Interoception, the central concept in the new analysis, is commonly defined as the process by which the nervous system senses, interprets, and integrates signals arising from within the body. Heartbeat, breathing rhythm, temperature, visceral tension, and the constellation of internal sensations that color every waking moment all travel upward through dedicated neural channels. The authors emphasize that a substantial portion of this traffic passes through the spinal cord, forming what they call spinal interoceptive pathways. These pathways deliver continuous updates about bodily states to a distributed interoceptive system in the brain, where they inform and constrain predictive models of what the body will experience next. In this framework, the brain is not a passive receiver but an active forecaster, constantly generating predictions about upcoming bodily states and comparing them against incoming signals.

The predictive dimension is where interoception connects most directly to emotion. According to the theoretical models reviewed by Romo-Nava and his colleagues, the brain uses its predictions about bodily states to adjust physiology through descending projections, a closed-loop architecture that maintains homeostasis—the finely tuned internal equilibrium on which survival depends. Emotional experience, in this view, is inseparable from the quality and accuracy of the bodily signals feeding the loop. When the ascending traffic is distorted, dampened, or amplified, the brain’s predictive models drift out of alignment with actual bodily conditions, and the subjective result may be the persistent malaise, heaviness, and dysphoria characteristic of depression. The authors argue that dysregulated signaling in spinal interoceptive pathways and the resulting interoceptive processing errors may play a genuine role in the depressive syndrome rather than being a mere byproduct of it.

What makes this proposal more than a philosophical reframing is its therapeutic implication. If the spinal cord carries a continuous stream of body-to-brain information that shapes mood, then the spinal cord is a physically accessible target. Unlike dispersed cortical networks buried deep within the brain, spinal pathways run through an anatomically well-mapped structure that clinicians already know how to stimulate, record from, and modulate. Neuromodulation technologies—devices and techniques that alter nerve activity through targeted electrical or other stimulation—are routinely applied to the spinal cord in other areas of medicine, most famously for pain management. The perspective article argues that the same general strategy could, in principle, be redirected toward the interoceptive traffic that informs emotional state, opening a novel route for studying and eventually treating major depressive disorder.

The scale of the unmet need gives the proposal urgency. Major depressive disorder affects hundreds of millions of people worldwide, and a large fraction of patients do not achieve lasting relief from available medications and psychotherapies. Existing neuromodulation treatments for depression, such as transcranial magnetic stimulation and implanted brain stimulation devices, work from the top of the loop, targeting the brain directly. An approach that intervenes from the bottom of the loop, at the spinal gateway where bodily signals enter, would represent a fundamentally different mechanistic strategy—one that could complement rather than compete with brain-focused therapies. The authors position spinal interoceptive modulation not as a replacement for existing care but as an additional lever on a system that current treatments leave largely untouched.

Yet the researchers are candid about a major obstacle: a substantial knowledge gap. Despite the theoretical appeal of the framework, the role of spinal interoceptive pathways in major depressive disorder remains poorly characterized. It is not yet established which specific spinal mechanisms are altered in depression, how those alterations propagate to the distributed interoceptive system in the brain, or how changes in spinal signaling correlate with changes in mood. The perspective article frames this gap as the central scientific challenge of the field and argues that closing it requires deliberate experimentation rather than assumption. The authors present their work as emerging evidence supporting the exploration of spinal interoceptive pathways as novel and feasible targets—emphasizing both words, novelty and feasibility, to signal that the approach is grounded in existing technology while pointing toward unexplored biology.

A key methodological problem the article confronts is how to prove that a spinal intervention is actually doing what it claims to do. In clinical neuroscience, this is the problem of target engagement: demonstrating that a treatment measurably modifies the biological mechanism it is designed to influence. Without reliable markers of spinal interoceptive target engagement, any clinical trial of spinal neuromodulation for depression would be flying blind, unable to distinguish between a therapy that failed because the mechanism was wrong and one that failed because the delivery was imprecise. The authors therefore devote significant attention to candidate experimental models and the critical next steps needed to identify markers that would show whether a given intervention is genuinely changing spinal interoceptive signaling. Such markers would be the measurement backbone for future studies, allowing researchers to connect stimulation parameters to physiological changes and physiological changes to clinical outcomes.

The research program described in the article is already backed by institutional investment. The work was supported by the Lindner Center of Hope and the University of Cincinnati, as well as by the National Institute of Mental Health, which funded the effort in part through grant 1R61MH133770-01A1. The breadth of the author team reflects the interdisciplinary demands of the project: the collaboration includes psychiatrists, neurologists, neurosurgeons, a biostatistician, and interoception specialists from the Laureate Institute for Brain Research and UCLA’s Semel Institute for Neuroscience and Human Behavior. Bringing together expertise in spine-level intervention, brain imaging, psychiatric assessment, and trial design is a prerequisite for a program that spans the length of the neuraxis—from peripheral bodily sensors through spinal relay stations to cortical interoceptive networks.

