Translingual Neural Stimulation With the Portable Neuromodulation Stimulator (PoNS®) Induces Structural Changes Leading to Functional Recovery In Patients With Mild-To-Moderate Traumatic Brain Injury Authors: Jiancheng Hou,1 Arman Kulkarni,2 Neelima Tellapragada,1 Veena Nair,1 Yuri Danilov,3 Kurt Kaczmarek,3 Beth Meyerand,2 Mitchell Tyler,2,3 *Vivek Prabhakaran1 1. Department of Radiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA 2. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA 3. Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin, USA *Correspondence to [email protected] Disclosure: Dr Tyler, Dr Danilov, and Dr Kaczmarek are co-founders of Advanced Neurorehabilitation, LLC, which holds the intellectual property rights to the PoNS® technology. Dr Tyler is a board member of NeuroHabilitation Corporation, a wholly- owned subsidiary of Helius Medical Technologies, and owns stock in the corporation. The other authors have declared no conflicts of interest. Acknowledgements: Professional medical writing and editorial assistance were provided by Kelly M. Fahrbach, Ashfield Healthcare Communications, part of UDG Healthcare plc, funded by Helius Medical Technologies. Dr Tyler, Dr Kaczmarek, Dr Danilov, Dr Hou, and Dr Prabhakaran were being supported by NHC-TBI-PoNS-RT001. Dr Hou, Dr Kulkarni, Dr Nair, Dr Tellapragada, and Dr Prabhakaran were being supported by R01AI138647. Dr Hou and Dr Prabhakaran were being supported by P01AI132132, R01NS105646. Dr Kulkarni was being supported by the Clinical & Translational Science Award programme of the National Center for Research Resources, NCATS grant 1UL1RR025011. Dr Meyerand, Dr Prabhakaran, Dr Nair was being supported by U01NS093650. This study is a part of the long-term clinical trial (NCT02158494), which was completed to investigate the efficacy of translingual neural stimulation (cranial nerve noninvasive neuromodulation). The authors are willing sharing their data and analysis with other qualified investigators upon request. Received: 26.02.20 Accepted: 17.07.20 Keywords: Dynamic Gait Index (DGI), grey matter volume (GMV), Sensory Organization Test (SOT), translingual neural stimulation (TLNS), traumatic brain injuries. Citation: EMJ Radiol. 2020;1[1]:64-71. Abstract Traumatic brain injury (TBI) of varying severity can result in balance and movement disorders, for which the benefits of treatment with physical therapy has limits. In this study, patients with post- TBI balance issues received translingual neural stimulation (TLNS) in concert with physical therapy 64 RADIOLOGY • September 2020 EMJ and the effects on the grey matter volume (GMV) were evaluated. TBI-related balance and movement impairments were also assessed through Sensory Organization Test (SOT) and Dynamic Gait Index (DGI) scoring. When comparing pre- and post-intervention results, the most prominent GMV changes were increases within the cerebellum, and temporal regions, which are involved in automatic processing of gait, balance, motor control, and visual-motion. Decreases of GMV in frontal, occipital lobes (involved in less automatic processing or more conscious/effortful processing of gait, balance, motor control, and vision) positively correlated to increases in SOT/DGI scores. These results indicate that TLNS can produce brain plasticity changes leading to positive changes in functional assessments. Overall, these data indicate that TLNS delivered in conjunction with physical therapy, is a safe, effective, and integrative way to treat TBI. INTRODUCTION changes (i.e., brain regions of pons, brainstem, and cerebellum), reduce symptoms, and begin 13,14,16,17 The Centers for Disease Control and Prevention normalising function. In TLNS, stimulation (CDC) report that up to 5.3 million people in of the tongue can occur with either a high- the USA are living with a disability related to frequency (HFP) or low-frequency (LFP) pulse traumatic brain injury (TBI),1 resulting in $76.5 device. A long-term clinical trial was recently billion per year2 in medical and rehabilitation completed to investigate the efficacy of TLNS costs. The majority of TBI are considered mild- in patients with mmTBI symptoms and compare 18 to-moderate (mmTBI)3 and development of outcomes of the HFP and LFP devices. balance impairments after injury is common, To better understand the effects of TLNS, the 4 occurring in 30% to 65% of patients. Currently, substudy presented here was developed with the the main approach for treating mmTBI primary objective of using structural MRI (sMRI) symptoms is physical therapy (PT), but its effect to evaluate cortical and subcortical changes in has limits and improvements in function are the brains of patients before (pre-) and