Direct Brain Stimulation Research Articles

Transcranial Direct Current Brain Stimulation (tDCS) to Decrease post-ERCP Pain: A Randomized Double-Blind Sham-controlled Trial

Transcranial Direct Current Brain Stimulation (tDCS) to Decrease post-ERCP Pain: A Randomized Double-Blind Sham-controlled Trial

Electrical Stimulation in Epilepsy: Vagus Nerve and Brain Stimulation

Vagus nerve stimulation (VNS) for epilepsy is a well established and effective treatment for medically intractable epilepsy. VNS is indicated if resective epilepsy surgery is unsuccessful or is not an option. About 50% of patients with VNS have a seizure reduction greater than 50%, but less than 10% become seizure-free. VNS also has an alerting effect on patients and may allow a reduction in sedating medications. The major adverse event is hoarseness, but treatment is generally well tolerated. The therapeutic effect can be delayed: patients may improve several months after VNS implantation. Direct brain stimulation (DBS) is an emerging treatment for epilepsy. Scheduled stimulation is similar to brain stimulation in Parkinson's disease. Only the anterior thalamic nucleus has been studied in a larger randomized, controlled trial, in which patients with the stimulator turned on had a significantly reduced seizure frequency. Responsive stimulation applies an electrical stimulus at the site of seizure onset to terminate the seizure if one occurs. The seizure-onset zone must be well defined before implantation. Responsive stimulation requires seizure detection and application of a stimulus online. A large pivotal trial showed a significant reduction in seizure frequency. Both DBS and responsive neurostimulation are well tolerated, but there has been some concern about depression with DBS. Infection, hemorrhage, and lead breakage are adverse events possible with any type of stimulator. None of the brain stimulation devices have been approved by the US Food and Drug Administration, but final approval is expected soon. These devices are indicated for patients with bilateral seizure onset or seizure onset in eloquent areas. Although the initial trials of brain stimulation do not show overwhelming improvement in seizure frequency, the technology will improve with time as we continue to learn about the use of brain stimulation for epilepsy. Optimization of VNS has been going on for 10years, and we need to ensure that brain stimulation is similarly developed further. In addition, sophisticated devices such as responsive neurostimulators can greatly enhance our understanding of the pathophysiology of epilepsy.

Brain stimulation for the treatment of epilepsy

Direct brain stimulation is an emerging treatment of epilepsy. Scheduled or responsive stimulation has been applied. The most explored targets for scheduled stimulation are the anterior nucleus of the thalamus and the hippocampus. The anterior nucleus of the thalamus was studied in a large multicenter trial. There was a significant seizure reduction with the stimulator "on" versus "off" during several months after stimulator implantation. The hippocampus as stimulation target has not yet been studied in a large randomized trial. Responsive stimulation applies a stimulus whenever epileptiform activity occurs. It requires on-line detection of epileptiform activity. This concept is based on the observation that epileptiform activity during functional mapping can be aborted by brief pulses of cortical stimulation. Current technology is able to detect seizure activity intracranially on-line and delivers a high frequency stimulus if epileptiform activity is detected. A large randomized multicenter trial has been conducted testing this system for focal epilepsy.

Perceived intensity of somatosensory cortical electrical stimulation

Artificial sensations can be produced by direct brain stimulation of sensory areas through implanted microelectrodes, but the perceptual psychophysics of such artificial sensations are not well understood. Based on prior work in cortical stimulation, we hypothesized that perceived intensity of electrical stimulation may be explained by the population response of the neurons affected by the stimulus train. To explore this hypothesis, we modeled perceived intensity of a stimulation pulse train with a leaky neural integrator. We then conducted a series of two-alternative forced choice behavioral experiments in which we systematically tested the ability of rats to discriminate frequency, amplitude, and duration of electrical pulse trains delivered to the whisker barrel somatosensory cortex. We found that the model was able to predict the performance of the animals, supporting the notion that perceived intensity can be largely accounted for by spatiotemporal integration of the action potentials evoked by the stimulus train.

