Anatomical connectivity and efficacy of electro-therapy for seizure control: A SANTE's single-center regression analyses.

OBJECTIVE: To assess based on a single-center data from a multicenter trial (Stimulation of the Anterior Nucleus for the Thalamus for Epilepsy (SANTE)), the role of anatomical connectivity and other factors (e.g., stimulating electrode placement) on efficacy of electro-therapy of the anterior thalamic nuclei (ATN), a node in Papez network, on pharmaco-resistant seizures. DATA SOURCE: Adults with at least 6 seizures /month were enrolled in this trial. Percent seizure reduction was compared between subjects with seizures emerging inside Papez's network (IPN) to those with seizures outside it (OPN). Statistical analyses were performed on the first year of the trial. RESULTS: Data from 11 subjects were analyzed. At Year 1, median seizure reduction was 80.5% (-100% to -40.3%) in 8/11 subjects with seizures IPN, vs. 52.8% (-61.4% to -23.7%) for 3/11 subjects with seizures OPN (2-sided Wilcoxon p = 0.08). At year 7, 3/11 subjects with seizures IPN had been seizure free for several years vs. 0/11 subjects with seizures OPN. Addition of 4 subjects from a pilot trial with nearly identical protocol to SANTE's, increased to 12/15 the number of subjects with seizures IPN. A 2-sided Fisher's exact test applied to seizure frequency reduction in the 12/15 cohort compared to the 3/15 with seizures OPN, showed significant (p = 0.04) differences in efficacy at the 70% seizure reduction rate. Median quality of life (QOL) scores for subjects with seizures IPN improved by 81% vs. 53% for subjects with seizures OPN. No other factors (e.g., current intensity) had a statistically significant effect on efficacy. CONCLUSIONS: Degree of anatomical connectivity between stimulation targets and epileptogenic networks (ENs) plays an important role in therapeutic efficacy. This may be explained by the minimization of signal attenuation inherent in impulse transmission in nervous tissue partly as a function of fiber tract length, tissue anisotropy, and number of synaptic relays between stimulation target and epileptogenic networks.

Placement of deep brain electrodes in the dog using the Brainsight frameless stereotactic system: a pilot feasibility study.

BACKGROUND: Deep brain stimulation (DBS) together with concurrent EEG recording has shown promise in the treatment of epilepsy. A novel device is capable of combining these 2 functions and may prove valuable in the treatment of epilepsy in dogs. However, stereotactic implantation of electrodes in dogs has not yet been evaluated. OBJECTIVE: To evaluate the feasibility and safety of implanting stimulating and recording electrodes in the brain of normal dogs using the Brainsight system and to evaluate the function of a novel DBS and recording device. ANIMALS: Four male intact Greyhounds, confirmed to be normal by clinical and neurologic examinations and hematology and biochemistry testing. METHODS: MRI imaging of the brain was performed after attachment of fiducial markers. MRI scans were used to calculate trajectories for electrode placement in the thalamus and hippocampus, which was performed via burr hole craniotomy. Postoperative CT scanning was performed to evaluate electrode location and accuracy of placement was calculated. Serial neurologic examinations were performed to evaluate neurologic deficits and EEG recordings obtained to evaluate the effects of stimulation. RESULTS: Electrodes were successfully placed in 3 of 4 dogs with a mean accuracy of 4.6 ± 1.5 mm. EEG recordings showed evoked potentials in response to stimulation with a circadian variation in time-to-maximal amplitude. No neurologic deficits were seen in any dog. CONCLUSIONS AND CLINICAL IMPORTANCE: Stereotactic placement of electrodes is safe and feasible in the dog. The development of a novel device capable of providing simultaneous neurostimulation and EEG recording potentially represents a major advance in the treatment of epilepsy.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience.

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a 'learning curve' both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior-posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Fitting Strategies for Multiple-Memory Programmable Hearing Instruments.

Fitting a multiple-memory programmable hearing instrument presents a new set of challenges to the dispenser, compared to conventional fittings. Rather than having to compromise on a single frequency-gain response (the prescriptive target), it is now possible to create a family of hearing aid responses from which the user can select an appropriate response for a given situation. This philosophy is also applicable in the prescription of compression characteristics. The flexibility designed into the 3M two-channel compression system allows the dispenser to program very different types of signal processing strategies (low frequency compression, high frequency compression, full spectrum compression, or linear processing) into a single instrument to match the requirements of different listening environments and to meet the needs of different users. Utilizing this approach, comfort, speech intelligibility, and sound quality can be optimized in a variety of situations by considering the listener's acoustic environment and the input signals to which the hearing aid must respond.

