Corticosteroid responses to limbic stimulation in man: localization of stimulus sites.

Corticosteroids in human plasma and urine increase after amygdala stimulation, and plasma corticosteroids decrease after hippocampus stimulation. Five subjects underwent unilateral temporal lobectomy, and histopathologic localization of electrode sites was attempted. Localization was successful for six sites: three in basolateral amygdala and three in hippocampus.

Endogenous potentials generated in the human hippocampal formation and amygdala by infrequent events.

Infrequent, attended, auditory and visual stimuli evoke large potentials in the human limbic system in tasks that usually evoke endogenous potentials at the scalp. The limbic potentials reverse polarity over small distances and correlate with unit discharges recorded by the same electrodes, indicating that they are locally generated.

Neuropsychologic correlates of depth spike activity in epileptic patients.

The statistical properties of depth spiking in the interictal EEG were assessed in 12 patients with intractable temporal lobe epilepsy in whom electrodes had been stereotactically implanted for diagnostic purposes. Prior to the implantation surgery each patient was administered a battery of neuropsychologic tests. Correlational analyses showed that the total amount of depth spike activity (TA) negatively correlated with measures of intelligence, while the laterality of the spike activity (LAT) appeared to be positively related to a memory score and the degree of psychologic independence. The results of this study are consistent with previous findings of a significant relationship between surface EEG recordings and performance. In addition, our data suggest a relationship between specific neuropsychologic functions and the patterns of in-depth EEG epileptiform discharges.

Cervical spondylotic radiculopathy and myelopathy. A long-term follow-up study.

The natural history of cervical spondylotic myelopathy in a series of 55 patients resulted in a moderate to severe disability during a mean period of 45 months. Results of operation for myelopathy indicated improvement in one group that was maintained for a mean of 85 months. In another group, progressive worsening occurred after operation, or late worsening occurred, in some instances as long as 8 to 12 years after improvement and plateau. Patients with cervical spondylotic radiculopathy tended to be separated from those with myelopathy with respect to presentation, symptom complex, and operative result. Results of operation for radiculopathy were consistently good. A worsened disability postoperatively for patients with cervical spondylotic myelopathy was associated with the preoperative symptom of sphincter disturbance and the sign of lower extremity weakness. Change in hand movement after operation for myelopathy and change in distance walking ability were not correlated with numerous preoperative factors. A trend of improvement in disability following anterior interbody fusion and a tendency to worsen in disability following all varities of laminectomy were significant.

Memory following intracarotid amobarbital injection contralateral to hippocampal damage.

We examined the relationship between memory performance and hippocampal damage in temporal lobe epileptics undergoing the intracarotid amobarbital sodium procedure (IAP). Overall memory performance in the course of IAP was correlated with seizure lateralization. The hemisphere of seizure focus had impaired IAP memory in 63% (19/30) of the patients. The IAP memory performance following perfusion of the hemisphere contralateral to severe hippocampal lesions was impaired in five of six patients. These patients also exhibited hypometabolism of the impaired temporal lobe as determined independently by positron emission tomography. The single patient with a severely damaged hippocampus who did not demonstrate IAP memory impairment with contralateral hemisphere injection did not exhibit perfusion of the ipsilateral posterior cerebral artery with amobarbital. Memory performance following intracarotid amobarbital injection contralateral to a less severely damaged hippocampus was impaired in 14 of 24 patients and was not related to extent of hippocampal damage, temporal lobe hypometabolism of labeled glucose, perfusion of the ipsilateral posterior cerebral artery, hemispheric language dominance, or order of injection. These results indicate that impaired memory performance during IAP may reflect severe hippocampal damage and/or epileptogenic abnormality.

Evoked response and after-discharge thresholds to electrical stimulation in temporal lobe epileptics.

The records of electrical stimulation of 30 psychomotor epileptics were examined for threshold levels of evoked responses and after-discharge production. Comparisons were made between anatomical sites, operated and nonoperated structures, and different disease states. It was found that patients with hippocampal sclerosis (HS) had higher thresholds in structures on the operated side. The patients with lesions other than HS were found to differ from those with hippocampal sclerosis in that there were no differences found between their diseased and nondiseased structures. For both patient groups, the amygdala had a much higher threshold for after-discharge production than either the hippocampus or the hippocampal gyrus.

Human brain binding of phenytoin.

