Intracortical visual prosthesis research - approach and progress.

Following the early work of Brindley in the late 1960's, the NIH began intramural and extramural funding for stimulation of the primary visual coretex using fine-wire electrodes that are inserted into area VI for the prupose of restoring vision in individuals with blindness. More recently researchers with experience in this projectbecame part of our multi-institutional team with the intention to identify and close technological gaps so that the intracortical approach might be tested in humans on a chronic basis. Our team has formulated an approach for testing a prototype system in a human volunteer. Here, we describe our progress and expectations.

Visuotopic mapping through a multichannel stimulating implant in primate V1.

We report on our efforts to establish an animal model for the development and testing of a cortical visual prostheses. One-hundred-fifty-two electrodes were implanted in the primary visual cortex of a rhesus monkey. The electrodes were made from iridium with an activated iridium oxide film, which has a large charge capacity for a given surface area, and insulated with parylene-C. One-hundred-fourteen electrodes were functional after implantation. The activity of small (2-3) neuronal clusters was first recorded to map the visually responsive region corresponding to each electrode. The animal was then trained in a memory (delayed) saccade task, first with a visual target, then to a target defined by direct cortical stimulation with coordinates specified by the stimulating electrode's mapped receptive field. The SD of saccade endpoints was approximately 2.5 larger for electrically stimulated versus visual saccades; nevertheless, when trial-to-trial scatter was averaged out, the correlation between saccade end points and receptive field locations was highly significant and approached unity after several months of training. Five electrodes were left unused until the monkey was fully trained; when these were introduced, the receptive field-saccade correlations were high on the first day of use (R = 0.85, P = 0.03 for angle, R = 0.98, P < 0.001 for eccentricity), indicating that the monkey had not learned to perform the task empirically by memorizing reward zones. The results of this experiment suggest the potential for rigorous behavioral testing of cortical visual prostheses in the macaque.

Postoperative changes in cerebral metabolism in temporal lobe epilepsy.

BACKGROUND: Fludeoxyglucose F 18 positron emission tomography ((18)F-FDG-PET) can detect focal metabolic abnormalities ipsilateral to the seizure focus in 80% of patients with temporal lobe epilepsy (TLE). Regions outside the epileptogenic zone can also be affected. We hypothesized that these remote regions might show altered metabolism, tending to return toward normal values, after surgery. DESIGN: Interictal preoperative and postoperative (18)F-FDG-PET metabolism were compared in patients with refractory TLE. Based on pathological findings, disease was classified in the following 3 groups: mesial temporal sclerosis, mass lesions, and no pathological diagnosis. Quantitative PET data analysis was performed using the region-of-interest template previously described. Global normalization was used to adjust for the effect of antiepileptic medication changes. Data were analyzed by Wilcoxon signed rank test and analysis of variance. SETTING: The Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health. PATIENTS: Twenty-two patients with refractory TLE. RESULTS: Preoperatively, in all groups, cerebral metabolic rate for glucose was decreased ipsilateral to the resection site in inferior lateral temporal, inferior mesial temporal, and inferior frontal areas and thalamus. Postoperatively, in all groups, cerebral metabolic rate for glucose increased in ipsilateral inferior frontal area and thalamus. In the mesial temporal sclerosis group, we found a statistically significant increase in the contralateral thalamus. CONCLUSION: Temporal lobe epilepsy is associated with extensive preoperative decreased metabolism in inferior lateral temporal, inferior mesial temporal, and inferior frontal areas and thalamus. Postoperatively, we found increased IF and thalamic metabolism. Seizures may have a reversible effect on brain areas connected with, but remote from, the epileptogenic cortex. Arch Neurol. 2000;57:1447-1452

Source localization determined by magnetoencephalography and electroencephalography in temporal lobe epilepsy: comparison with electrocorticography: technical case report.