The broader scientific context makes the timing of this proposal notable. Across neuroscience, interoception has moved from a niche topic to a central framework for understanding psychiatric illness, with conditions including anxiety, eating disorders, and depression increasingly interpreted as disorders of bodily signal processing. Predictive processing models of the brain have given the field a common theoretical language, describing perception and emotion as consequences of prediction and prediction error rather than simple stimulus response. The spinal cord, in this emerging picture, is no longer a mere cable between brain and body but an active processing station that shapes the information it transmits. The Romo-Nava perspective extends that shift by insisting that the clinical implications run in both directions: just as the brain constrains the body through descending projections, the body constrains the brain through ascending spinal channels, and either side of the loop can be an intervention point.

If the research program succeeds, the consequences could extend well beyond depression. Spinal interoceptive pathways plausibly contribute to the physical symptoms that accompany many psychiatric conditions—chronic pain, fatigue, autonomic dysregulation—and a validated method for measuring and modulating spinal interoceptive signaling could illuminate all of them. For now, the authors’ contribution is a roadmap: a reasoned case that the spinal cord is a feasible, mechanistically motivated target for depression research, an honest account of what remains unknown, and a set of candidate models and engagement markers to guide the experiments ahead. As the field confronts the limits of treatments aimed solely at the brain, the message of this perspective is that mood may be built, in part, from signals that begin their journey in the body—and that the gateway through which those signals travel may one day become a place where depression is treated.

Subject of Research: The role of spinal interoceptive pathways in major depressive disorder and their potential as neuromodulation targets

Article Title: Spinal interoceptive pathways as therapeutic targets in depression

Article References: Romo-Nava, F., Awosika, O. O., Phan, P., Basu, I., Liu, J. C., Charnas, C., Georgiev, G., Mori, N. N., Welge, J., Blom, T., Fleck, D. E., Cao, X., Khalsa, S., Paulus, M., & McElroy, S. L. (2026). Spinal interoceptive pathways as therapeutic targets in depression. Discover Mental Health. https://doi.org/10.1007/s44192-026-00597-z

Image Credits: AI Generated

DOI: 10.1007/s44192-026-00597-z

Keywords: interoception, spinal cord, major depressive disorder, neuromodulation, predictive processing, homeostasis, psychiatry, spinal interoceptive pathways, target engagement, neuroscience, Spinal, interoceptive

Heterotopic ossification affects a substantial fraction of people with spinal cord injury, with estimates in clinical literature ranging from around 20 percent to more than 60 percent depending on how aggressively patients are screened. The condition typically emerges below the level of the lesion, most often around the hips, knees and elbows, and produces swelling, stiffness, progressive joint immobility and, in severe cases, complete ankylosis of the affected joint. For individuals already coping with paralysis, the added loss of joint range can devastate independence, interfering with seating, transfers, dressing and the ability to use a wheelchair comfortably. Current treatment options are limited and unsatisfying: nonsteroidal anti-inflammatory drugs and bisphosphonates are used prophylactically with mixed evidence, radiation therapy is occasionally deployed in high-risk cases, and surgical excision remains the definitive intervention, despite high recurrence rates and considerable operative risk.

What has been missing is a coherent account of how a wound in the spinal cord communicates with skeletal muscle distant from the injury site. Inflammation at the muscle level has long been implicated, and macrophages, the versatile immune cells that flood damaged tissue, have been suspected participants. Bone morphogenetic protein signaling, particularly through BMP2 and related ligands, is known to be a powerful inducer of ectopic bone. Yet none of these observations explained the striking temporal and anatomical link to the central nervous system injury itself. The new work addresses that gap by identifying adrenomedullin as the long-range signal, and by showing that it does not act alone but through a choreographed interaction between the nervous system, the immune system and mesenchymal progenitors residing in muscle.

Adrenomedullin is a 52-amino-acid peptide first isolated from human pheochromocytoma tissue in the early 1990s and subsequently recognized as a near-universal stress messenger. It is produced by vascular smooth muscle, endothelial cells, epithelia and neurons, and it participates in vasodilation, angiogenesis, immune modulation and tissue repair. Its receptors, composed of the calcitonin receptor-like receptor paired with receptor activity-modifying proteins, are widely distributed. In the context of spinal cord injury, the researchers found that adrenomedullin expression rises markedly in the injured cord, and that the peptide reaches the circulation and downstream tissues at levels capable of instructing cells far from the lesion. This elevation is not a passive byproduct of tissue damage; the study demonstrates that it is functionally required for the ectopic bone program to begin.

The mechanistic core of the paper lies in what adrenomedullin does once it arrives in muscle. Using rodent models of spinal cord injury combined with pharmacological blockade and genetic approaches, the team showed that adrenomedullin recruits and polarizes macrophages toward a pro-inflammatory, pro-osteogenic state. These macrophages, in turn, become a rich local source of bone morphogenetic protein 2, the master osteoinductive cue. Meanwhile, adrenomedullin acts directly on mesenchymal stromal cells and muscle-resident progenitors, sensitizing them to the BMP2 signal and pushing them along an osteoblastic differentiation pathway. The result is a feed-forward circuit: the neural signal summons and shapes the immune response, the immune response supplies the osteogenic ligand, and the sensitized progenitors execute the bone-forming program. The authors describe this as a neuro–immune–bone axis, a three-node signaling architecture in which each node is necessary for the pathology to unfold.