Human brain tissue from nine patients (eight biopsy, one autopsy) was investigated for 3H-phenytoin-binding activity. Protein-related binding was determined by ultrafiltration and was found to resemble experimental animal tissue binding. Phenytoin binding was enhanced by prior lipid removal. Human brain lipid also interacted with 3H-phenytoin as measured by a partition coefficient technique employing hexane. Both human protein and lipid were quantitatively less active than in animals. Measurement of brain, serum, and CSF levels of phenytoin in six patients showed that brain levels were 4 to 10 times higher than free drug as measured in the CSF. It is concluded that under usual clinical circumstances, human brain accumulates phenytoin against a concentration gradient; the accumulative process may be due to binding of phenytoin to tissue proteins and phospholipids.

The magnetic field of epileptic spikes agrees with intracranial localizations in complex partial epilepsy.

The magnetoencephalogram (MEG) and electroencephalogram (EEG) were measured during interictal epileptic spikes in nine patients with complex partial seizures. The MEG localization estimates were compared with localizations by intraoperative cortical electrodes, subdural electrodes, stereotaxic depth electrodes, anatomic imaging, postoperative pathologic analysis, and postoperative follow-up. In all patients, MEG localization estimates were in the same lobe as the epileptic focus determined by invasive methods and EEG. In two patients, it was possible to quantify precisely the accuracy of MEG localization by mapping a spike focus that was visually indistinguishable on MEG and cortical recordings. In both patients, MEG localization was approximately 12 mm from the center of the cortical spike focus on intracranial recordings. In eight patients, MEG showed tangential dipolar field patterns on the spontaneous record, but EEG did not. In one patient, a cortical epileptic discharge was detected only on MEG for some discharges and only on EEG for other discharges. The MEG did not detect deep spikes with present levels of environmental noise.

Ictal localization of temporal lobe seizures with scalp/sphenoidal recordings.

We assessed the reliability and accuracy of scalp/sphenodial recordings for ictal localization by retrospectively analyzing 706 noninvasive ictal recordings from 110 patients who subsequently underwent stereoencephalographic evaluation. Strictly defined unilateral temporal/sphenoidal ictal patterns correctly predicted findings of depth electrode examination in 82 to 94% of cases. These strictly defined predictive patterns could be detected with excellent interrater reliability. The patterns are misleading in only a minority of cases, but cannot be used in isolation for definite ictal localization.

The magnetic and electric fields agree with intracranial localizations of somatosensory cortex.

We measured the magnetoencephalogram (MEG), electroencephalogram (EEG), and electrocorticogram (ECoG) after stimulation of contralateral median nerve in four patients with partial epilepsy evaluated for surgery. Quantitative localization estimates from equivalent source modeling were compared with locations of central fissure in hand sensorimotor area determined by cortical stimulations, intraoperative photographs, and examination after excision in frontal lobe. We also measured MEG and EEG in nine control subjects. MEG and EEG localizations were within 2.5 cm of the estimated location of central fissure in all 13 subjects. In the three patients who had complete mapping of all three fields, the average distance of localizations from central fissure was approximately 4 mm in both MEG and EEG, 3 mm in ECoG, and 3 mm in combined MEG and EEG. MEG was simpler than EEG, which was simpler than ECoG. MEG resolved ambiguities in both EEG and ECoG. The combination of the three fields added information about the spatiotemporal activity of somatosensory cortex. Localization of central fissure was essential to surgical treatment.

Focal functional anatomy of dorsolateral frontocentral seizures.

We compared 6 patients with dorsolateral frontocentral seizures to 7 patients with temporal lobe seizures. We determined general seizure location by structural lesions in 7 patients, bilateral depth electrodes in 4, and EEG and semiology in 2. We then mapped seizure cortex and essential cortex using chronic ECoG arrays. Two ECoG patterns were similar in frontal and temporal seizures. Focal patterns were near lesions and resections. Regional patterns were distant from lesions but not associated with worse surgical outcome. "Dipolar" seizure patterns occurred in one-half of frontal patients with maps like somatosensory evoked responses, consistent with focal seizure anatomy and involvement of sensorimotor cortex. Dipole location estimates were near centers of seizure cortex determined by lesions, semiology, and outcome. Six temporal patients had focal excisions that gave significant seizure reduction in all. All frontocentral patients had focal excisions that significantly reduced seizures except in 1 patient with progressive disease. We conclude that dorsolateral frontocentral seizures have focal functional anatomy that can be predicted by ictal ECoG.

