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Biomedical subjects

D D Spencer

Publications and source records attributed to D D Spencer.

At least 19 recordsLinked to original sources
PubMed1995

Vasoactive intestinal polypeptide and its receptor changes in human temporal lobe epilepsy.

The distribution of the VIP receptor in the human hippocampus was studied by receptor autoradiography using [3-iodotyrosyl-125I]Vasoactive Intestinal Peptide (VIP) as a ligand, and the relationship of receptor distribution to the distribution of the peptide (visualized by immunocytochemistry) was examined in hippocampi surgically removed from patients with medically intractable temporal lobe epilepsy (TLE) and hippocampi obtained at autopsy from neurologically normal subjects. In the autopsy hippocampi and hippocampi from TLE patients with extrahippocampal temporal lobe lesions [125I]VIP binding was highest in the dentate molecular layer, with lower levels in the fields of Ammon's Horn (CA fields) and the subiculum. In hippocampi from patients with no temporal lobe lesions but considerable hippocampal neuronal loss there were significant elevations in the levels of ligand binding in all CA fields and the subiculum. Ligand binding densities in all CA fields of the patient hippocampi were strongly negatively correlated with neuronal numbers. Immunocytochemical localization of VIP shows no obvious change in the distribution patters of VIP immunoreactivity in the patient groups. This is the first demonstration of VIP and its receptor distribution in the human hippocampus. It is suggested that the elevated levels of receptor binding in the hippocampal seizure focus may indicate a mechanism for greater excitability of neurons and/or for their survivability in the face of the increased excitation and potential for injury in a seizure focus.

Adolescent↗
PubMed1995

Hippocampal GABA transporter function in temporal-lobe epilepsy.

Electrophysiological studies of human temporal-lobe epilepsy suggest that a loss of hippocampal GABA-mediated inhibition may underlie the neuronal hyperexcitability. However, GABA (gamma-aminobutyric acid)-containing cells are preserved and GABA receptors are maintained in the surviving hippocampal neurons. Diminished GABA release may therefore mediate the loss of inhibition. Here we show that, in the human brain, potassium-stimulated release of GABA was increased, and glutamate-induced, calcium-independent release of GABA was markedly decreased, in epileptogenic hippocampi, in contrast with contralateral, non-epileptogenic hippocampi. The glutamate-induced GABA release in vivo was transporter-mediated in rats. Furthermore, in amygdala-kindled rats, a model for human epilepsy, a decrease in glutamate-induced GABA release was associated with a 48% decrease in the number of GABA transporters. These data suggest that temporal-lobe epilepsy is characterized in part by a loss of glutamate-stimulated GABA release that is secondary to a reduction in the number of GABA transporters.

Amygdala↗
PubMed1995

Significance of spikes recorded on electrocorticography in nonlesional medial temporal lobe epilepsy.

Whether spikes recorded by intraoperative electrocorticography imply active epileptogenicity has not been adequately addressed. We performed preresection and postresection electrocorticography on 47 patients with nonlesional medial temporal lobe epilepsy who were undergoing surgery for the treatment of medically refractory epilepsy. A standard anteromedial temporal lobectomy was performed on all patients, with no additional resection, regardless of electrocorticographic findings. Patients were divided into two groups: Group I (no seizures or rare seizures) and Group II (recurrent seizures). Recorded spikes were analyzed for distribution and spike discharge rate. On preresection electrocorticography, 83% of Group I and 82% of Group II had spikes in the anterior temporal lobe. The spike discharge rate was equally distributed between high frequency and low frequency for both groups (not significant). Although spikes localized to the posterior temporal neocortex were seen more in Group II (64%) than Group I (39%), this was not a significant difference (p > 0.1). Most of these patients had a low-frequency spike discharge rate. On postresection electrocorticography, 80% of Group I and 75% of Group II had residual spikes. The majority of these had a low-frequency spike discharge rate and were localized to the margin of resection. We found no correlation between residual spikes on preresection and postresection electrocorticography and outcome. These findings do not support the role of intraoperative electrocorticography in guiding mesial temporal lobe resection.

Adolescent↗
PubMed1995

Depth electrode studies and intracellular dentate granule cell recordings in temporal lobe epilepsy.

Hippocampal depth electrodes are often used to localize seizure onset in patients who may have temporal lobe epilepsy (TLE). A number of features of the spontaneous seizures and of their ictal onset patterns can be analyzed from these recordings. We compared a number of the typical electroencephalographic (EEG) changes at seizure onset with several cellular parameters recorded in dentate granule cells from the same 14 patients diagnosed with medial temporal sclerosis (MTS) to examine the pathophysiological correlates of this spontaneous EEG activity in this form of TLE. The intracellularly recorded parameters include the propensity to fire evoked epileptiform bursts, the absence of evoked inhibitory potentials, the presence of polysynaptic excitatory postsynaptic potentials, and the presence of spontaneous excitatory activity. We noted several correlations between the EEG data and the intracellular recordings. The absence of synaptically evoked bursts was correlated with the presence of low-voltage fast activity at seizure onset. In addition, the loss of inhibitory postsynaptic potentials was correlated with the presence of periodic spiking pre-ictally. Several other correlations were also noted. These data indicate that EEG findings may be predictive of anatomical and cellular pathological changes and provide clues to the physiological mechanisms involved in this form of epilepsy.

