Letter to the Editor of JAMA.

Salience Network Hypoconnectivity in Core AHI Cases Warrants Diagnostic Weight.

Letter is available here: https://www.researchgate.net/publication/397439010

To the Editor of JAMA:

We read with interest the March 2024 NIH-led studies on Anomalous Health Incidents (AHIs) by Pierpaoli et al. and Chan et al.[1,2] While both underscore the absence of overt structural brain injury in the overall AHI cohort, we believe the neuroimaging interpretation underrepresents a reproducible and clinically meaningful signal within the core AHI1 subgroup.

Patients in AHI1 met core diagnostic criteria and were initially verified by neuro-vestibular testing methods based on Hoffer et al. (2018).[3] In a predefined subgroup analysis, Pierpaoli et al. reported significantly reduced resting-state connectivity in the anterior and posterior salience networks in AHI1 vs AHI2 participants. However, the authors did not emphasize the AHI1 vs healthy control comparison in the main text. Supplementary data (eTable 7) show that AHI1 participants exhibited significantly lower salience network connectivity compared with controls, with Benjamini–Hochberg adjusted P = .021 for the anterior and .029 for the posterior salience network.[1] These results confirm a reproducible group-level difference, with the anterior network difference remaining statistically significant and the posterior network narrowly missing the stricter multiple-comparison threshold set by the authors.

The conclusion that no consistent neuroimaging signature was identified overlooks this alignment between vestibular-confirmed injury and functional network disruption. Rather than being “of uncertain significance,” salience network hypoconnectivity may represent a functional correlate of the vestibular-cognitive injury pattern now emerging as a model of non-kinetic brain injury (NKBI).[4]

Such findings are consistent with early-stage mild TBI, where functional changes often precede visible structural lesions. In other conditions—fibromyalgia, PTSD, PPPD—altered network activity has supported syndrome recognition in the absence of definitive imaging markers.[5]

Given that AHI1 represents the best-characterized subset, we urge the authors and the broader community to reconsider the salience network findings not as incidental, but as diagnostically relevant, reproducible, and consistent with the plausible RF mechanism proposed by previous National Academies and IC Scientific reports.

References:

1. Pierpaoli C, Kim JH, Donahue MJ, et al. JAMA. 2024;331(13):1122–1134. doi:10.1001/jama.2024.1966

2. Chan L, King C, Kelsey P, et al. JAMA. 2024;331(13):1109–1121. doi:10.1001/jama.2024.1965

3. Hoffer ME, Balaban C, Szczupak M, et al. Acute findings in an acquired neurosensory dysfunction. Laryngoscope Investigative Otolaryngology. 2019;4(1):124–131. doi:10.1002/lio2.144

4. Ber L. Helping Physicians to Understand “Havana Syndrome” and a Novel Method of Managing AHIs. Adv Med Sci. 2025;12(1):1–8. doi: 10.5121/ams.2025.12101

5. Seeley WW, Menon V, Schatzberg AF, et al. J Neurosci. 2007;27(9):2349–2356. doi:10.1523/JNEUROSCI.5587-06.2007