OBJECTIVE AND IMPORTANCE: Source modeling by magnetoencephalography (MEG) and electroencephalography (EEG) may be useful techniques for noninvasive localization of epileptogenic zones for surgery in patients with partial seizures. CLINICAL PRESENTATION: Simultaneous recordings of MEG and EEG, obtained in two patients, were coregistered on each patient's magnetic resonance image for direct comparison of these two methods with intracranial electrocorticography. TECHNIQUE: The average difference between MEG and EEG for localization of the same interictal spikes was approximately 2 cm in one patient and 3.8 cm in the other patient. One patient experienced a complex partial seizure during testing, which permitted comparison between interictal and ictal source localization by both MEG and EEG. The EEG ictal localization differed from the interictal one, whereas the MEG ictal and interictal localizations were more similar. In this patient, the MEG interictal source seemed to localize close to the ictal source, whereas EEG did not. The patients underwent temporal lobectomy after electrocorticography, and the results were compared with the findings of MEG and EEG. Although the results of both techniques agreed with the findings of electrocorticography, in one patient the MEG localization seemed to be more accurate. Both patients experienced good surgical outcomes. CONCLUSION: Both MEG and EEG source localization can add useful and complementary information for epilepsy surgery evaluation. MEG seemed to be more accurate than EEG, especially when comparing interictal versus ictal localization. Further study is needed to evaluate the validity of source localization as useful noninvasive techniques to localize the epileptogenic zone.

A direct comparison of PET activation and electrocortical stimulation mapping for language localization.

Mapping eloquent language cortex in presurgical patients typically is accomplished using highly invasive direct cortical stimulation techniques. Functional imaging during language activation using positron emission tomography (PET) is a promising, noninvasive alternative that requires validation. In seven patients undergoing surgical evaluation for intractable epilepsy, we performed both direct cortical stimulation and PET activation mapping of language cortex using identical tasks. MRI, PET, and CT scans were coregistered to directly compare the location of language centers determined by cortical stimulation versus activation PET. We found that cortical regions that showed increased cerebral blood flow during both visual and auditory naming tasks were located in the same regions as subdural electrodes which disrupted language during electrical stimulation. Cortical regions underlying electrodes that did not disrupt language also showed no consistent changes in regional cerebral blood flow during PET activation. Used cautiously, PET activation produces language maps similar to those obtained with direct cortical stimulation, with more complete brain coverage and considerably less invasion.

Semantic, phonological, and perceptual changes following left and right intracarotid injection (Wada) with a low amytal dosage.

Intracarotid injection of a low dosage of amobarbital (75 mg, 5% solution) was studied in 30 temporal lobectomy candidates while naming achromatic, incongruously, and congruously colored pictorial objects and reading real, nonsense, and embedded words. Semantic errors and phonological alexia followed the left injection, while the right injection induced visuoperceptual errors. When the contralateral hemisphere was anesthetized, the left brain formulated supraordinate categories for words and objects, while the right brain applied concrete labels. The basic language proficiency of patients influenced recovery and outcome; left temporal patients who were interictally anomic performed especially poorly after both injections. Codifying phonological and perceptual changes during the intracarotid amobarbital procedure can improve interpretations about language laterality and organization.

FDG-positron emission tomography and invasive EEG: seizure focus detection and surgical outcome.

PURPOSE: To study the value of [18F]2-deoxyglucose (FDG)-positron emission tomography when surface ictal EEG is nonlocalizing. METHODS: FDG-PET scans were performed in 46 patients with complex partial seizures (CPS) not localized by ictal surface-sphenoidal video-EEG (VEEG) telemetry. Interictal PET was performed with continuous EEG monitoring, and images were analyzed with a standard template. Forty patients subsequently had subdural and 6 had depth electrodes (invasive EEG, IEEG); 22 had bilateral implants. A focus was detected in 40, and 35 had temporal lobectomy based on IEEG localization. RESULTS: There was a close association between IEEG and PET localization (p < 0.01): 26 patients had relative unilateral temporal FDG-PET hypometabolism, all had congruent IEEG, and 18 of 23 were seizure-free after temporal lobectomy. Five patients had unilateral frontotemporal hypometabolism (3 of 5 were seizure-free), 1 had frontal hypometabolism, and 14 had no lateralized PET abnormality (4 of 7 were seizure-free). Patients who became seizure-free had significantly higher lateral temporal asymmetry index (AI). PET showed > or = 15% relative temporal hypometabolism (AI) in 12 of 22 patients with nonlateralized surface ictal VEEG and was capable of distinguishing between frontal and temporal foci in 16 of 24 patients with lateralized, but not localized, surface ictal video-EEG. CONCLUSIONS: FDG-PET provides valuable data in patients with unlocalized surface ictal EEG and can reduce the number of patients who require IEEG studies. Quantitation is necessary for optimal PET interpretation.

