A Visual and Narrative Timeline Review of Spinal Cord Stimulation Technology and US Food and Drug Administration Milestones.

OBJECTIVES: The aim of this study was to present key technologic and regulatory milestones in spinal cord stimulation (SCS) for managing chronic pain on a narrative timeline with visual representation, relying on original sources to the extent possible. MATERIALS AND METHODS: We identified technical advances in SCS that facilitated and enhanced treatment on the basis of scientific publications and approvals from the United States (US) Food and Drug Administration (FDA). We presented milestones limited to first use in key indications and in the context of new technology validation. We focused primarily on pain management, but other indications (eg, motor disorder in multiple sclerosis) were included when they affected technology development. RESULTS: We developed a comprehensive visual and narrative timeline of SCS technology and US FDA milestones. Since its conception in the 1960s, the science and technology of SCS neuromodulation have continuously evolved. Advances span lead design (from paddle-type to percutaneous, and increased electrode contacts) and stimulator technology (from wireless power to internally powered and rechargeable, with miniaturized components, and programmable multichannel devices), with expanding stimulation program flexibility (such as burst and kilohertz stimulation frequencies), as well as usage features (such as remote programming and magnetic resonance imaging conditional compatibility). CONCLUSIONS: This timeline represents the evolution of SCS technology alongside expanding FDA-approved indications for use.

Minocycline plus N-Acetylcysteine Reduce Behavioral Deficits and Improve Histology with a Clinically Useful Time Window.

There are no drugs to manage traumatic brain injury (TBI) presently. A major problem in developing therapeutics is that drugs to manage TBI lack sufficient potency when dosed within a clinically relevant time window. Previous studies have shown that minocycline (MINO, 45 mg/kg) plus N-acetylcysteine (NAC, 150 mg/kg) synergistically improved cognition and memory, modulated inflammation, and prevented loss of oligodendrocytes that remyelinated damaged white matter when first dosed 1 h after controlled cortical impact (CCI) in rats. We show that MINO (45 mg/kg) plus NAC (150 mg/kg) also prevent brain injury in a mouse closed head injury (CHI) TBI model. Using the CHI model, the concentrations of MINO and NAC were titrated to determine that MINO (22.5 mg/kg) plus NAC (75 mg/kg) was more potent than the original formulation. MINO (22.5 mg/kg) plus NAC (75 mg/kg) also limited injury in the rat CCI model. The therapeutic time window of MINO plus NAC was then tested in the CHI and CCI models. Mice and rats could acquire an active place avoidance task when MINO plus NAC was first dosed at 12 h post-injury. A first dose at 12 h also limited gray matter injury in the hippocampus and preserved myelin in multiple white matter tracts. Mice and rats acquired Barnes maze when MINO plus NAC was first dosed at 24 h post-injury. These data suggest that MINO (22.5 mg/kg) plus NAC (75 mg/kg) remain potent when dosed at clinically useful time windows. Both MINO and NAC are drugs approved by the Food and Drug Administration and have been administered safely to patients in clinical trials at the doses in the new formulation. This suggests that the drug combination of MINO plus NAC may be effective in treating patients with TBI.

Measurement of Peripheral Vision Reaction Time Identifies White Matter Disruption in Patients with Mild Traumatic Brain Injury.

This study examined whether peripheral vision reaction time (PVRT) in patients with mild traumatic brain injury (mTBI) correlated with white matter abnormalities in centroaxial structures and impairments in neuropsychological testing. Within 24 h after mTBI, crossed reaction times (CRT), uncrossed reaction times (URT), and crossed-uncrossed difference (CUD) were measured in 23 patients using a laptop computer that displayed visual stimuli predominantly to either the left or the right visual field of the retina. The CUD is a surrogate marker of the interhemispheric transfer time (ITT). Within 7 days after the injury, patients received a diffusion tensor-MRI (DTI) scan and a battery of neuropsychological tests. Nine uninjured control subjects received similar testing. Patients 18-50 years of age were included if they had a post-resuscitation Glasgow Coma Scale >13 and an injury mechanism compatible with mTBI. Healthy controls were either age- and gender-matched family members of the TBI patients or healthy volunteers. CUD deficits >2 standard deviations (SD) were seen in 40.9% of patients. The CUD of injured patients correlated with mean diffusivity (MD) (p < 0.001, ρ = -0.811) in the posterior corpus callosum. Patients could be stratified on the basis of CUD on the Stroop 1, Controlled Oral Word Association Test (COWAT), and the obsessive-compulsive component of the Basic Symptom Inventory tests. These studies suggest that the PVRT indirectly measures white matter integrity in the posterior corpus callosum, a brain region frequently damaged by mTBI.

Righting Reflex Predicts Long-Term Histological and Behavioral Outcomes in a Closed Head Model of Traumatic Brain Injury.

Blunt impact produces a heterogeneous brain injury in people and in animal models of traumatic brain injury. We report that a single closed head impact to adult C57/BL6 mice produced two injury syndromes (CHI-1 and CHI-2). CHI-1 mice spontaneously reinitiated breathing after injury while CHI-2 mice had prolonged apnea and regained breathing only after cardiopulmonary resuscitation and supplementation of 100% O2. The CHI-1 group significantly regained righting reflex more rapidly than the CHI-2 group. At 7 days post-injury, CHI-1, but not CHI-2 mice, acquired but had no long-term retention of an active place avoidance task. The behavioral deficits of CHI-1 and CHI-2 mice were retained one-month after the injury. CHI-1 mice had loss of hippocampal neurons and localized white matter injury at one month after injury. CHI-2 had a larger loss of hippocampal neurons and more widespread loss of myelin and axons. High-speed videos made during the injury were followed by assessment of breathing and righting reflex. These videos show that CHI-2 mice experienced a larger vertical g-force than CHI-1 mice. Time to regain righting reflex in CHI-2 mice significantly correlated with vertical g-force. Thus, physiological responses occurring immediately after injury can be valuable surrogate markers of subsequent behavioral and histological deficits.

Electrodes for high-definition transcutaneous DC stimulation for applications in drug delivery and electrotherapy, including tDCS.

Transcutaneous electrical stimulation is applied in a range of biomedical applications including transcranial direct current stimulation (tDCS). tDCS is a non-invasive procedure where a weak direct current (<2 mA) is applied across the scalp to modulate brain function. High-definition tDCS (HD-tDCS) is a technique used to increase the spatial focality of tDCS by passing current across the scalp using <12 mm diameter electrodes. The purpose of this study was to design and optimize "high-definition" electrode-gel parameters for electrode durability, skin safety and subjective pain. Anode and cathode electrode potential, temperature, pH and subjective sensation over time were assessed during application of 2 mA direct current, for up to 22 min on agar gel or subject forearms. A selection of five types of solid-conductors (Ag pellet, Ag/AgCl pellet, rubber pellet, Ag/AgCl ring and Ag/AgCl disc) and seven conductive gels (Signa, Spectra, Tensive, Redux, BioGel, Lectron and CCNY-4) were investigated. The Ag/AgCl ring in combination with CCNY-4 gel resulted in the most favorable outcomes. Under anode stimulations, electrode potential and temperature rises were generally observed in all electrode-gel combinations except for Ag/AgCl ring and disc electrodes. pH remained constant for all solid-conductors except for both Ag and rubber pellet electrodes with Signa and CCNY-4 gels. Sensation ratings were independent of stimulation polarity. Ag/AgCl ring electrodes were found to be the most comfortable followed by Ag, rubber and Ag/AgCl pellet electrodes across all gels.