Deep Brain Stimulation Improves the Symptoms and Sensory Signs of Persistent Central Neuropathic Pain from Spinal Cord Injury: A Case Report

Central neuropathic pain (CNP) is a significant problem after spinal cord injury (SCI). Pharmacological and non-pharmacological approaches may reduce the severity, but relief is rarely substantial. While deep brain stimulation (DBS) has been used to treat various chronic pain types, the technique has rarely been used to attenuate CNP after SCI. Here we present the case of a 54-year-old female with incomplete paraplegia who had severe CNP in the lower limbs and buttock areas since her injury 30 years prior. She was treated with bilateral DBS of the midbrain periaqueductal gray (PAG). The effects of this stimulation on CNP characteristics, severity and pain-related sensory function were evaluated using the International SCI Pain Basic Data Set (ISCIPBDS), Neuropathic Pain Symptom Inventory (NPSI), Multidimensional Pain Inventory and Quantitative Sensory Testing before and periodically after initiation of DBS. After starting DBS treatment, weekly CNP severity ratings rapidly decreased from severe to minimal, paralleled by a substantial reduction in size of the painful area, reduced pain impact and reversal of pain-related neurological abnormalities, i.e., dynamic-mechanical and cold allodynia. She discontinued pain medication on study week 24. The improvement has been consistent. The present study expands on previous findings by providing in-depth assessments of symptoms and signs associated with CNP. The results of this study suggest that activation of endogenous pain inhibitory systems linked to the PAG can eliminate CNP in some people with SCI. More research is needed to better-select appropriate candidates for this type of therapy. We discuss the implications of these findings for understanding the brainstem’s control of chronic pain and for future progress in using analgesic DBS in the central gray

Neurophysiology

Contains research objectives and summary of research.National Institutes of Health (Grant 1 RO1 EY01149-01)National Institutes of Health (Grant 5 P01 GM14940-07)Bell Telephone Laboratories, Inc. (Grant)National Institutes of Health (Grant 5 TO1 GM01555-07)M. I. T. Sloan Fund for Basic Researc

Neurophysiology

Contains research objectives and summary of research on ten research projects.National Institutes of Health (Grant 5 R01 EY01149-02)National Institutes of Health (Grant 1 T01 EY00090-01)Bell Telephone Laboratories, Inc. (Grant)National Institutes of Health (Grant 5 TO1 GM00778-19)National Institutes of Health (Grant 5 TO1 GM01555-08

Neurophysiology

Contains research objectives and summary of research on seventeen research projects and reports on four research projects.National Institutes of Health (Grant 5 TOl EY00090-02)Bell Telephone Laboratories, Inc. (Grant)National Institutes of Health (Grant 5 ROI EY01149-03)National Institutes of Health (Grant NS 12307-01)National Institutes of Health (Grant 1 K04 NS00010

Observations on field potentials at their point of generation

A technique for evoking then recording field potentials through one extracellular electrode was studied in the dentate gyrus of pentobarbital-anesthetized rats. In the molecular layer (the location of granule cell dendrites), a −5 μA pulse (0.4 ms, 0.2 Hz) consistently elicited a ‘focal’ response the major component of which was a negative-going wave of about 1 ms latency, 10 ms duration, and −0.8 to −1.5 mV amplitude. This wave resembled, and could partially occlude, field excitatory post-synaptic potentials (EPSPs) elicited electrically from the perforant path. It fatigued during high-frequency stimulation and is suggested to consist largely of granule-cell EPSPs produced by directly activated, perforant-path terminals. Focal and perforant-path tetanic stimulation led to stable potentiation of the focal negative phase. Stimulus-response curves for the negative phase were roughly linear over most or all of the stimulus range of −1 to −5 μA, but on a finer scale were serrated and irregular. After a tetanus, different stimulus-response curves showed parallel leftward shifts or slope changes along all or part of their range, implying multiple mechanisms of potentiation that might include both threshold and amplification changes. Several uses are suggested in the paper for focal recording of compound potentials in research and diagnosis

Detection of abnormal cerebral excitability by coincident stimulation and recording

Objective: A method for mapping brain excitability and detecting abnormalities, by concurrently stimulating and recording ‘focal’ compound responses through one microelectrode, was evaluated in three rat epilepsy models in comparison with distal stimulation of perforant path afferents. Methods: A fixed trajectory from neocortex to dentate gyrus was mapped under halothane anesthesia. Several weeks earlier, tetanus toxin or vehicle was microinjected into the dentate polymorphic layer, or else rats were genetically epilepsy-prone (GEPR-9) or epilepsy-resistant (GERR-0). Other (unmapped) rats received acute penicillin microinjections within the dentate granular layer. Results: Focal responses, although widespread, proved largest in the dentate (>±0.5 mV). Tetanus toxin diminished focal responses near the microinjection site versus vehicle-microinjected (66%) or contralateral controls (55%), but enhanced them elsewhere in the dentate. It enhanced distal responses at all hippocampal locations. Focal but not distal responses were higher in GEPR-9 than in GERR-0 rats at widespread forebrain locations (mean 233%). Penicillin facilitated both focal and distal dentate responses, but the focal facilitation peaked sooner (about 75 versus 180 min). Conclusions: Focal responses better uncover pervasive or discrete excitability differences. Significance: Focal mapping may aid in diagnostic imaging and intraoperative targeting, offering high resolution, rapid performance, low stimulus currents and minimal invasion