Feasibility of a visual prosthesis for the blind based on intracortical microstimulation of the visual cortex.

The feasibility of producing a visual prosthesis for the blind using intracortical microstimulation (ICMS) of the visual cortex was studied in a 42-year-old woman who had been totally blind for 22 years secondary to glaucoma. Thirty-eight microelectrodes were implanted in the right visual cortex, near the occipital pole, for a period of 4 months. Percepts reported as small spots of light, called phosphenes, were produced with 34 of the 38 implanted microelectrodes. Threshold currents for phosphene generation with trains of biphasic pulses were as low as 1.9 microA, and most of the microelectrodes had thresholds below 25 microA. Phosphene brightness could be modified with stimulus amplitude, frequency and pulse duration. Repeated stimulation over a period of minutes produced a gradual decrease in phosphene brightness. Phosphenes did not flicker. The apparent size of phosphenes ranged from a "pin-point' to a "nickel' (20 mm diameter coin) held at arm's length. Phosphene size usually decreased as stimulation current was increased but increased slightly as the train length (TL) was increased. At levels of stimulation near threshold, the phosphenes were often reported to have colours. As the stimulation level was increased, the phosphenes generally became white, greyish or yellowish. Individual phosphenes appeared at different distances from the subject. When two phosphenes were simultaneously generated, the apparent distances of the individual phosphenes sometimes changed to make them appear to be at about the same distance. When three or more phosphenes were simultaneously generated, they became coplanar. Except for rare occasions, phosphenes extinguished rapidly at the termination of the stimulation train. When stimulation TLs were increased beyond 1 s, phosphenes usually disappeared before the end of the train. The duration of phosphene perception could be increased by interrupting a long stimulation train with brief pauses in stimulation. Intracortical microelectrodes spaced 500 microns apart generated separate phosphenes, but microelectrodes spaced 250 microns typically did not. This two-point resolution was about five times closer than has typically been achieved with surface stimulation. With some individual microelectrodes, a second closely spaced phosphene was sometimes produced by increasing the stimulation current. Phosphenes moved with eye movements. When up to six phosphenes were simultaneously elicited, they all moved with the same relative orientation during eye movements. All phosphenes were located in the left hemi-field with the majority above the horizontal meridian. There was a clustering of most of the phosphenes within a relatively small area of visual space. The potentially greater microelectrode density and lower power requirements of ICMS compared with surface stimulation appears encouraging for a visual prosthesis. However, further studies with blind subjects are required to optimize stimulation parameters and test complex image recognition before the feasibility of a visual prosthesis based on ICMS can be established.

Cortical stimulation elicits regional distinctions in auditory and visual naming.

We used electrical stimulation mapping to compare performance on auditory and visual naming tasks in inferotemporal, lateral temporal, frontal, and parietal cortex in 8 temporal lobe epilepsy (TLE) patients with subdural electrodes placed for preoperative language localization. Performance on auditory responsive naming (ARN) and visual confrontation naming (VCN) was best during stimulation of parietal cortex and was equally impaired during stimulation of inferotemporal and frontal cortex. In contrast, ARN performance was significantly poorer than VCN performance during stimulation of anterior and posterior lateral temporal cortex. In most patients, stimulation of inferotemporal cortex at relatively low stimulus intensities (< or = 5 mA) during either ARN or VCN elicited reproducible errors in which patients could describe, gesture, spell, or draw, but not name, in response to auditory or visual cues. Inferotemporal and frontal cortex appear to be multimodality language regions distinct from lateral temporal cortex.

