Neurostimulation for Functional Neurological Disorder: Evaluating Longitudinal Neurophysiology

Functional neurological disorders (FND) are common, disabling, burdensome on healthcare resources, and challenging to manage.1 Noninvasive neurostimulation is a promising new treatment strategy for patients with FND;2, 3 however, therapeutic mechanisms are poorly understood, and there are no established neurophysiological correlates/markers for treatment.4 In this study, we investigate the cortical neurophysiology of a patient with functional weakness before, immediately after, and six months after peripheral electrical stimulation (PES) treatment. A 26-year-old female with subacute, unilateral, right arm/hand functional weakness was prospectively enrolled. The patient was a student with a medical history of anxiety and currently taking no medications. All neurological investigations, including MRI brain, were normal. The neurostimulation treatment consisted of a single 30-minute session of 30Hz electrical stimulation, applied to the right median, ulnar, and radial nerves. A burst pattern (4s on, 6s off) was used to simulate voluntary muscle contraction and demonstrate limb movement to the patient.5 The minimum stimulus intensity to induce visible muscle contraction was used (10 to 18 mA). A transcranial magnetic stimulation (TMS) Figure-of-8 coil was used to collect measures of motor cortex excitability across the three study time-points. First dorsal interosseous motor evoked potential (MEP) amplitude (58% maximum stimulator output; 1mV at baseline), resting motor threshold, and short-interval intracortical inhibition (SICI) were recorded.6 Both left and right motor cortex were evaluated, the latter acting as an internal control. For MEP amplitude and SICI, 10 trials were conducted for each cortex side at each of the three study time points. This data were analyzed using two-way ANOVA with factors of time-point and cortex side. Motor threshold was analyzed descriptively. Grip strength measurements and symptom-based neuropsychiatric questionnaires were also recorded across the study time-points. Our patient had no immediate change in symptoms after treatment, but reported gradual improvement over weeks, and full recovery by six months. This was supported by changes in grip strength (Figure 1D) and symptom-based questionnaire scores (Supporting Table 1). (A) to (C) Transcranial magnetic stimulation measures of cortical excitability measured over the three study time points. Average MEP amplitude measurements were conducted at 58% maximum stimulator output for all trials (this intensity produced 1mV MEPs at baseline). Error bars = standard error. (D) Right hand (symptomatic) grip strength measured by a dynamometer. For reference, left hand (asymptomatic) grip strength = 12 pounds. Abbreviations: MEP, Motor evoked potential; PES, Peripheral electrical stimulation; SICI, Short interval intracortical inhibition. Paralleling this clinical course, the patient showed no significant difference in left or right MEP amplitude from pre- to immediately posttreatment. However, at six months, left MEP amplitude significantly increased from 0.98 mV pretreatment to 2.81 mV (p < 0.001), whereas right MEP amplitude did not significantly change (1.45 mV to 1.52 mV, p = 0.85). Consistent with this finding, left motor threshold decreased from 49% of maximum stimulator output pre- and immediately posttreatment to 42% at six months, whereas right motor thresholds were stable. There were no significant differences in SICI. (For complete neurophysiological data, see Fig. 1 A-C). No adverse effects were reported. To our knowledge, this is the first neurostimulation treatment study of FND to measure longitudinal neurophysiology. We found that TMS excitability measures of the left motor cortex increased in parallel with clinical improvement of right-sided functional weakness. Given that our internal control (right motor cortex) remained stable over time, general changes of state between testing sessions (e.g., alertness) would be unlikely to account for the observed neurophysiological changes.7 Our study also demonstrated that PES for FND was safe, feasible, and well-tolerated. However, the design and sample of this study preclude drawing conclusions regarding PES efficacy; the electrophysiological changes may simply correlate with spontaneous recovery or could represent cortical responses directly induced or encouraged by PES. Proposed therapeutic mechanisms of neurostimulation for FND include neuromodulation, placebo, and cognitive behavioral effects.4 A recent study comparing cortical to spinal root stimulation favored the latter, but did not assess neurophysiological measures.8 Previous research has also shown that FND patients may have abnormal suppression of cortical excitability during movement imagination tasks.9 How this phenomenon may change longitudinally pre and post treatment could provide valuable insight regarding potential mechanisms-of-action. This hypothesis-generating study provides a basis for further investigation of cortical excitability as a potential neurophysiological outcome marker for treatment of functional weakness. More extensive studies in this line of research may also further help delineate therapeutic mechanisms of neurostimulation for FND. 1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript: A. Writing of the first draft, B. Review and Critique. M.J.B.: 2A, 2B, 2C, 3A R.C.: 2A, 3B A.E.L.: 2A, 3B A.F.: 2A, 3B R.I.: 2B, 2C C.G.: 2B, 2C G.J.: 2B, 2C Ethical Compliance Statement: This study was approved by the University Health Network Research Ethics Board (15-9676-AE, 11/19/2015) and written informed consent was obtained. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: This work was supported by the Canadian Institutes of Health Research (CIHR). The authors have no conflicts of interest to report. Financial Disclosure for previous 12 months: Dr. Burke, Dr. Isayama, Ms. Jegatheeswaran and Ms. Gunraj have nothing to disclose. Dr. Feinstein received speaker honoraria from Sanofi-Genzyme, Teva, Novartis, Merck-Serono, Biogen-Idec; received publising royalties from Cambridge University Press, Johns Hopkins University Press and Amadeus Press. Dr. Lang has served as an advisor for Abbvie, Acorda, Biogen, Bristol Myers Squibb, Janssen, Sun Pharma, Kallyope, Merck, Paladin, and Corticobasal Degeneration Solutions; received honoraria from Sun Pharma, Medichem, Medtronic, AbbVie and Sunovion; received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. Dr. Chen consults for Allergan, GE Healthcare, Merz; received research support from Medtronic Inc; received compensation for serving as Editor-in-Chief, Canadian Journal of Neurological Sciences. Supporting information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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