An ear asymmetry for gap detection following anterior temporal lobectomy.

A threshold elevation in the performance of auditory temporal order judgment in man has been reported in the ear contralateral to the side of an anterior temporal lobectomy. On the basis of temporal order judgments alone it is not possible to determine whether the deficit is attributable to an impairment of recognition, identification, or temporal resolution. The present monaural experiments compared the performance of the two ears in the detection of a gap in a broad-band noise burst in normal and temporal lobectomized subjects. The results revealed a right-left symmetry in gap detection performance by normal subjects but a significant deficit in gap detection in the ear contralateral to the side of an anterior temporal lobectomy--a finding interpreted as revealing the existence of a bonafide deficit in auditory temporal resolution induced by such resection.

Synaptic reorganization by mossy fibers in human epileptic fascia dentata.

This study was designed to identify whether synaptic reorganizations occur in epileptic human hippocampus which might contribute to feedback excitation. In epileptic hippocampi, (n = 21) reactive synaptogenesis of mossy fibers into the inner molecular layer of the granule cell dendrites was demonstrated at the light microscopic and electron microscopic levels. There was no inner molecular layer staining for mossy fibers in autopsy controls (n = 4) or in controls with neocortex epilepsy having no hippocampal sclerosis (n = 2). Comparing epileptics to controls, there were statistically significant correlations between Timm stain density and hilar cell loss. Since hilar neurons are the origin of ipsilateral projections to the inner molecular layer, this suggests that hilar deafferentation of this dendritic zone precedes mossy fiber reafferentation. Quantitative Timm-stained electron microscopy revealed large, zinc-labelled vesicles in terminals with asymmetric synapses on dendrites in the inner molecular and granule cell layers. Terminals in the middle and outer molecular layers did not contain zinc, were smaller and had smaller vesicles. These histochemical and ultrastructural data suggest that in damaged human epileptic hippocampus, mossy fiber reactive synaptogenesis may result in monosynaptic recurrent excitation of granule cells that could contribute to focal seizure onsets.

Activity of human hippocampal formation and amygdala neurons during sleep.

Fine wire microelectrodes were implanted for diagnostic purposes in 17 patients suffering from psychomotor epilepsy. Single- and multiunit activity during waking and natural nocturnal slow wave sleep and REM sleep was recorded in the hippocampus (n = 42), hippocampal gyrus (n = 53), and amygdala (n = 32). The firing rates of hippocampal gyrus units usually decreased during slow wave sleep and then increased to levels equal to or above waking during REM. In contrast, the firing rates of hippocampal neurons generally increased during slow wave sleep and fell to very low levels during REM. The amygdala presented a more mixed pattern. Since the projection from the hippocampal gyrus to hippocampus is excitatory, their opposite patterns during sleep suggest that the tonic firing patterns of HC neurons may be mainly the result of subcortical afferents.

Vasoactive intestinal peptide in cerebrospinal fluid.

Immunoreactive vasoactive intestinal peptide (VIP) was measured in lumbar and ventricular cerebrospinal fluid (CSF) from patients with various neurological disorders and in 2 hour aliquots of cisternal fluid removed continuously from rhesus monkeys. Although most of the VIP in concentrated pools of human ventricular fluid and of monkey cisternal fluid co-eluted with synthetic porcine VIP28 on a column of Sephadex G-25 superfine, there was evidence that smaller immunoreactive fragments were also present. A circadian pattern of CSF VIP concentration was observed in 2 of the 3 monkeys studied, with highest levels occurring at night and lowest during the day. Ventricular fluid VIP levels were highest in hydrocephalic children and lowest in patients with multiple sclerosis or epilepsy, while VIP was not detectable in ventricular fluid from patients in coma following a severe head injury. There were no significant differences in VIP concentrations in CSF from patients with dystonia. Parkinson's disease, or Alzheimer's disease, suggesting that VIP containing neurons are not affected in these disorders. Lumbar fluid VIP levels were low in patients undergoing aneurysm surgery. Since VIP is a potent vasodilator, these findings may have important implications in relation to the development of vasospasm following subarachnoid hemorrhage.

Neurons in the human basolateral amygdala and hippocampal formation do not respond to odors.

