Introduction

Head and neck cancer is the sixth most common malignancy and 70% of these patients have oropharyngeal cancer (OPC), most commonly caused from human papillomavirus (HPV) infection (most common HPV-related malignancy in the U.S.). Radiation, the mainstay OPC treatment, can induce neuropathy along the lower cranial nerves (the glossopharyngeal, and hypoglossal nerves) with a 10-48% incidence, resulting in tongue motor and sensory deficits. RICN results in dysphonia, dysphagia, loss of taste, tongue fibrosis and atrophy (causing loss of motor control). Thus, patients’ quality of life is impaired and it can even result in mortality due to aspiration. Although clinical trials show that steroids (NCT04151082) and gabapentin (NCT03747562) temporarily reduce pain, their adverse effects compromise treatment tolerance and adherence. Thus, we need new treatments.

Here we show the strengthening of motor and sensory networks that regulate swallowing and tongue motor sensory control (TMSC) through our individualized fMRI neuromodulation, termed iNM (U.S. Patent No.16/954,256). fMRI measures the magnitude and spatial extent of the ratio of oxygenated (O₂) to deoxygenated hemoglobin [Hb]. (1) iNM is a non-invasive, precision-medicine intervention that can strengthen primary motor and sensory areas that regulate TMSC in the brain with 1mm precision without interfering with other treatments or medications. (2) iNM targets each patient’s unique anatomical and functional circuitry that regulate swallowing and TMSC. (3) iNM is guided by reinforcing or inhibiting the HbO2 intensity and extent of each patient’s unique brain network, as opposed to the self-regulation of the HbO2 intensity.

Methods

Healthy subjects (n=30) participated in a two-day iNM study. On Day one, we decoded the brain spatial patterns and amplitude generated by TMSC in four directions (up, down, left, right), interleaved with periods of tongue-rest (baseline) and swallow. Our innovation is based on targeting individualized networks by extracting HbO2 magnitude and spatial extents. Each participant’s TMSC cortical selectivity were extracted and targeted for iNM. On Day two, participants underwent iNM and control-NOiNM conditions. Support vector machine (SVM) classified cortical direction selectivity patterns versus tongue-at-rest generated via iNM and control. We quantified the HbO2 magnitude for each network’s areas separately, by computing the area under the curve (AUC), variance and dynamic causal modeling to elucidate the association between brain states and the physiological responses of TMSC.

Results

The mechanisms associated with attention-memory and sensorimotor iNM are: 1) 45% increase in the HbO2 magnitude area under the curve (p<0.001); 2) 14% decrease in the BOLD’s intensity variance (p<0.01); and 3) 20% increase in spatial network expansion (p<0.001). Dynamic causal modeling uncovered an iNM-driven dominant state (95% of the trials versus 76% of the control trials): 1) 71% motor-to-motor (M1, motor cerebellum, basal ganglia) and 63% motor-to-sensory connectivity; 2) 63% sensory-to-sensory (intraparietal lobule, insula, claustrum, sensory cerebellum, ACC); and 3) 76% sensorimotor-to-attention-memory connectivity. 

Conclusion

iNM establishes spatiotemporal causality between swallow and TMSC dynamics and sensorimotor networks, which can serve as a clinical biomarker for the alleviation of radiation-induced neuropathy.