In search of missing links in otology. I. Development of a collagen-based biomaterial.

Experiments leading to the development and use of a biomaterial based on reconstituted collagen for use in tympanoplasty are presented. A stable, even membrane with optimal strength and an organized matrix of collagen protein strands has been obtained. Biocompatibility was documented by subcutaneous implantation, cytotoxicity with agar overlay, cell contact, and cell-growth inhibition studies. Experimental grafting in chinchillas with perforated tympanic membranes demonstrated that the collagen membrane performed well in all cases. Histopathological studies in chinchillas showed that the collagen membrane compared favorably with fascia grafts. Of significance is that: 1. The membrane has a matrix of microperforations that enhance tissue ingrowth, allow stable anchoring, and permit aeration of the middle ear cavity. 2. The membranes obtained are not exposed to aldehyde cross-linking; therefore, tissue reaction due to aldehydes is avoided.

Mechanisms of salicylate ototoxicity.

The ototoxic effects of salicylates, reversible hearing loss and tinnitus, are well documented. However, the pharmacological mechanisms underlying these changes in cochlear function are not well understood. The studies reported here were an investigation of the site and mechanism of salicylate ototoxicity through an examination of its effects on ionic, neural and mechanical aspects of cochlear transduction. Salicylate administration produced an intensity dependent reduction of the AP and SP, with the predominant effects occurring at low stimulus levels. In direct contrast, a significant increase was observed for corresponding CM responses, independent of stimulus intensity. Salicylates also reduced the magnitude of efferent induced shifts in the AP, CM and EP. Cochlear mechanics were altered as evidenced by the reduction in two-tone distortion products, electrically evoked emissions, and electrophonic APs. These changes in cochlear function are attributed to a salicylate mediated increase in the membrane conductance of the outer hair cells. This change in membrane permeability interferes with the reverse transduction process, effectively reducing the gain of the cochlear amplifier. Results of single unit recordings suggest parallels between salicylate intoxication and noise trauma, which are discussed with regard to potential mechanisms of tinnitus generation.

Ultrastructural studies of the peripheral extensions (dendrites) of type I ganglion cells in the cat.

An ultrastructural study of peripheral extensions (dendrites) of type I ganglion cells in seven healthy adult cats and one cat that underwent bilateral cochlear injection of neomycin was undertaken. Morphologic evidence revealed that the peripheral process (dendrite) consistently has a smaller diameter than the central process. As the dendrite reaches the cell body, there is a constricted segment with a length that ranges from 10 to 30 microns, and a diameter of 0.5 microns. This region is covered by a continuous myelin sheath that does not thin. The central process (axon) does not have a corresponding constriction, and consists of a myelin covered, smoothly tapered segment that extends to the first axonal node of Ranvier. In the deafened cat, some cell bodies of the surviving ganglion cells appeared to have a residual portion of dendrite. These morphologic characteristics might have physiologic implications both in the mechanisms of normal hearing and in cochlear implantation.

Clinical evaluation of a new ECoG recording electrode.

Noninvasive, extratympanic electrocochleography (ECoG) was performed on 13 normal-hearing subjects with three different types of ECoG electrodes. Two of these electrodes, the Life-Tech and Axonics-3M designs are commercially available, and widely used clinically. The third electrode, the TM electrode, is a newly designed system intended to be placed directly onto the tympanic membrane. The purpose of this study was to assess the clinical performance of these different electrodes with particular attention to response amplitudes, response variability, and practical ease of use. The results indicate that the TM electrode provides improved ECoG response amplitudes while minimizing clinical preparation time.

Surgical evaluation of candidates for cochlear implants.

The customary presentation of surgical procedures to patients in the United States consists of discussions on alternative treatment methods, risks of the procedure(s) under consideration, and potential benefits for the patient. Because the contents of the normal speech signal have not been defined in a way that permits a surgeon systematically to provide alternative auditory signals to a deaf patient, the burden is placed on the surgeon to make an arbitrary selection of candidates and available devices for cochlear prosthetic implantation. In an attempt to obtain some information regarding the ability of a deaf patient to use electrical signals to detect and understand speech, the Good Samaritan Hospital and Neurological Sciences Institute cochlear implant team has routinely performed tympanotomies using local anesthesia and has positioned temporary electrodes onto the round windows of implant candidates. The purpose of this paper is to review our experience with this procedure and to provide some observations that may be useful in a comprehensive preoperative evaluation for totally deaf patients who are being considered for cochlear implantation.

Single fiber mapping of spatial excitation patterns in the electrically stimulated auditory nerve.