Extracellular action potentials were recorded from human hippocampal, hippocampal gyrus, and basolateral amygdala neurons during passive and active olfactory stimulation. Introduction of an odor into a continuous stream of air passing over the olfactory mucosa resulted in no detectable change in firing. Actively sniffing from an odorous flask, whether or not the odor was detected or recognized, also failed to elicit an immediate unit response. However, after a latency of 10-15 sec, the slight hyperventilation inherent in sniffing did induce a strong change in firing by many neurons. In contrast to these unit responses, a short-latency EEG spindle was recorded in the amygdala that appeared directly related to mechanical stimulation of the olfactory mucosa.

Olfactory memory in patients with anterior temporal lobectomy.

Right and left temporal lobectomy patients, matched in age and intelligence, made more errors in odor recall than a control group. Patients with right temporal lobe excisions recalled significantly fewer odors correctly than patients with left temporal lobe excisions. Olfactory memory scores were not related to other memory deficits associated with left or right temporal lobe dysfunction or to intelligence or lesion size. However, in patients with right temporal lobectomy, percent of odors recalled correctly correlated positively with a general memory index. The findings presented are consistent with previous reports that the right temporal lobe is more involved with nonverbal memory than the left temporal lobe.

Stereotactic investigation of limbic epilepsy using a multimodal image analysis system. Technical note.

A methodology has been developed for stereotactic investigation of limbic epilepsy using an image-analysis system that simultaneously displays different structural and functional images of the brain. The validity and accuracy of this system were established with phantom studies. Surgical planning and electrode implantation are guided by stereotactic magnetic resonance imaging, digital subtraction angiography, and position emission tomography. This methodology provides the spatiotemporal relationship of cerebral structure and function necessary to identify seizure onset and propagation in human limbic system epilepsy.

Electrophysiological studies of long-term electrical stimulation of the cerebellum in monkeys.

Six rhesus monkeys were stimulated on the paravermal cortex for 205 hours (18 days) with different charge densities in order to determine the electrode performance and neural damage that may result from long-term cerebellar stimulation comparable to that being used in man. The electrode-tissue interface was relatively stable and no neural damage was found when the charge/phase (0.5 muC/ph) or charge density (7.4 muC/sq cm/ph) was very low. At all higher charge levels tested (2.4, 4.8, 10, and 22 muC/ph), changes in the electrode-tissue interface, meningeal encapsulation, and neural damage were directly related to the charge density delivered. Unstimulated electrodes on the opposite paravermal cortex exhibited mild tissue reactivity and cell damage, probably due to mechanical compression of the molecular layer and pial vessels. Motor cortex field potentials could be evoked by charges as low as 0.1 muC/ph delivered to paravermal cortex; for a given charge/phase longer pulses were more effective than short pulses. After neural damage resulting from 205 hours of 4.8 muC pulses at 10 per second (total charge 14.76 C), the threshold for the motor cortex evoked potential increased by a factor of four or more. With the charge held constant to different-sized electrodes placed bilaterally in the same monkey, damage was greater under the smaller electtrode. This finding suggests that the charge density to cerebellar cortex must be controlled to avoid neural damage.

Tissue reactions to long-term electrical stimulation of the cerebellum in monkeys.

Light and electron microscopic analyses were carried out on the stimulated and unstimulated paravermal cortices of six rhesus monkeys that had electrodes implanted on their cerebella for 2 months. The electrodes and the stimulation regime (10 p.p.s.: 8 min on, 8 min off) were similar to those used to stimulate the human cerebellum for treatment of certain neurological disorders. Mere presence of the electrode array in the posterior fossa for 2 months resulted in some meningeal thickening, attenuation of the molecular layer, and loss of Purkinje cells immediately beneath the electrode array. There was no evidence of scarring. After 205 hours of stimulation (7.35 X 10(6) pulses) over 18 days, a charge of 0.5 muC/ph or estimated charge density of 7.4 muC/sq cm/ph resulted in no damage to the cerebellum attributable to electrical stimulation per se. Such a charge/phase is about five times the threshold for evocation of cerebellar efferent activity, and might be considered "safe" for stimulation of human cerebellum. Charge density/phase and charge/phase were directly related to increased cerebellar injury in the six other cerebellar cortices stimulated. Leptomeningeal thickening increased with increased charge density. Injury included severe molecular layer attenuation, ongoing destruction of Purkinje cells, gliosis, ongoing degeneration of myelinated axons, collagen intrusion, and increased levels of local polysaccharides. In all cases, even with damage that destroyed all conducting elements beneath the electrodes, there was no damage further than 1 to 2 mm from the edges of the electrode arrays.