SBIR-STTR Award

Diabetic neuropathic pain (DNP) is one of the most common and difficult to treat complications of diabetes [1, 2]. Current therapies [3-10] do not directly address the fact that pain sensation is processed in the brain [10-13] and most act at the neuropathy site (i.e., in the periphery), although DNP patients also have a central pain component due to their injury [10-13]. DNP symptomatology correlates with chronic pain induced changes in brain activity and/or structure [13-19]. Non-Invasive Brain Stimulation (NIBS) has been successfully applied for the treatment of chronic pain in some disease states, where treatment induced changes in brain activity revert maladaptive plasticity associated with the perception/sensation of chronic pain [20-23]. However, the most common NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), have shown limited, if any, efficacy in treating neuropathic pain and DNP [12, 24-30]. It has been postulated that limitations in these techniques' focality, penetration, and targeting control limit their therapeutic efficacy [31-35]. Electrosonic Stimulation (ESStim™) is an improved NIBS modality that overcomes the limitations of other technologies by combining independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue [36]. This proposal is focused on evaluating whether our noninvasive ESStim system can effectively treat DNP. First in Phase I, to assess the feasibility of the proposed work, we will follow 20 DNP patients after giving a fixed dose of ESStim for 5 consecutive days, 20 min/day (10 SHAM ESStim, 10 ESStim™). We will administer a battery of safety, pain, quantitative sensory testing (QST), motor function, and global self-assessments (e.g., QOL), and actigraphy measures in the patients, evaluated over the treatment period and for at least six weeks following the last treatment session. Next in Phase II, we will follow 40 DNP patients (20 ESStim, 20 SHAM) after giving a fixed dose of stimulation for 5 consecutive days, 20 min/day, followed by three weeks of bi- weekly stimulation, 20 min/day (11 total stimulations). We will evaluate these patients with the same battery of assessments validated in Phase I, and compare the efficacy of the tested interventions for at least eight weeks following the last treatment session. In parallel with the DNP treatments, we will build MRI derived models of the stimulation fields in the heads (electric and acoustic field models) of the DNP patients to calculate the stimulation field characteristics at the brain target sites. Multivariate linear and generalized linear regression models will then be built and evaluated to predict the DNP patient outcomes related to pain, physical function, and psychosocial assessments as a function of baseline disease characteristics and the MRI based dosing models. The computational work will be combined to develop an optimized DNP ESStim dosing model. Overall, we hypothesize that the proposed experiments, computational studies, and technology development will allow us to optimize ESStim™ for treatment of central pain in DNP.

Public Health Relevance Statement:
Project Narrative Diabetes is a major cause of morbidity and mortality in the United States. Diabetic neuropathic pain is one of the most common and difficult to treat complications of diabetes. This study explores the optimization of electrosonic stimulation (ESStim™), a novel form of noninvasive brain stimulation, for treating the symptoms of diabetic neuropathic pain.

Project Terms:
Acoustics; actigraphy; Address; Aftercare; American; Area; Authorization documentation; base; Behavior; behavioral study; Biophysics; Brain; Brief Pain Inventory; central pain; Characteristics; chronic pain; Clinic; Clinical; commercialization; comparative efficacy; Complications of Diabetes Mellitus; computer studies; Confidential Information; Coupling; Data; Development; Diabetes Mellitus; diabetic; diaries; Disease; Dose; Double-Blind Method; Effectiveness; efficacy testing; Electromagnetics; Electrophysiology (science); Equilibrium; Equipment and supply inventories; Esthesia; experimental study; Foundations; functional outcomes; Head; Health Surveys; Home environment; human subject; improved; Injury; instrument; Intervention; Knee Osteoarthritis; Linear Regressions; Magnetic Resonance Imaging; Measures; metabolic abnormality assessment; Methods; Modality; Modeling; Morbidity - disease rate; mortality; Motor; Motor Cortex; Neurologic; Neuropathy; novel; outcome prediction; overtreatment; Pain; Pain management; pain outcome; pain patient; pain reduction; pain sensation; pain symptom; painful neuropathy; Patient-Focused Outcomes; Patients; Penetration; Perception; Phase; Physical Function; Placebos; Procedures; Process; prognostic; psychosocial; Psychosocial Assessment and Care; Quality of life; Randomized; relating to nervous system; Research; Rights; Safety; Self Assessment; Sensory; SF-36; Site; Sleep; Small Business Innovation Research Grant; Source; Stratification; Structure; symptom treatment; symptomatology; System; Techniques; Technology; technology development; Testing; Therapeutic Effect; Tissues; Transcranial magnetic stimulation; treatment duration; Treatment Efficacy; Ultrasonics; United States; United States National Institutes of Health; vector; Work