Brain stimulation for surgical epilepsy

Direct brain stimulation is an emerging treatment of epilepsy especially in patients that are not candidates for epilepsy surgery. Several different approaches of brain stimulation in epilepsy have been developed: stimulation is applied to interrupt epileptic networks in subcortical structures or a stimulus is directly applied to the seizure onset zone. Scheduled stimulation targets mainly subcortical structures like the anterior thalamic nucleus or the centromedian nucleus of the thalamus. The anterior nucleus of the thalamus was studied in a randomized trial in humans. Several case series reported reduction of seizures targeting other subcortical structures. Scheduled stimulation of the seizure onset zone in the hippocampus has also been shown to be safe and effective in a small number of patients. The application of electrical pulses to test for certain brain functions has long been established for the purposes of brain mapping. Traditionally stimulation at 50Hz for several seconds has been used. This stimulus frequently causes afterdischarges or seizures. Afterdischarges can be terminated by applying a very brief stimulus at the same frequency. Responsive stimulation is based on detection on this principle. Seizures are recorded intracranially and a high-frequency pulse applied whenever seizures evolve electrically. An automated implanted device for seizures detection and stimulation has been developed and shown to be safe for human use. A large clinical trial is currently ongoing. In conclusion, the optimal target and mode of stimulation for the treatment of epilepsy remains under investigation and requires large and costly controlled trials.

Physiological Responses to Brain Stimulation During Limbic Surgery: Further Evidence of Anterior Cingulate Modulation of Autonomic Arousal

In view of conflicting neuroimaging results regarding autonomic-specific activity within the anterior cingulate cortex (ACC), we investigated autonomic responses to direct brain stimulation during stereotactic limbic surgery. Skin conductance activity and accelerative heart rate responses to multi-voltage stimulation of the ACC (n = 7) and paralimbic subcaudate (n = 5) regions were recorded during bilateral anterior cingulotomy and bilateral subcaudate tractotomy (in patients that had previously received an adequate lesion in the ACC), respectively. Stimulations in both groups were accompanied by increased autonomic arousal. Skin conductance activity was significantly increased during ACC stimulations compared with paralimbic targets at 2 V (2.34 +/- .68 [score in microSiemens +/- SE] vs. .34 +/- .09, p = .013) and 3 V (3.52 +/- .86 vs. 1.12 +/- .37, p = .036), exhibiting a strong "voltage-response" relationship between stimulus magnitude and response amplitude (difference from 1 to 3 V = 1.15 +/- .90 vs. 3.52 +/- .86, p = .041). Heart rate response was less indicative of between-group differences. This is the first study of its kind aiming at seeking novel insights into the mechanisms responsible for central autonomic modulation. It supports a concept that interregional interactions account for the coordination of autonomic arousal.

Intraoperative Motor Evoked Potential Monitoring: Overview and Update

Amidst controversy about methodology and safety, intraoperative neurophysiology has entered a new era of increasingly routine transcranial and direct electrical brain stimulation for motor evoked potential (MEP) monitoring. Based on literature review and illustrative clinical experience, this tutorial aims to present a balanced overview for experienced practitioners, surgeons and anesthesiologists as well as those new to the field. It details the physiologic basis, indications and methodology of current MEP monitoring techniques, evaluates their safety, explores interpretive controversies and outlines some applications and results, including aortic aneurysm, intramedullary spinal cord tumor, spinal deformity, posterior fossa tumor, intracranial aneurysm and peri-rolandic brain surgeries. The many advances in motor system assessment achieved in the last two decades undoubtedly improve monitoring efficacy without unduly compromising safety. Future studies and experience will likely clarify existing controversies and bring further advances.

