Ronald P. Lesser

Placebo-controlled pilot study of centromedian thalamic stimulation in treatment of intractable seizures.

Summary: Stimulation of centromedian (CM) thalamic nuclei has been proposed as a treatment for seizures. We implanted programmable subcutaneous (s.c.) stimulators into CM bilaterally in 7 patients with intractable epilepsy to test feasibility and safety. Stimulation was on or off in 3‐month blocks, with a 3‐month washout period in a double‐blind, cross‐over protocol. Stimuli were delivered as 9O‐μs pulses at 65 pulses/s, 1 min of each 5 min for 2 h/day, with voltage set to half the sensory threshold. Stimulation was safe and well‐tolerated, with a mean reduction of tonic‐clonic seizure frequency of 30% with respect to baseline when stimulator was on versus a decrease of 8% when the stimulator was off. There was no improvement in total number of generalized seizures with stimulation, and treatment differences were not statistically significant. Stimulation at low intensity did not alter the EEG acutely, but high‐intensity stimulation induced slow waves or 2–3 Hz spike‐waves with ipsilateral frontal maximum. In an open‐label follow‐up segment with stimulator trains continuing for 24 h/day, 3 of 6 patients reported at least a 50% decrease in seizure frequency. There were no side effects. This pilot project demonstrated the feasibility of controlled study of thalamic stimulation in epilepsy, but further study will be needed to demonstrate efficacy.

Electrocorticographic gamma activity during word production in spoken and sign language

Objective: To investigate the functional-neuroanatomic substrates of word production using signed versus spoken language. Methods: The authors studied single-word processing with varying input and output modalities in a 38-year-old woman with normal hearing and speech who had become proficient in sign language 8 years before developing intractable epilepsy. Subdural electrocorticography (ECoG) was performed during picture naming and word reading (visual inputs) and word repetition (auditory inputs); these tasks were repeated with speech and with sign language responses. Cortical activation was indexed by event-related power augmentation in the 80- to 100-Hz gamma band, and was compared with general principles of functional anatomy and with subject-specific maps of the same or similar tasks using electrical cortical stimulation (ECS). Results: Speech outputs activated tongue regions of the sensorimotor cortex, and sign outputs activated hand regions. In addition, signed word production activated parietal regions that were not activated by spoken word production. Posterior superior temporal gyrus was activated earliest and to the greatest extent during auditory word repetition, and the basal temporal-occipital cortex was activated similarly during naming and reading, reflecting the different modalities of input processing. With few exceptions, topographic patterns of ECoG gamma were consistent with ECS maps of the same or similar language tasks. Conclusions: Spoken and signed word production activated many of the same cortical regions, particularly those processing auditory and visual inputs; however, they activated different regions of sensorimotor cortex, and signing activated parietal cortex more than did speech. This study illustrates the utility of electrocorticographic gamma for studying the neuroanatomy and processing dynamics of human language.

Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation

Objective: To determine whether cortical electrical stimulation can terminate bursts of epileptiform activity in humans, we used afterdischarges (ADs) as a model of epileptiform activity. Methods: Cortical stimulation was performed for clinical localization purposes using subdural electrodes implanted in patients undergoing preresection evaluations for treatment of medically intractable seizures. We used 0.3-millisecond pulses of alternating polarity, repeated at 50 pulses/second. When stimulation produced AD, we often applied short additional brief bursts of pulse stimulation (BPS). We examined the effectiveness of BPS in aborting ADs in 17 patients using survival analysis. Results: With BPS, ADs stopped within 2 seconds in 115 cases, 2 to 5 seconds in 22 cases, and in more than 5 seconds in 89 cases. Without BPS, ADs stopped within 2 seconds in 21 cases, 2 to 5 seconds in 114 cases, and in more than 5 seconds in 340 cases. BPS was an effective method to abort ADs (Cox proportional hazards model: p < 0.0001). At any time during the course of ADs, the instantaneous rate of stopping ADs within 2 seconds after BPS was applied was 4.6 times greater than when BPS was not applied (95% CI = 3.7, 5.7). In eight cases, ADs progressed to the occurrence of clinical seizures, always when BPS was not applied. Conclusions: Afterdischarges significantly decreased in duration after we applied brief bursts of pulse stimulation. Although afterdischarges are not identical to spontaneous epileptiform activity, these results support the idea that electrical stimulation, applied in an appropriate manner at seizure onset, could abort seizures in humans.

Determination of current density distributions generated by electrical stimulation of the human cerebral cortex

With the use of a 3-dimensional finite element model of the human brain based on structural data from MRI scans, we simulated patterns of current flow in the cerebral hemisphere with different types of electrical stimulation. Five different tissue types were incorporated into the model based on conductivities taken from the literature. The boundary value problem derived from Laplaces equation was solved with a quasi-static approximation. Transcranial electrical stimulation with scalp electrodes was poorly focussed and required high levels of current for stimulation of the cortex. Direct cortical stimulation with bipolar (adjacent) electrodes was found to be very effective in producing localized current flows. Unipolar cortical stimulation (with a more distant reference electrode) produced higher current densities at the same stimulating current as did bipolar stimulation, but stimulated a larger region of the cortex. With the simulated electrodes resting on the pia-arachnoid, as usually occurs clinically, there was significant shunting of the current (7/8 of the total current) through the CSF. Possible changes in electrodes and stimulation parameters that might improve stimulation procedures are considered.