Diabetic neuropathic pain (DNP) is one of the most common and difficult to treat complications ofdiabetes [1, 2]. Current therapies [3-10] do not directly address the fact that pain sensation is processed in thebrain [10-13] and most act at the neuropathy site (i.e., in the periphery), although DNP patients also have acentral pain component due to their injury [10-13]. DNP symptomatology correlates with chronic pain inducedchanges in brain activity and/or structure [13-19]. Non-Invasive Brain Stimulation (NIBS) has been successfullyapplied for the treatment of chronic pain in some disease states, where treatment induced changes in brainactivity revert maladaptive plasticity associated with the perception/sensation of chronic pain [20-23]. However,the most common NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Direct CurrentStimulation (tDCS), have shown limited, if any, efficacy in treating neuropathic pain and DNP [12, 24-30]. It hasbeen postulated that limitations in these techniques' focality, penetration, and targeting control limit theirtherapeutic efficacy [31-35]. Electrosonic Stimulation (ESStim™) is an improved NIBS modality that overcomesthe limitations of other technologies by combining independently controlled electromagnetic and ultrasonicfields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue [36]. Thisproposal is focused on evaluating whether our noninvasive ESStim system can effectively treat DNP. First inPhase I, to assess the feasibility of the proposed work, we will follow 20 DNP patients after giving a fixed doseof ESStim for 5 consecutive days, 20 min/day (10 SHAM ESStim, 10 ESStim™). We will administer a batteryof safety, pain, quantitative sensory testing (QST), motor function, and global self-assessments (e.g., QOL),and actigraphy measures in the patients, evaluated over the treatment period and for at least six weeksfollowing the last treatment session. Next in Phase II, we will follow 40 DNP patients (20 ESStim, 20 SHAM)after giving a fixed dose of stimulation for 5 consecutive days, 20 min/day, followed by three weeks of bi-weekly stimulation, 20 min/day (11 total stimulations). We will evaluate these patients with the same battery ofassessments validated in Phase I, and compare the efficacy of the tested interventions for at least eight weeksfollowing the last treatment session. In parallel with the DNP treatments, we will build MRI derived models ofthe stimulation fields in the heads (electric and acoustic field models) of the DNP patients to calculate thestimulation field characteristics at the brain target sites. Multivariate linear and generalized linear regressionmodels will then be built and evaluated to predict the DNP patient outcomes related to pain, physical function,and psychosocial assessments as a function of baseline disease characteristics and the MRI based dosingmodels. The computational work will be combined to develop an optimized DNP ESStim dosing model. Overall,we hypothesize that the proposed experiments, computational studies, and technology development will allowus to optimize ESStim™ for treatment of central pain in DNP.

Public Health Relevance Statement:
Project Narrative Diabetes is a major cause of morbidity and mortality in the United States. Diabetic neuropathic pain is one of the most common and difficult to treat complications of diabetes. This study explores the optimization of electrosonic stimulation (ESStim™), a novel form of noninvasive brain stimulation, for treating the symptoms of diabetic neuropathic pain.

Project Terms:
pain treatment ; Behavior ; Biophysics ; biophysical foundation ; biophysical principles ; biophysical sciences ; Brain ; Brain Nervous System ; Encephalon ; Diabetes Mellitus ; diabetes ; Disease ; Disorder ; Double-Blind Method ; Double-Blind Study ; Double-Blinded ; Double-Masked Method ; Double-Masked Study ; Electromagnetics ; Electrophysiology (science) ; Electrophysiology ; Neurophysiology / Electrophysiology ; electrophysiological ; Equilibrium ; balance ; balance function ; Foundations ; Head ; Health Surveys ; Equipment and supply inventories ; Inventory ; Linear Regressions ; Magnetic Resonance Imaging ; MR Imaging ; MR Tomography ; MRI ; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance ; NMR Imaging ; NMR Tomography ; Nuclear Magnetic Resonance Imaging ; Zeugmatography ; Methods ; Morbidity - disease rate ; Morbidity ; mortality ; Motor Cortex ; Pain ; Painful ; Patients ; Perception ; Placebos ; Sham Treatment ; sham therapy ; Quality of life ; QOL ; Safety ; Self Assessment ; Esthesia ; Sensation ; Sleep ; Technology ; Testing ; Tissues ; Body Tissues ; United States ; Work ; Measures ; chronic pain ; Injury ; injuries ; base ; improved ; Procedures ; Site ; Area ; Clinical ; Penetration ; Phase ; Neurologic ; Neurological ; prognostic ; central pain ; cortical pain ; diabetic ; metabolic abnormality assessment ; Abnormal Assessment of Metabolism ; Metabolic Studies ; Metabolism Studies ; Diabetes Complications ; Diabetes-Related Complications ; Diabetic Complications ; Complications of Diabetes Mellitus ; diaries ; knee OA ; knee joint OA ; knee joint osteoarthritis ; Knee Osteoarthritis ; Transcranial magnetic stimulation ; Clinic ; neuropathic ; Neuropathy ; Treatment Period ; treatment days ; treatment duration ; Sensory ; Techniques ; System ; Physical Function ; psychosocial ; American ; tech development ; technology development ; neural ; relating to nervous system ; Structure ; novel ; Modality ; Modeling ; Intervention Strategies ; interventional strategy ; Intervention ; actigraph ; actigraphy ; Effectiveness ; Address ; Dose ; psychosocial assessment ; psychosocial care ; psychosocial studies ; psychosocial support ; Psychosocial Assessment and Care ; Ultrasonic ; Ultrasonics ; Brief Pain Inventory ; Motor ; randomisation ; randomization ; randomly assigned ; Randomized ; Stratification ; Patient-Focused Outcomes ; Patient outcome ; Patient-Centered Outcomes ; SF-36 ; Characteristics ; Process ; Therapeutic Effect ; Development ; developmental ; painful neuropathy ; neuropathic pain ; vector ; computer studies ; computational studies ; functional outcomes ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Coupling ; efficacy testing ; comparative efficacy ; compare efficacy ; behavioral study ; behavior study ; outcome prediction ; predictive outcomes ; predictors of outcomes ; symptomatology ; pain symptom ; painful symptom ; symptom treatment ; symptomatic treatment ; treat symptom ; experimental study ; experiment ; experimental research ; pain sensation ; painful sensation ; pain outcome ; pain reduction ; reduce pain ; pain patient ; overtreatment ; over-treatment ; safety assessment ; noninvasive brain stimulation ; non-invasive brain stimulation ; Home ; Acoustics ; Acoustic ; Aftercare ; After Care ; After-Treatment ; post treatment ; Pain management ; Pain Control ; Pain Therapy ;