Rhythmicity of Biopotentials: Its Origin and Involvement in Information Processing

Experimental data and mathematical simulation of a neural network were used to develop ideas concerning the origin of the rhythmicity of biopotentials and its involvement in information processing. Baseline slow oscillations—the primate α rhythm, the α-like rhythms of lower animals, the Δ rhythm of humans and animals, secondary components of sensory evoked potentials or responses to direct brain stimulation, and pathological epileptiform potentials—develop as a result of interactions between excitatory and inhibitory postsynaptic potentials. The main inhibitory transmitter in the brain cortex is γ-aminobutyric acid (GABA). EEG activation in the form of a decrease in the amplitude of baseline oscillations and the appearance of the stress rhythm in the θ band upon exposure to new or biologically significant stimuli is associated with a relative decay of inhibitory hyperpolarization processes. The cholinergic and noradrenergic neurotransmitter systems are substantially involved in the rearrangement of the neural activity associated with EEG activation. An enhancement of high-amplitude baseline oscillations and phasic activity of neurons, i.e., alternation of activation and inhibition of firing, which reflects a relative enhancement of hyperpolarization processes, restricts excitation propagation over brain structures and impedes the fixation of new information. As a result of the decay of the inhibitory processes, EEG activation is accompanied by a higher regularity of neuronal firing and a decrease in entropy in the time distribution of firing in the form of tonic or grouped (in the stress rhythm) discharges. The resulting ordered streams of impulses transfer information, control its propagation, and ensure its fixation and reproduction.

Electrophysiological effects and clinical results of direct brain stimulation for intractable epilepsy.

Epilepsy can be considered as a result of the imbalance of the excitatory and inhibitory processes. Therefore, the artificial enhancement of the activity of brain inhibitory mechanisms might lead to a beneficial therapeutic effect for intractable epilepsy patients. Studies of the inhibitory effects of electrical stimulation of the head of the caudate nucleus (HCN), cerebellar dentate nucleus (CDN), thalamic centromedian nucleus (CM), and neocortical and temporal lobe mesiobasal epileptic foci were performed on 150 patients with implanted intracerebral electrodes. Chronic brain stimulation with implanted neurostimulators was performed on 54 patients. Sixteen were followed up to 1.5 years (mean 1.2 years). The study demonstrated that 4-8 Hz HCN and 50-100 Hz CDN stimulation suppressed the subclinical epileptic discharges and reduced the frequency of generalized, complex partial, and secondary generalized seizures. CM stimulation (20-130 Hz) desynchronized the EEG and suppressed partial motor seizures. Direct subthreshold 1-3 Hz stimulation of the epileptic focus may suppress rhythmic afterdischarges (ADs). Seizures were eliminated for 26 of 54 patients (48%), worthwhile improvement was achieved for 23 of 54 patients (43%), and no improvement was observed in 5 of 54 patients (9%). The artificial increase of the activity of brain inhibitory system may suppress the activity of epileptic foci, and, in long run, stabilize this epileptic foci activity at a lower, perhaps normal, level. Therapeutic direct brain stimulation, therefore, might serve as a useful tool in the treatment of intractable and multifocal epilepsy, and might be combined with ablative surgical methods.

Libet's Temporal Anomalies: A Reassessment of the Data

Benjamin Libet compared the perceived time of direct brain stimulation to the perceived time of skin stimulation. His results are among the most controversial experiments at the interface between psychology and philosophy. The new element that I bring to this discussion is a reanalysis of Libet's raw data. Libet's original data were difficult to interpret because of the manner in which they were presented in tables. Plotting the data as psychometric functions shows that the observers have great uncertainty about the relative timing of events, as seen the shallow psychometric slopes. A second indication of uncertainty comes from Libet's use of three response categories, A first; B first; and A and B simultaneous. The large number of “perceptually simultaneous” responses provides a further measure of the difficulty of the judgment. There are thus a very broad range of stimulus delays in which the subject is unable to make an accurate ordering response. These points provide evidence that there is no compelling reason to invent exotic or ad hoc mechanisms to account for Libet's data since the uncertainty window is large enough to allow simple mechanism such as memory shifts. Libet argued that his data provide evidence for a backward referral in time. I argue that even though Libet's own data are weak, there are good arguments for a backward referral mechanism to help the subject make sense out of the tangled chaos of asynchronous information associated with experienced events.