A long-lasting wireless stimulator for small mammals

The chronic effects of electrical stimulation in unrestrained awake rodents are best studied with a wireless neural stimulator that can operate unsupervised for several weeks or more. A robust, inexpensive, easily built, cranially implantable stimulator was developed to explore the restorative effects of brainstem stimulation after neurotrauma. Its connectorless electrodes directly protrude from a cuboid epoxy capsule containing all circuitry and power sources. This physical arrangement prevents fluid leaks or wire breakage and also simplifies and speeds implantation. Constant-current pulses of high compliance (34 volts) are delivered from a step-up voltage regulator under microprocessor control. A slowly pulsed magnetic field controls activation state and stimulation parameters. Program status is signaled to a remote reader by interval-modulated infrared pulses. Capsule size is limited by the two batteries. Silver oxide batteries rated at 8 mA-h were used routinely in 8 mm wide, 15 mm long and 4 mm high capsules. Devices of smaller contact area (5 by 12 mm) but taller (6 mm) were created for mice. Microstimulation of the rat's raphe nuclei with intermittent 5-min (50% duty cycle) trains of 30 μA, 1 ms pulses at 8 or 24 Hz frequency during 12 daylight hours lasted 21.1 days ±0.8 (mean ± standard error, Kaplan-Meir censored estimate, n = 128). Extended lifetimes (>6 weeks, no failures, n = 16) were achieved with larger batteries (44 mA-h) in longer (18 mm), taller (6 mm) capsules. The circuit and electrode design are versatile; simple modifications allowed durable constant-voltage stimulation of the rat's sciatic nerve through a cylindrical cathode from a subcutaneous pelvic capsule. Devices with these general features can address in small mammals many of the biological and technical questions arising neurosurgically with prolonged peripheral or deep brain stimulation

Coincident recording and stimulation of single and multiple neuronal activity with one extracellular microelectrode

This paper describes how an extracellular microelectrode may be used to stimulate neurons with brief, rectangular pulses and afterwards directly record the resultant activity. Two obstacles are the stimulus artifact lingering in the electrical circuitry and transient tip potentials (TTPs) arising from ion depletion at the electrode-tissue interface. Electronic switching between the stimulus source and the recording amplifier eliminates direct stimulus artifact from the electrical circuitry, although high but acceptable switching artifact remains. TTPs revert with time constants that are prominent in the desired recording (0.1–1 ms) and can reach 50 mV when more than 1 μA passes through a typical electrolyte-filled micropipette (for example 2–4 MΩ, filled with 3 M NaCl, and placed in 0.1 M NaCl). They are always negative when cations flow into the tip, they are accompanied by a rise in microelectrode impedance, and they increase as a function of the resting electrode impedance, the duration and amplitude of applied current, and the dilution of the external electrolyte. TTPs were subtracted by differential recording and stimulation through matched micropipettes (one in the brain and one in contiguous electrolyte) and in addition were reduced by pressure ejection of electrolyte. Directly elicited spikes (single or multiple) were detected about 0.5 ms after delivery of a rectangular stimulus pulse in the cerebellar cortex of pentobarbital-anesthetized rats. Typically, 3–4 units could be excited by less than 3 μA cathodal currents at any recording site. All-or-nothing properties, thresholds, and refractoriness to a second pulse within 2–4 ms verified the neuronal nature of the recorded signals. Complex wave forms, probably generated synaptically, were also seen. The technique of coincident extracellular recording and stimulation can be used as a universal search stimulus during microelectrode penetrations through the brain and in determining threshold-distance relations for extracellular stimulation. Where cell penetrations are unstable, it might be usefully substituted for intracellular technique in testing a neuron's behavioral or physiological influences or in exploring a cell membrane's response to drugs (in terms of excitability rather than voltage and impedance)

Practical modelling of monopolar axonal stimulation

Three models describing monopolar electrical stimulation of unmyelinated axons in large, uniformly conducting volumes are presented. The first is a representation of the axon as a continuous and straight electric cable of finite length with sealed ends. It has a power-series solution for the steady state which after truncation beyond the fifth term provides an accurate reflection of the imposed membrane potential for all parts of the axon except, under certain conditions, near terminals and directly opposite a closely apposed electrode. At these points, the inclusion of higher-order terms improves the accuracy quite slowly — II terms are sometimes still unsatisfactory. The second is a steady-state solution, in terms of higher transcendental functions, for the point opposite the stimulating electrode in a similar but infinitely long cable. This turns out to be practical for estimating the membrane potential at the site of cathodal excitation under the majority of realistic geometrical and electrical parameters, and consequently complements the first method. It may be calculated with ease from mathematical tables. The third, a simulation of the cable by means of discrete electrical components (compartments), can give the complete distribution of membrane potential as a function of time with potentially unlimited accuracy. However, it takes special computer programs to set up and solve either the steady-state determinant or, if transients are desired, the time-dependent differential equation. Calculation of the voltage distribution with one of the analytical methods will often be faster for a reasonable level of accuracy, since their algorithms are independent of the total number of points introduced

The membrane potential along an ideal axon in a radial electric field

An equation is developed for the membrane potential expected along a short, closed, straight, unbranched and unmyelinated fiber when a point source of steady current resides in the infinite, uniform, 3-dimensional medium. Most electrode placements induce a membrane potential whose absolute value is greater at terminals than midpoint — between 4.3 and 26.4 times greater in several arbitrary worked examples. Such natural phenomena as the effect of electric fields on the growth of nerve fibers could depend on this heightened susceptibility of terminals to external currents