The experimental evidence supporting this model is notably multi-layered. In mice subjected to spinal cord injury, heterotopic bone formed in paralyzed limbs on a timeline consistent with the human clinical course, and the extent of ossification correlated with circulating adrenomedullin. Neutralizing the peptide with antibodies, antagonizing its receptors, or depleting macrophages each substantially reduced ectopic bone formation. Conversely, administering exogenous adrenomedullin to animals with otherwise insufficient neural drive promoted macrophage accumulation and osteogenic differentiation in muscle. Conditional genetic strategies further clarified the cellular division of labor: macrophage-derived BMP2 proved essential, while the osteogenic competence of the mesenchymal compartment depended on adrenomedullin receptor signaling. Transcriptional profiling of the affected muscle revealed enrichment of inflammatory, angiogenic and osteogenic gene programs, consistent with a tissue being actively converted from a muscle identity toward a bone-forming niche.

Perhaps the most clinically resonant finding concerns timing and reversibility. The adrenomedullin-driven cascade was shown to be active during a defined window after cord injury, and interventions that blocked the axis during that window prevented or markedly attenuated heterotopic ossification. This reframes the condition not as an inevitable consequence of paralysis but as a targetable signaling disease, one that could in principle be intercepted in the days to weeks following injury, before the first radiographic sign of bone appears. Because adrenomedullin antagonists and anti-BMP2 strategies already exist in various experimental and clinical forms, the pathway offers a plausible translational route. The caveat, which the authors acknowledge, is that adrenomedullin performs beneficial functions in vascular integrity, wound healing and immune regulation, so systemic blockade carries risks. Local delivery strategies, short treatment windows, or agents tuned to the specific receptor subtype involved may be needed to separate therapeutic benefit from collateral harm.

The study also carries broader implications beyond spinal cord medicine. Heterotopic ossification arises in other settings, including traumatic brain injury, severe burns, blast injuries in military personnel, and genetic conditions such as fibrodysplasia ossificans progressiva. In several of these contexts, central nervous system trauma or systemic inflammatory storms are part of the clinical picture, raising the possibility that neuro–immune–bone communication is a general principle of ectopic bone formation rather than a peculiarity of cord injury. If adrenomedullin or related neural signals contribute to ossification after burns or brain injury, the therapeutic horizon widens considerably. Even in fibrodysplasia ossificans progressiva, where an activating ACVR1 mutation provides the primary osteogenic driver, inflammatory flares are known to precipitate bone episodes, and understanding how neural and immune signals amplify that driver could inform combination therapies.

From a basic science perspective, the work adds to a growing recognition that the nervous system is not merely a bystander in regenerative and pathological processes but an active endocrine organ whose injury products reshape distant tissues. The concept of a neuro–immune–bone axis echoes earlier discoveries of neuroimmune interactions in pain, cachexia and bone homeostasis, but here the axis is shown to operate in a pathologically constructive direction, building ectopic skeleton rather than maintaining existing bone. It also underscores the macrophage’s dual identity: the same cells that clear debris and support repair can be commandeered by a circulating peptide into serving as local factories for osteoinductive ligands. Dissecting which macrophage subsets respond to adrenomedullin, and whether their polarization can be selectively redirected, represents an obvious next step.

For the millions of people worldwide living with spinal cord injury, and for the clinicians who manage the secondary complications of paralysis, the identification of a single, druggable molecular trigger for heterotopic ossification is a genuine advance. It converts a decades-old clinical observation, that paralyzed limbs sometimes grow bone, into a defined signaling pathway with named nodes, testable intermediates and established pharmacological levers. Clinical translation will require careful validation in human tissue and trials that respect the peptide’s physiological roles, but the conceptual shift is already complete: heterotopic ossification after spinal cord injury is now understood as a systemic endocrine event, initiated in the damaged cord, amplified by the immune system, and executed by progenitors in muscle that never asked to become bone cells.

Subject of Research: Adrenomedullin-driven heterotopic ossification after spinal cord injury via a neuro–immune–bone axis

Article Title: Adrenomedullin from spinal cord injury drives heterotopic ossification in skeletal muscle via a neuro–immune–bone axis

Article References: Chen, J., Wang, Z., Zeng, X., Wu, X., Li, G., Miao, N., Deng, Y., Zhang, D., Chen, X., Lai, H., Wan, Y., Wang, L., & Li, X. (2026). Adrenomedullin from spinal cord injury drives heterotopic ossification in skeletal muscle via a neuro–immune–bone axis. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01836-7

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01836-7

Keywords: spinal cord injury, heterotopic ossification, adrenomedullin, macrophages, BMP2, neuro–immune–bone axis, mesenchymal progenitors, ectopic bone, osteogenesis, Experimental & Molecular Medicine, spinal, cord