Intraoperative validation of functional magnetic resonance imaging and cortical reorganization patterns in patients with brain tumors involving the primary motor cortex

The purpose of the present study was to compare the results of functional magnetic resonance (fMR) imaging with those of intraoperative cortical stimulation in patients who harbored tumors close to or involving the primary motor area and to assess the usefulness of fMR imaging in the objective evaluation of motor function as part of the surgical strategy in the treatment of these patients. A total of 11 consecutive patients, whose tumors were near to or involving the central region, underwent presurgical blood oxygen level-dependent fMR imaging while performing a motor paradigm that required the patients to clench and spread their hands contra- and ipsilateral to the tumor. Statistical cross-correlation functional maps covering the primary and secondary motor cortical areas were generated and overlaid onto high-resolution anatomical MR images. Intraoperative electrical cortical stimulation was performed to validate the presurgical fMR imaging findings. In nine (82%) of 11 patients, the anatomical fMR imaging localization of motor areas could be verified by intraoperative electrical cortical stimulation. In seven patients two or more activation sites were demonstrated on fMR imaging, which were considered a consequence of reorganization phenomena of the motor cortex: contralateral primary motor area (nine sites), contralateral premotor area (four sites), ipsilateral primary motor area (two sites), and ipsilateral premotor area (four sites). Functional MR imaging can be used to perform objective evaluation of motor function and surgical planning in patients who harbor lesions near or involving the primary motor cortex. Correlation between fMR imaging findings and the results of direct electrical brain stimulation is high, although not 100%. Based on their study, the authors believe that cortical reorganization patterns of motor areas might explain the differences in motor function and the diversity of postoperative motor function among patients with central tumors.

O-22-319 - Intraoperative cortical mapping by direct brain stimulation under local anesthesia

O-22-319 - Intraoperative cortical mapping by direct brain stimulation under local anesthesia

Somatosensory evoked response source localization using actual cortical surface as the spatial constraint.

We localized right median nerve somatosensory evoked responses in a normal human subject using an equivalent dipole method applied to magnetic field recordings. High resolution, 3-dimensional MRI data were used to confine source locations to the cortical surface. Results localized in Brodmann area 3b corresponding to location of hand somatosensory cortex derived from direct brain stimulation studies. The solution was unique and total computational time for an exhaustive, brute-force search was small and the results realistic due to applied anatomical constraints. This study demonstrates feasibility of accurate, non-invasive, realistic localization of dynamic human cortical function using spatial constraints provided by MRI images.

Electrical stunning by direct brain stimulation in pigs

The effects of electrical stunning of slaughter pigs by electrodes shot into the brain, on sensibility and on the incidence of haemorrhages in the shoulder postmortem, were studied. To determine the efficiency of this method 37 slaughter pigs were equipped with EEG (electroencephalograph) and ECG (electrocardiograph) electrodes and stunned twice via the EEG electrodes. In the first experiment the pigs were stunned with 25 V and in the second with 25 V followed by a relaxation current. The day after slaughter the shoulders were scored for haemorrhages. Under more practical conditions three groups of 10 pigs each were electrically stunned via electrodes shot into the brain using 25, 50 or 75 V, followed by a relaxation current. The day after stunning the shoulders were scored for haemorrhages. The pigs did not react to shooting electrodes frontally into the head. After stunning all animals showed a general epileptiform seizure. However, after the second stun the tonic and clonic muscle cramps were impaired. The heart rate increased significantly ( P < 0·01) after stunning, and extra systolae and irregular heart rates were observed. In the shoulders of 27% of the carcasses no haemorrhages were found and in the remainder only minor haemorrhages were seen. Under practical conditions a voltage of 87(± 2) V and a current of 511(±20) mA seemed to be necessary for an effective stun. When lower voltages were applied fewer carcasses with shoulder haemorrhages were found. It may be concluded from these experiments that 25 V (∼134 mA; 150 Hz) is sufficient for effective stunning of slaughter pigs when electrodes are in direct contact with the brain. But as the optimum position of the electrodes may not be reached under practical conditions a voltage of approximately 90 V (∼550 mA; 150 Hz) is recommended. After this stunning method only a few haemorrhages were observed in the shoulders.

