01/03/2026
Normal imaging does not mean normal biology.
That single observation has shaped much of our clinical research over the past year.
As 2026 begins, I wanted to step back and reflect on the questions that guided our work in 2025. Across very different projects, the same theme kept emerging: brain injury and neurodegeneration are not single-event problems. They are system problems.
When pain becomes the disability after traumatic brain injury
In clinical practice, persistent pain is often what limits recovery after mild traumatic brain injury, even when imaging looks normal.
Two recent papers focused on why pain persists in these cases. One examined central sensitization as a dominant mechanism in chronic post-mTBI pain, emphasizing altered neural processing rather than ongoing tissue damage. Another addressed multidisciplinary pain management, highlighting the importance of classifying pain mechanisms instead of relying on one-size-fits-all treatment strategies.
Across both studies, the message was consistent: precision matters more than intensity. Treatment works best when it is matched to the underlying mechanism.
Post-traumatic headache: expanding the toolkit
Post-traumatic headache remains one of the most disabling sequelae of traumatic brain injury. In patients with refractory symptoms, we reviewed outcomes following targeted peripheral nerve blocks, showing meaningful improvement in carefully selected cases.
This work is not about replacing preventive therapies. It is about expanding the toolkit when conventional approaches fall short.
Looking upstream in neurodegeneration
Several publications this year approached Alzheimer’s disease from an upstream perspective, before amyloid and tau dominate the conversation.
We examined blood-based metabolic biomarkers with diagnostic promise, revisited the persistent role of oxidative stress and why antioxidant trials have struggled, explored the complex relationship between lipid biology and Alzheimer’s disease, reviewed viral infection hypotheses, and assessed the current state of stem cell interventions in neurology.
Across these studies, a common thread emerged: timing, biology, and context matter as much as targets.
Repair biology is not peripheral
Some of our work focused on nutrition, tryptophan metabolism, melatonin, and nitric-oxide–related pathways. These were not tangential interests.
In brain injury and neurodegeneration, the capacity for repair is constrained by metabolic substrate, redox balance, vascular coupling, and sleep biology. Repair is a biological process. Ignoring that reality limits recovery.
A unifying framework
Taken together, this body of work reinforces a simple idea: neurological disorders demand multidimensional evaluation.
Biology includes biomarkers, metabolomics, and oxidative pathways. Function includes neurophysiology, symptoms, and recovery capacity. Structure is reflected in imaging. Environment includes nutrition, sleep, and comorbidity.
No single measurement tells the whole story. No single intervention fixes a systems problem.
Looking ahead
In the coming months, I plan to expand on these themes individually, including persistent pain after traumatic brain injury, post-traumatic headache, biomarkers and metabolomics, and the biology of repair. Each deserves focused discussion as the science continues to evolve.
Question for colleagues:
If you could change one thing about how we evaluate or treat brain injury and neurodegeneration in 2026, what would it be?
This summary reflects where our clinical research work has been focused recently, but many of these topics deserve deeper treatment. In the months ahead, I will be sharing focused posts on each of these areas, highlighting what is established, what remains uncertain, and where the field appears to be heading. I welcome the opportunity to continue the conversation with colleagues facing the same challenges.
Selected peer-reviewed publications from this body of work are listed below for those interested.This summary reflects where our clinical research work in the last period has been focused, but many of these topics deserve deeper treatment. In the months ahead, I’ll be sharing focused posts on each of these areas, highlighting what’s established, what’s still uncertain, and where the field appears to be heading. I welcome the opportunity to continue the conversation with colleagues who are facing the same challenges.
1. Esneault BS, Maddox MB, Loewe EM, Pappolla MA, Parker-Actlis TQ, Shekoohi S, Kaye AD.
Pharmacologic and Nonpharmacologic Pain Management in Patients with Traumatic Brain Injury: A Multidisciplinary Approach. J Clin Med. 2025 Dec 9;14(24):8713. doi: 10.3390/jcm14248713. PMID: 41464613.
2. Poeggeler B, Singh SK, Sambamurti K, Pappolla MA.
Special Issue “Tryptophan in Nutrition and Health 3.0.” Int J Mol Sci. 2025 Aug 30;26(17):8443. doi: 10.3390/ijms26178443. PMID: 40943365.
3. File C, Nader R, Villasante-Tezanos A, Ahmed R, Pappolla S, Ahmed F, Miranda-Morales EG, Zhao Y, Fang X, Kaye AD, Pappolla MA.
Pain Management in Mild Traumatic Brain Injury: Central Sensitization as a Multispecialty Challenge. Pain Physician. 2025 May;28(3):231-240. PMID: 40464888.
4. File C, Fang X, Ahmad R, Harazeen A, Jung J, Ahmed F, Ahmad N, Pappolla S, Nader R, Pappolla MA.
Efficacy of Nerve Blocks for Managing Refractory Posttraumatic Headaches. Pain Physician. 2025 Mar;28(2):137-145. PMID: 40168565.
5. Zhao Y, Villasante-Tezanos A, Miranda-Morales EG, Pappolla MA, Fang X.
Discovery of Novel Metabolic Biomarkers in Blood Serum for Diagnosis of Alzheimer’s Disease. J Alzheimers Dis. 2024 Nov;102(1):237-253. doi: 10.3233/JAD-240280. Epub 2024 Oct 25. PMID: 39497321.
6. Pappolla MA, Martins RN, Poeggeler B, Omar RA, Perry G.
Oxidative Stress in Alzheimer’s Disease: The Shortcomings of Antioxidant Therapies. J Alzheimers Dis. 2024;101(s1):S155-S178. doi: 10.3233/JAD-240659. PMID: 39422961.
7. Pappolla MA, Refolo L, Sambamurti K, Zambon D, Duff K.
Hypercholesterolemia and Alzheimer’s Disease: Unraveling the Connection and Assessing the Efficacy of Lipid-Lowering Therapies. J Alzheimers Dis. 2024;101(s1):S371-S393. doi: 10.3233/JAD-240388. PMID: 39422957.
8. Pappolla MA, Wu P, Fang X, Poeggeler B, Sambamurti K, Wisniewski T, Perry G.
Stem Cell Interventions in Neurology: From Bench to Bedside. J Alzheimers Dis. 2024;101(s1):S395-S416. doi: 10.3233/JAD-230897. PMID: 39422938.
9. Kaye AD, File CJ, Borne GE, Daniel CP, Sharma R, Shekoohi S, Pappolla MA.
Melatonin: Evolving Physiological Understanding and Potential Therapeutic Role in Pain Medicine Including Intervertebral Disc Degeneration. Pain Physician. 2024 Jul;27(5):273-282. PMID: 39087961.
10. Rippee-Brooks MD, Wu W, D**g J, Pappolla M, Fang X, Bao X.
Viral Infections: Are They a Trigger and Risk Factor of Alzheimer’s Disease? Pathogens. 2024 Mar 8;13(3):240. doi: 10.3390/pathogens13030240. PMID: 38535583.