Hematoma-related seizures detected during subdural electrode monitoring.

A 28-year-old woman with epilepsy developed the new onset of paroxysmal tongue tingling during subdural electrode monitoring. Her symptoms coincided with electrographic seizure activity arising from an area of the perisylvian region that had not previously been involved in her habitual seizures. At electrode removal, a focal 2 x 2 cm hematoma was detected and evacuated from beneath these electrode contacts. Unexpected episodic events may represent nonhabitual seizure activity related to the surgical procedure.

FDG-PET in children and adolescents with partial seizures: role in epilepsy surgery evaluation.

We used FDG-PET to measure interictal glucose metabolism in 16 children and adolescents (mean age 14.7 years) and complex partial seizures (CPS) (mean seizure onset age 5.0 years). Video-EEG localized the epileptic foci. Glucose metabolism was determined in 14 paired anatomic areas using a standard template. PET hypometabolism was defined as greater than 15% asymmetry. Nine of the 13 (69%) patients with a unilateral EEG focus had regional hypometabolism ipsilateral to the epileptogenic zone. Three subjects had bilateral EEG foci; all had nonfocal PET. MRI (15 patients) concurred with EEG and PET in two, and was normal in seven of nine with focal hypometabolism. One of seven patients with normal PET had a focal MRI abnormality. FDG-PET results are similar to those found in adults, but are present earlier in the natural history of CPS (9.7 vs 22.2 years duration epilepsy) than previously reported. The presence of FDG-PET hypometabolism may be associated with a poor response to drug treatment. PET can identify metabolic abnormalities associated with epileptic foci in children and adolescents and is useful in directing surgical intervention for the control of refractory complex partial epilepsy.

Increased expression of gelatinase-a and timp-2 in primary human glioblastomas.

The highly invasive growth of glioblastomas may be a consequence of an abnormal profile of proteinases and proteinase inhibitors involved in remodeling of the basement membrane and normal vasculature. We have detected a 1.5-3-fold increase in the transcription of gelatinase A and TIMP-2 (Tissue Inhibitor of Metalloproteinase) in glioblastomas as compared to the normal brain tissue. Increased expression of gelatinase A and TIMP-2 in these tumors was also evident by immunohistochemical analysis. Our data suggest that increased expression and perturbation of the balance between metalloproteinases and their inhibitors that are involved in extracellular matrix remodeling and angiogenesis may contribute to the invasive phenotype of glioblastomas.

Event-related desynchronization and movement-related cortical potentials on the ECoG and EEG.

Event-related desynchronization (ERD) 2.0 sec before and 1.0 sec after movement in the frequency bands of 8-10, 10-12, 12-20 and 20-30 Hz and movement-related cortical potentials (MRCPs) to self-paced movements were studied from subdural recordings over the central region in 3 patients, and from scalp-recorded EEGs in 20 normal volunteers. In direct cortical recordings, the peak ERD response and peak MRCP amplitude to self-paced finger movements were maximal over recording sites in the contralateral hand motor representations. The topography and time of onset of the ERD response to finger and foot movements suggest that the ERD responses in the 8-10 Hz and 10-12 Hz bands are more somatotopically restricted than the responses in the higher frequency bands. The power recovery and subsequent overshoot in the different frequency bands occurred in an orderly fashion with the faster frequencies recovering earlier. The ERD responses on the scalp-recorded EEGs were of lower magnitude and more widely distributed than those occurring on the subdural recordings. Across the population, there was no relation between the magnitude of the ERD response in any of the frequency bands studied and the peak amplitude of the negative slope (pNS') and the frontal peak of the motor potential (fpMP) of the MRCPs. MRCPs and ERD responses originate in similar cortical regions and share some common timing features, but the magnitude and spatial distribution of the two responses appear to be independent of each other, which suggests that the physiological mechanisms governing these two events are different and may represent different aspects of motor cortex activation. Differences in the timing and topographical features of the ERD responses in the various frequency bands also suggest a distinct functional significance for the various spectral components of the electrical activity in the motor cortex.