The effects of Δ 9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study

The effect of systemically administered Δ 9-tetrahydrocannabinol (THC), the psychoactive ingredient marijuana, on the potassium-evoked release of dopamine (DA) was examined in the neostriatum of the chloral hydrate anesthetized rat. Both in vivo electrochemical and in vivo microdialysis techniques were employed. A low dose of THC (0.5 mg/kg, i.p.) increased the time course of potassium-evoked in vivo electrochemical signals corresponding to released extracellular DA. In vivo microdialysis showed an increase in potassium-evoked DA release following 0.5 and 2.0 mg/kg doses of THC. Potassium-evoked electrochemical signals corresponding to released extracellular DA were augmented in time course following i.p. administration (5.0 mg/kg) of nomifensine, a recognized and potent catecholaminergic reuptake blocker. In addition, in vivo brain microdialysis studies of nomifensine (5.0 mg/kg i.p.) on neostriatal potassium-evoked DA release showed that DA levels were augmented in magnitude over the time course of the microdialysis. Taken together, these studies indicate that THC has a potent presynaptic augmenting effect on at least the neostriatal portions of the mesotelencephalic DA system in the rat, although the possibility that this effect could be mediated transsynaptically cannot be ruled out. Given the previous extensive evidence for an involvement of portions of the mesotelencephalic DA system in mediating the reinforcing and euphorigenic properties of many classes of abused drugs, and in mediating direct electrical brain stimulation reward, we suggest that the presently demonstrated effects of THC on forebrain dopamine function may be related to marijuana's euphorigenic properties and, thus, to its abuse potential.

Evaluation of conduction in central motor pathways: techniques, pathophysiology, and clinical interpretation.

This communication summarizes the highlights of this symposium and reviews our current understanding of the clinical neurophysiology of conduction in central motor pathways produced by transcranial or direct brain stimulation. Direct (D wave) and indirect (I wave) volleys of descending impulses in the pyramidal system result from motor cortex stimulation and determine the measured responses. The advantages and disadvantages of the electrical and the magnetic stimulating modalities are assessed. The increased latency produced by magnetic as opposed to electrical stimulation is considered. Present clinical applications are discussed. The safety record is encouraging, but has aspects that must be addressed. Potential problems of the interpretation of motor evoked potentials in patients with central nervous system disease are emphasized in light of the pathophysiological mechanism underlying these potentials.

The effect of low frequency and direct current stimulation on the kindling phenomenon in rats.

An experiment was conducted to evaluate the effect of 1-Hz or direct current brain stimulation on kindling behavior induced by 60-Hz sine wave stimulation. The effective threshold intensity to elicit a convulsion was determined on four separate occasions with 5 days of daily trials between determinations. On each day one group of experimental rats was stimulated with 1-Hz sine wave current before and after stimulation with 60-Hz sine wave current (1-60-1 group). Another group received direct current stimulation and 60-Hz current (D-60-D group). A third group received only 60-Hz stimulation. Suppression of kindling behaviour usually induced by the 60-Hz stimulation occurred with 1-Hz stimulation; the mean threshold value increased on each successive determination. Suppression was most pronounced for the direct current group; it appeared after a single trial and persisted for 32 days after the last threshold determination. In contrast, most of the rats in the 1-60-1 group had recovered from the suppression after the 32 day period of nonstimulation. A second phase of the experiment indicated that the increase in threshold values for the D-60-D group occurred after a single DC stimulation. These results are consistent with the hypothesis generated by previous research that suppression following 1-Hz stimulation is not due to tissue damage.