Spatial maps of electrical excitation were constructed by comparing electrical threshold with acoustic CF for large populations of auditory nerve fibers in cats. Thresholds among fibers with the same CF varied by factors of 4 or more. Monopolar electrodes, both intracochlear and extracochlear, excited fibers throughout the cochlea without spatial selectivity. Stimulation with intracochlear bipolar electrodes produced a minimum in the threshold distribution adjacent to the electrodes. With longitudinally oriented pairs, the width, depth, and location of the minimum shifted with stimulus polarity; spread of excitation throughout the cochlea occurred with stimulus intensities 6.2 to 14 dB above the lowest threshold. With radially oriented pairs, minima were sharper and deeper; spread of excitation occurred at intensities 23.7 to 32.8 dB above the minimum threshold.

Temporal response patterns of single auditory nerve fibers elicited by periodic electrical stimuli.

Single auditory nerve fibers exhibit firing synchronized to one or both phases of periodic AC stimulus currents. Responses to biphasic pulses depend on order and excitation sites of the two phases. Sine and triangle stimuli between 100 Hz and 500 Hz elicit similar response patterns. Responses to square waves are sometimes more synchronized and generally shifted in phase with respect to sine wave responses. Preferred firing phase(s): (1) are largely independent of stimulus intensity; (2) vary among fibers; (3) may shift continuously or discontinuously over several seconds before steady state is achieved. Responses to an unprocessed synthetic vowel stimulus were dominated by pitch period, first formant, and 'spurious' components.

Electrophysiologic evaluation of the cochlear implant patient.

Electrically evoked auditory brain stem responses (EABRs) have been measured in experimental animals and human subjects. The EABR may hold promise as a clinical tool in the evaluation of the auditory system in candidates or users of cochlear prostheses.

Behavioral effects of cochlear prosthesis on deafened monkeys.

No deleterious effects of electrical stimulation on deafened young monkeys were noted using the behavioral techniques described. Due to the small size of this study and the variability of individual monkey behavior, it is impossible to draw definitive conclusions from this study. However, the results strongly suggest that deafened young monkeys with functioning cochlear implants showed apparent improvement in social behavior over deafened nonimplanted subjects. These changes may result from environmental and vocalization sound awareness and/or prevention of auditory deprivation provided by the prosthesis.

Characterization of the electrically evoked auditory brainstem response (ABR) in cats and humans.

Electrically evoked auditory brainstem response (EABR) recordings were made from 38 humans implanted with one of three cochlear prostheses, and from 25 cats. Recognizable auditory potentials were identified in 27 of the profoundly deaf implanted subjects. In both cats and humans EABR waveform morphology and magnitude were independent of electrode configuration and paralleled those of the normal acoustic ABR, but with reduced absolute latencies. EABR recordings are highly susceptible to contamination by stimulus artifact and by elicited non-auditory potentials. Latency, morphology, and magnitude criteria are proposed for identification and analysis of EABR components.

Physiological properties of the electrically stimulated auditory nerve. I. Compound action potential recordings.

The electrically evoked compound action potential (CAP) of the auditory nerve exhibits two peaks, termed N0, at 350 microseconds latency, and N1, at 550 microseconds latency. At low stimulus intensities the CAP consists solely of the long latency N1 peak. As the stimulus strength is increased the higher threshold N0 appears. At high stimulus intensities N1 disappears and only the N0 component of the CAP remains. It is postulated that N1 represents action potentials propagated from the dendritic processes of the auditory neurons and that N0 represents action potentials initiated on the axons of these cells. The N1 peak exhibits anomalous refractory behavior which can be identified in the electrically evoked auditory brainstem response (EABR). That behavior may be useful diagnostically in assessing the extent of dendrite degeneration in cochlear implant candidates and users.

Physiological properties of the electrically stimulated auditory nerve. II. Single fiber recordings.

Single fiber recordings from the electrically stimulated auditory nerve yield post-stimulus time (PST) histograms demonstrating several response patterns. With pulsatile stimulation of the cochlea, the PST histogram for most fibers at threshold consists of a long-latency (500-800 microseconds), broad response peak with significant latency variability. At increased stimulus intensities, the response pattern changes to a short-latency (300-500 microseconds), high-synchrony peak. In preparations where stimulation is applied directly to the axons of the auditory nerve, the response pattern consists solely of a short-latency, high-synchrony peak. It is postulated that threshold excitation of normal auditory neurons occurs on the dendritic processes. At higher stimulus intensities, the site of excitation appears to shift to the axonal region of the cells. Two additional response patterns to electrical stimulation which are attributed to synaptic excitation of the auditory neurons via the hair cells are described.