Positron emission tomographic measurement of cerebral blood flow and temporal lobectomy.

We used positron emission tomography (PET) and bolus injection of H2(15O) to measure interictal cerebral blood flow (CBF) in 32 patients who had temporal lobectomy for uncontrolled complex partial seizures. Seizure focus localization was confirmed by ictal video-electroencephalographic (video-EEG) telemetry, and patients who had imaging findings suggesting the presence of a tumor were excluded. PET-CBF studies were interpreted using a standard template by raters blinded to EEG and clinical data, and were not used in surgical planning. After surgery, patients were followed for 32 +/- 18 months. Twenty-six patients were seizure free and 6 had persistent seizures. Mean lateral temporal hypoperfusion was 8 +/- 14% in patients who became seizure free and 9 +/- 6% in patients with persistent seizures. Fourteen patients had at least 15%, and 11 at least 20% hypoperfusion, but were not more likely to be seizure free. Three additional patients had 15 to 20% hypoperfusion in the temporal lobe contralateral to their EEG focus. PET measurement of CBF using bolus H2(15O) should not be used to help select patients for temporal lobectomy.

Plasticity in the adult human oligodendrocyte lineage.

Preoligodendrocytes have been described in cultures and tissue prints of adult human white matter (Armstrong et al., 1992). To characterize further these precursors of human oligodendrocytes, we have investigated whether they express genes playing a critical role in oligodendrocyte development. In the intact human brain, platelet-derived growth factor receptor alpha (PDGF alpha R) and myelin transcription factor 1 (MyTI) transcripts are expressed in 1-2% of cells of the oligodendrocyte lineage (OL), and clusters of such cells can be found in the periventricular region. Myelin basic protein transcripts containing exon 2 information (exon 2+ MBP), which are characteristic of the premyelinating stage, are detected in 15-20% of OL cells in vivo. When OL cells are separated from human white matter and allowed to regenerate in vitro, a much larger proportion of these cells express developmentally regulated genes, while exon 2- MBP and proteolipid protein (PLP) transcripts characteristic of mature OL cells appear transiently downregulated. Basic fibroblast growth factor (bFGF), even in the presence of PDGF, does not promote DNA synthesis in these cultured OL cells. Yet bFGF induces human oligodendrocytes to regenerate their processes rapidly in vitro and to express O4 antigens as well as exon 2+ MBP, MyTI, and PLP transcripts. While bFGF accelerates early regenerative processes, it also maintains high expression of exon 2+ MBP transcripts in OL cells for up to 2 weeks in vitro. In contrast, high levels of insulin in the absence of bFGF allow accumulation of exon 2- MBP and PLP transcripts in most OL cells at 2-3 weeks in vitro. We propose that the myelinated human brain harbors a small pool of precursors of oligodendrocytes and that growth factor-regulated phenotypic plasticity rather than mitogenic potential accounts for the regeneration of oligodendrocytes in the initial stages of demyelinating diseases such as multiple sclerosis.

Postictal behavior. A clinical and subdural electroencephalographic study.

OBJECTIVE: To examine postictal behaviors after temporal lobe complex partial seizures (CPSs) and to correlate these behavioral phenomena with side of origin and ictal spread pattern. DESIGN: Review language and other behavioral phenomena after seizures defined by subdural electroencephalography. SETTINGS: A surgical epilepsy center. PATIENTS: We studied postictal behavior following 65 CPSs in 18 patients with left hemisphere language dominance using subdural electrode recordings. INTERVENTION: Subdural electrodes. MAIN OUTCOME MEASURES: Language function, affect, orientation, and postictal automatisms. RESULTS: Following the CPS ictal discharge, the mean interval for initial nonreflexive response to an environmental stimulus was 43 seconds (left foci, 57 seconds; right foci, 29 seconds; not significantly) and for first correct verbal response was 219 seconds (left foci, 275 seconds; right foci, 167 seconds; not significant). Impaired comprehension with fluent but unintelligible speech, as well as anomia, occurred after seizures arising from either temporal lobe. All nine seizures followed by global or nonfluent aphasia originated on the left side. Paraphasic errors were significantly more common after left temporal CPSs. Prolonged disorientation for place and flat affect were significantly more common after right temporal CPS. Postictal automatisms were frequent and included rubbing of the face, fumbling and picking hand movements, and repetitive oral movements. CONCLUSIONS: Postictal paraphasias, disorientation for place, and flat affect most likely reflect the functions of the area from which seizures arise but not the areas involved by spread.