The Influence of the Psyche and the Brain on Immunity and Disease Susceptibility: A Critical Review

In critically reviewing the sources of evidence connecting psyche and brain with the immune system, the authors include a brief review of current knowledge of the immune system, its interactions with the neuroendocrine system, and other factors influencing its regulation. These include developmental stages, aging, rhythmicity, and a variety of exogenous influences. The need for developing further information about normal base lines is emphasized. Against that background, many sources of data demonstrating connections between the central nervous system and the immune system are presented: indirect evidence from clinical and experimental illnesses involving the immune system, and direct changes in either humoral or cellular immunity after natural or experimental stress, conditioning, hypnosis, and direct brain stimulation. Possible mechanisms are discussed, as well as some important methodological issues for further research.

A method of direct chemical brain stimulation in behavioral studies using microiontophoresis

A method of microinotophoresis for direct chemical brain stimulation in chronic, awake animals for behavioral studies is described. Carbachol-induced drinking was employed to test the method. Fluid-filled micropipettes (tip diameters: 5–15 μ) were stereotaxically implanted in the region of the nucleus of the diagonal band. Up to 3 weeks after recovery, ions could be ejected directly into the brain of awake animals by passing a direct current through the pipette. Iontophoretic ejection of carbachol in doses as low as 0.05 μg elicited drinking. This effect could be blocked by intraperitoneal injection of 0.5 mg/kg scopolamine. Passage of choline ions produced no detectable effect. The microiontophoretic technique allows direct chemical brain stimulation in chronic, awake animals without major changes in tonicity or volume that can occur with crystalline or fluid implants through cannulae. Additionally, the technique allows precise localization, precise control of dosage, and minimal damage at the site of stimulation.

Electrophysiological correlates of pathology and surgical results in temporal lobe epilepsy.

Routine pre-operative EEG studies as well as direct brain recording and stimulation carried out during operations were analysed for 59 patients subjected to a standard unilateral anterior temporal lobectomy for the treatment of epilepsy. All patients in the present series were 16 years old or older at the time of operation, which was invariably carried out under local scalp analgesia only. Electrophysiological findings was correlated with pathological changes noted in the resected temporal lobes, and with the effects of surgery upon seizure activity. Pre-operative EEG data correlated with each of four pathological categories when sphenoidal electrodes and intravenous barbiturate narcosis were emplyed. Thirty of 31 patients with mesial temporal sclerosis demonstrated medial temporal primary spike foci, frequently with independent contralateral and extratemporal secondary foci. In addition, one-third of these patients demonstrated unilateral focal decreased barbiturate-induced fast activity in the corresponding sphenoidal to ear channels. Twelve patients with other specific medial focal lesions (mostly hamartomas) also had medial temporal primary foci, often with independent contralateral secondaries but never with extratemporal foci. Two patients in this group also demonstrated focal decreased fast activity in the appropriate sphenoidal-ear channel. Both of these groups did very well post-operatively with respect to their epilepsy. Five patients with large temporal convexity cicatrices antedating seizures all demonstrated lateral temporal primary spike foci without independent secondary foci or focal decreased fast activity and did not do as well post-operatively as the first two groups. Eleven patients had only non-specific changes in the resected temporal lobe and in general did not benefit from surgery. Various combinations of primary and independent secondary spike foci were seen. Only this group demonstrated diffuse or bifrontal spikes during initial EEG recording, and basal mid-line spikes with intravenous thiopentone. Pecilar sharp notched spike were also very common in this group, but not unique to it. Focal decreases in barbiturate-induced fast activity were not noted.