect of the model, which suggests that coherent bioelectric signaling across connective tissue and neural networks may contribute to interoceptive organization, is presented as a hypothesis requiring further investigation rather than an established mechanism. By explicitly labeling this component as speculative, the authors maintain scientific rigor while still generating testable predictions about rehabilitation-associated changes in behavior, autonomic regulation, gait function, and chronic pain adaptation. The CMRA framework, in its current form, is offered as a testable theoretical model rather than a confirmed mechanistic explanation, inviting the research community to design experiments that either support or refute its central claims across species.

Subject of Research: A systems-level hypothesis linking interoceptive signaling, cingulate cortex, and mitochondrial bioenergetics to rehabilitation outcomes in dogs with chronic pain.

Article Title: The cingulate–mitochondrial–resonome axis: a conceptual framework integrating rehabilitation, interoception, and affective–motor processing in canine chronic pain

Article References: The cingulate–mitochondrial–resonome axis: a conceptual framework integrating rehabilitation, interoception, and affective–motor processing in canine chronic pain. (n.d.). https://doi.org/10.3389/fpain.2026.1807872

Image Credits: AI Generated

DOI: 10.3389/fpain.2026.1807872

Keywords: chronic pain, dogs, interoception, rehabilitation, cingulate cortex, mitochondria, autonomic nervous system, gait analysis, thermography, canine health, neuroscience, hypothesis