Peripheral benzodiazepine receptors and glucose metabolism in human gliomas.

Peripheral benzodiazepine receptors (PBR) are increased in gliomas and augmented glucose metabolism is seen in malignant brain tumors. We investigated the relationship between PBR density (Bmax) and glucose utilization rate (GUR) in 17 patients with cerebral gliomas of different grades. PBR Bmax was assessed by [3H]PK-11195 in vitro binding in surgical specimens and GUR was measured by Positron Emission Tomography with [18F]2-Fluorodeoxyglucose before the surgery. In untreated tumors there was a positive correlation between PBR Bmax and GUR (2r = 0.84). This correlation was not observed in patients who had been treated with radiation and/or chemotherapy prior to surgery (r2 = 0.13). In addition, in untreated patients, the increase in PBR density and GUR appeared to be related to the degree of malignancy.

Systemic histiocytosis presenting as multiple sclerosis.

A patient resembling one with progressive multiple sclerosis in clinical presentation and by magnetic resonance imaging was studied in detail. Some features atypical for multiple sclerosis prompted a persistent search for an alternative cause. The diagnosis of a non-Langerhans systemic histiocytosis involving brain and bone was established and showed a partial response to radiation therapy. This patient illustrates the continued importance of a broad approach to the evaluation of possible multiple sclerosis, with particular attention to atypical features.

Temporal lobectomy for uncontrolled seizures: the role of positron emission tomography.

We evaluated the role of positron emission tomography (PET) with [18F]deoxyglucose (FDG) (FDG-PET) for planning surgery in 53 patients who had temporal lobectomy for uncontrolled seizures at National Institutes of Health from 1981 to 1990. Investigators blinded to PET data used results of telemetered video-electroencephalographic ictal monitoring and other standard criteria to decide whether subdural electrodes (22 patients, i.e., the "invasive" group) should be implanted or surgery performed. PET scans were analyzed using a standard regional template. Mean lateral but not mesial temporal asymmetry was significantly higher in patients who became seizure free (p < 0.03). Patients with > or = 15% hypometabolism were significantly more likely to be seizure free in the entire study population and the invasive subgroup. Visual identification of hypometabolism was less accurate. When a clear temporal ictal surface electroencephalographic focus was present, FDG-PET provided less additional information. FDG-PET may be particularly valuable if the surface electroencephalographic scan is nonlocalizing. In addition to helping to identify the seizure focus, it may allow limitation of invasive electrode placement to those necessary for functional mapping. When PET is used to identify epileptic foci, quantitative measurements of asymmetry should be made.

Comparison of PET measurements of cerebral blood flow and glucose metabolism for the localization of human epileptic foci.

We compared the relative sensitivity of two interictal PET techniques, bolus injection of [15O] labeled water for estimation of cerebral blood flow (H2(15)O CBF-PET), and 18F 2-deoxyglucose (18FDG-PET) for cerebral glucose metabolism (CMRglc), and T2-weighted magnetic resonance imaging, in 28 patients with medically intractable complex partial seizures undergoing evaluation for surgery. There were statistically significant associations between lateralization by 18FDG-PET, and MRI, but not H2(15)O CBF-PET, and lateralization of the epileptic focus as defined by scalp-sphenoidal ictal EEG. Fifteen patients had surgery or subdural electrodes. 18FDG-PET was more closely associated with a good outcome than H2(15)O CBF-PET, which, in addition, showed hypoperfusion contralateral to the epileptic temporal lobe in several cases. H2(15)O sensitivity may have been reduced by technical factors, but 18FDG-PET appears to be more specific for localization of epileptic zones.