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Understanding mechanism(s) of low-amplitude stimulation

Although in wide use, the SCS field cannot explain how “stimulation” at amplitudes ~6% of the perception threshold result in an analgesic effect, and hypotheses vary widely.  It is possible that the application of the electric field does not directly stimulate neural elements, and clinical phenomena consistent with this possibility include the observation of wash-in times ranging from immediate (our new discovery at Boston Scientific) or very long (hours to days), and relationships between stimulation parameters that we’ve discovered empirically in clinical studies, but that do not have an identified relationship with first principles of neurostimulation (e.g., strength duration curve).  In my laboratory, we will use pre-clinical models (including models of neuropathic pain) to further characterize sub-perception stimulation effects on pain, determine whether or not clinically relevant “stimulation” parameters applied to peripheral nerve or dorsal columns directly excite or inhibit neural elements (one possible mechanistic basis), and evaluate alternative hypotheses (e.g., glial-based effects, non-synaptic effects, etc.).  We anticipate that as mechanistic understanding unfolds in the laboratory, the principles will be applicable to other neuromodulation applications, such as deep brain stimulation (DBS) and afford new opportunities.  

Mechanisms and applications of photobiomodulation

The use of light at specific wavelengths to elicit a physiological response or photobiomodulation (PBM) has a history dating back to the late 1960’s[1] and includes a large body of literature, but the field has not yet produced a high impact therapy.   I believe that the reasons for this are surmountable (e.g., much work done with transcutaneous preps and implantable PBM would overcome some of the inherent limitations), and that the literature describes effects of PBM on neural systems that compel further consideration.  One observation is the ability of light with wavelength of approx. 800 nm to halt C-fiber conduction of action potentials.  Although still early, the phenomenon has been published by multiple labs[2],[3],,[5].  In collaboration with optics experts at �ǿմ�ý, we are characterizing this phenomenon, further investigating mechanisms, and evaluating application as a pain therapy.  We will expand these efforts to understand other neural-related PBM phenomena of interest, such as anti-inflammatory effects[6], and neuroprotective properties[7]. 

Computational modeling

Computational modeling of neuronal excitation/inhibition is an important part of our lab activities.  In addition to modeling of electric fields and non-linear models of neurons, our lab models light transport, and we will use both types of models to understand electrical stimulation and PBM-based mechanisms, to predict required therapeutic dosing, and to do model-based design of candidate therapy systems.

[1] Mester EL, Ludany G, Selyei M, Szende B. THE STIMULATING EFFECT OF LOW POWER LASER RAYS ON BIOLOGICAL SYSTEMS. Medical Univ., Budapest; 1968 Jan 1.

[2] Tsuchiya K, Kawatani M, Takeshige C, Sato T, Matsumoto I. Diode laser irradiation selectively diminishes slow component of axonal volleys to dorsal roots from the saphenous nerve in the rat. Neuroscience letters. 1993 Oct 14;161(1):65-8.

[3] Chow RT, David MA, Armati PJ. 830 nm laser irradiation induces varicosity formation, reduces mitochondrial membrane potential and blocks fast axonal flow in small and medium diameter rat dorsal root ganglion neurons: implications for the analgesic effects of 830 nm laser. J Peripher Nerv Syst. 2007 Mar;12(1):28-39.

[4] Holanda VM, Chavantes MC, Wu X, Anders JJ. The mechanistic basis for photobiomodulation therapy of neuropathic pain by near infrared laser light. Lasers Surg Med. 2017 Jul;49(5):516-524.

[5] de Sousa MVP, Kawakubo M, Ferraresi C, Kaippert B, Yoshimura EM, Hamblin MR. Pain management using photobiomodulation: Mechanisms, location, and repeatability quantified by pain threshold and neural biomarkers in mice. J Biophotonics. 2018 Jul;11(7).

[6] Hu D, Zhu S, Potas JR.  Red LED photobiomodulation reduces pain hypersensitivity and improves sensorimotor function following mild T10 hemicontusion spinal cord injury. J Neuroinflammation. 2016 Aug 26;13(1):200.

[7] Darlot F, Moro C, El Massri N, Chabrol C, Johnstone DM, Reinhart F, Agay D, Torres N, Bekha D, Auboiroux V, Costecalde T, Peoples CL, Anastascio HD, Shaw VE, Stone J, Mitrofanis J, Benabid AL.  Near-infrared light is neuroprotective in a monkey model of Parkinson disease. Ann Neurol. 2016 Jan;79(1):59-75.