after 5 often lost if therapy is not sustained. Recent (post-) treatment. Specifically, the grey matter studies have demonstrated the effective volume (GMV) results before and after treatment outcomes with motor-behavioural interventions were compared to investigate if individuals 6-9 and cognitive skill training after injury, experienced a reduction in compensatory brain which support the development of a regions and, conversely, growth in deficient unified and multidisciplinary approach to automatic brain regions. These structural 10-12 mmTBI treatment. changes were then correlated to behavioural A treatment plan utilising translingual neural assessments of balance and gait before and stimulation (TLNS) combines electrical after treatment. stimulation of cranial nerves V (trigeminal) and VII (facial) with physical therapy mainly aimed METHODS AND MATERIALS at restoring balance and gait.13 TLNS can be provided via the Portable Neuromodulation Participants Stimulator (PoNS®, Helius Medical Technologies, Newtown, Pennsylvania, USA), an investigational Participants were recruited through print and medical device that delivers sequenced patterns radio advertising and were required to have mm of electrical stimulation on the tongue. These TBI that occurred 1 year before enrolment, stimuli then trigger the trigeminal and facial reached a functional plateau in their recovery nerves to excite a natural flow of neural impulses (as defined by a discharge note from their to the brainstem or cerebellum and promote physical therapist), and a NeuroComa Sensory changes in targeted brain structures.14-16 Results Organization Test (SOT) composite score 16 from pilot studies of TLNS treatment of patients points below normal after adjustment for age. after mmTBI suggest that, in the absence of Mild and moderate TBI diagnoses were made identifiable tissue damage, a combination of based on guidelines established by Veterans neurostimulation and rehabilitation that is both Affairs/Department of Defense.19 All participants targeted and challenging will induce neuroplastic had a nonremarkable neuroradiographic report Creative Commons Attribution-Non Commercial 4.0 September 2020 • RADIOLOGY 65 after their most recent TBI, meaning that the other than those attributed to their primary findings were not significant per the clinical diagnosis, history of treatment for cancer judgement of the neuroradiologist. Reports other than basal cell carcinoma within the past were reviewed to rule out refractory subdural year, a penetrating head injury, craniotomy, or haematomas, evidence of tumours, anatomical refractory subdural haematoma. Long-term use anomalies, or evidence of loss of grey matter. of psychoactive or psychostimulant medications Neuroradiographic reports and therapy that, in the opinion of the investigators, discharge notes were obtained through a would compromise the participant’s ability to medical records request; MRI prior to enrolment comprehend and perform study activities was was required if a participant lacked a also grounds for exclusion, as was the presence neuroradiographic report. Potential participants of a pacemaker or elevated risk for cardiovascular were excluded if they had oral or other health events. Individuals with a lower extremity problems that would preclude TLNS or, in the biomechanical prosthetic, history of seizures, or a opinion of the investigators, were unable to ‘severe’ score in any of the attention, memory, or successfully complete the stimulation intensity executive functions categories on the Cognitive level setting procedure for the device. Additional Linguistic Quick Test (CLQT) were also excluded.20 inclusion and exclusion criteria are available (please see next paragraph for the detailed Intervention criteria for inclusion and exclusion about all the The intervention TLNS training programme nine mmTBI participants who received HFP focussed on balance and gait, and consists of or LFP stimulation). Rolling recruitment was twice-daily in-lab training for 2-weeks (with at- used, and enrolled participants had a unique home training during the intervening weekend). 3-digit identifier that was used for double blinding The participants also received physical exercise and 1:1 randomisation by a clinical monitor. training to develop improved motor coordination Nine participants with mmTBI (at least 1 year and mobility as part of the TLNS training. post-injury) were involved (age range: 43–62 All participants returned to the clinic weekly years; mean age: 53.11; standard deviation: 6.60; 6 during the at-home phase for a single session of female and 3 male) in the study. The Institutional retraining and progression, and participated in Review