Cortical somatosensory evoked potentials in response to hand stimulation

Somatosensory evoked potentials were recorded from chronically implanted subdural electrodes in six patients with intractable seizures. The following conclusions were reached: 1) The initial cortical negativity-positivity (N1 with a latency of about 20 msec and P2 with a latency of about 24 msec) recorded in the postcentral area was an expression of the classical primary surface positivity, but N1 was generated by the posterior pole of an early horizontal dipole in area 3b, and P2 was generated by the positive pole of a slightly delayed vertical dipole in area 1 and 2.2) P2 permitted the most accurate localization of the primary somatosensory area. 3) No potentials were elicited in the primary somatosensory area by stimulation of the ipsilateral hand. 4) No cortical potentials were seen at stimulation intensities below the sensory threshold. The cortical distribution of evoked potentials evoked by weak and strong intensities had significantly different distribution. 5) The recovery function of cortical evoked potentials showed a U-curve with an early period of facilitation (10 to 30 msec) followed by a prolonged period of subnormality which peaked at about 50 msec. The recovery curve at different cortical loci differed.

Parameters for direct cortical electrical stimulation in the human: histopathologic confirmation

Safe parameters for electrical cortical stimulation in humans are difficult to estimate from the animal experimental literature. We therefore examined the light microscopic histology at a total of 11 sites of direct subdural electrical stimulation, taken as part of anterior temporal lobectomies in 3 patients. Stimulations had been done through 3.175 mm diameter electrodes, with 0.3 msec square wave pulses of alternating polarity at 50 pulses/sec. In 2 patients, one site each had been used as a common reference for stimulation, receiving over 251 stimulation trials, most of 2-5 sec duration, at currents of 12.5-15.0 mA, 1 day prior to resection. The maximum charge per phase was 4.0-4.4 microC; the maximum charge density was 52-57 microC per geometric cm2 per pulse at the electrode surfaces. Comparison of hematoxylin and eosin, periodic acid-Schiff, and cresyl violet-stained material from the electrode sites with that from other regions did not show any histologic abnormalities attributable to the electrical stimulation. The relatively brief and intermittent periods utilized for human stimulation testing do not appear to cause structural damage at the light microscopic level at charge densities that exceed the threshold for damage established in animal studies with more continuous, chronic stimulation schedules.

Extraoperative cortical functional localization in patients with epilepsy

Functional localization prior to cortical resections for intractable seizures has usually been performed in the operating room in awake patients. Chronically placed subdural electrodes offer the possibility of performing such testing outside of the operating room and without the unavoidable stresses and time limitations of the surgical setting. The use of the technique is reviewed.

Functional significance of the mu rhythm of human cortex: an electrophysiologic study with subdural electrodes ☆

The existence of the mu rhythm and its general anatomical and physiological relationships are well known. There are few data, however, regarding the details of its anatomical and physiological specificity. We implanted fronto-temporal subdural electrode grids in 9 patients with intractable epilepsy to facilitate their surgical management. A 7-11 Hz cortical mu rhythm was observed in 5-16 electrodes located over the sensorimotor cortex as mapped by electrical stimulation. The mu rhythm was blocked by contralateral face and arm movements, passive movements of contralateral arm, and by ipsilateral arm movements. There was correspondence between the body area movement of which blocked the mu at a given site and the body region that was affected by stimulation at the same site. Power spectral analysis showed an overall decrease in power in all frequency bands. This was less prominent in the 14-100 Hz band resulting in a relative increase in high frequency power in association with movement. We conclude that both the presence and blocking of mu rhythm are specific to the somatic representation of the cortex from which it is recorded. Its functional significance may be similar to other sensory rhythms like the occipital alpha rhythm.

The lateralizing significance of versive head and eye movements during epileptic seizures.

We studied 37 patients who had head and eye turning during 74 spontaneous epileptic seizures. Videotapes and EEGs were analyzed independently. Turning movements were classified without knowledge of EEG or clinical data as either versive (unquestionably forced and involuntary, resulting in sustained unnatural positioning) or nonversive (mild, unsustained, wandering, or seemingly voluntary). Videotape observations were then correlated with the EEG location of seizure onset. Contralateral versive head and eye movements occurred during 61 seizures in 27 patients, but ipsilateral versive movements did not occur. Nonversive lateral head and eye movements occurred ipsilaterally and contralaterally with equal frequency and were nonlocalizing, but versive movement was a reliable lateralizing sign.

Clinical outcome after complete or partial cortical resection for intractable epilepsy

This is the first epilepsy surgery series to analyze the definition of “completeness” of resection, based solely on results of chronic scalp and subdural EEG recording. When patients had complete removal of all cortical areas with ictal and interictal epileptiform discharges, the clinical outcome was usually good. When areas with epileptiform discharges were left behind, good outcome was significantly less frequent. This correlation between complete resection and good outcome was independent of the presence or absence of CT-detected structural lesions or sharp waves on post-resection electrocorticography. These results support completeness of resection, defined by prolonged extraoperative EEG, as an important factor in seizure surgery.