Action Potentials↗
PubMed1995

Regional distributions of hippocampal Na+,K(+)-ATPase, cytochrome oxidase, and total protein in temporal lobe epilepsy.

Na+,K(+)-ATPase (the sodium pump) is a ubiquitous enzyme that consumes ATP to maintain an adequate neuronal transmembrane electrical potential necessary for brain function and to dissipate ionic transients. Reductions in sodium pump function augment the sensitivity of neurons to glutamate, increasing excitability and neuronal damage in vitro. Temporal lobe epilepsy (TLE) is one disease characterized by hyperexcitability and marked hippocampal neuronal losses that could depend in part, on impaired sodium pump capacity secondary to changes in sodium pump levels and/or insufficient ATP supply. To assess whether abnormalities in the sodium pump occur in this disease, we used [3H]ouabain to determine the density of Na+,K(+)-ATPase for each anatomic region of hippocampus by in vitro autoradiography. Tissues were surgically obtained from epileptic patients with hippocampal sclerosis and compared with specimens from patients with seizures originating from temporal lobe tumors and autopsy controls. Changes in cellular population arising from neuronal losses or gliosis were assessed by protein densities derived from quantitative computerized densitometry of Coomassie-stained tissue sections. We estimated regional differences in capacity for ATP generation by determining cytochrome c oxidase (CO) activity. Principal neurons of hippocampus exhibit high levels of sodium pump enzyme. Both epilepsy groups exhibited slight but significant increases in sodium pump density/unit mass of protein in the dentate molecular layer, CA2, and subiculum as compared with autopsy controls. Greater hilar sodium pump density was also observed in sclerotic hippocampi. In contrast, CO activity was reduced in both epilepsy types throughout hippocampus. Results suggest that although sodium pump protein in surviving neurons appears to be upregulated in epilepsy, sodium pump capacity may be limited by the reduced levels of CO activity. Functional reduction in sodium pump capacity may be an important factor in hyperexcitability and neuronal death.

Autoradiography↗
PubMed1995

Wada memory disparities predict seizure laterality and postoperative seizure control.

We examined the efficacy of a memory difference score (DS: right minus left hemisphere memory) during the Wada test (intracarotid amobarbital procedure, IAP) for predicting seizure laterality and postoperative seizure outcome in 70 left speech dominant patients from two epilepsy centers. DS > or = 2, after addition of 1 point to the left hemisphere injection score to account for aphasia, were noted in 71.4% of patients and correctly predicted surgery side for 98.0% of these patients. The DS related significantly to seizure outcome at 1-year follow-up (p < 0.002) and correctly predicted 80% of patients who were seizure-free. Patients whose DS did not correctly predict seizure laterality more frequently required invasive studies to establish seizure onset. The relationship of the DS to laterality did not differ significantly by class of IAP memory stimuli. When seizures originate from the temporal lobe, the IAP memory DS predicts seizure laterality by assessing the functional adequacy of the involved hemisphere and is predictive of seizure control.

Adolescent↗
PubMed1995

Bilateral hippocampal atrophy in medial temporal lobe epilepsy.

Quantitative evidence of hippocampal atrophy has been correlated with site of seizure onset, hippocampal neuronal loss, and seizure relief after resection. Most studies have quantified hippocampal atrophy using ratios or differences between right and left hippocampal values. However, bilateral hippocampal atrophy may remain undetected by these techniques. To assess the frequency and implications of bilateral hippocampal atrophy, we studied absolute hippocampal volumes in 53 temporal lobectomy patients who had undergone intracranial electroencephalogram recordings preoperatively. Coronal images were constructed perpendicular to the longitudinal axis of the hippocampus. Atrophy was defined as > 2 SD below control values in the volume of the posterior 1.5 cm of the hippocampus. Five of 53 patients (9%) had bilateral hippocampal atrophy; four of these cases were undetected by ratios. Surgery was performed on the side of ictal onset in all five patients; four have been seizure-free for > 2 years. These results suggest that (a) mesial temporal sclerosis can be present bilaterally and may go undetected by hippocampal ratio or difference measures; (b) absolute hippocampal volume values as well as ratios are needed to detect all patients with bilateral hippocampal atrophy; and (c) temporal lobectomy is not contraindicated in patients with bilateral hippocampal atrophy, but success depends on electroencephalographic documentation of the side of predominant ictal onset.

Atrophy↗
PubMed1995

Prolonged GABA responses in dentate granule cells in slices isolated from patients with temporal lobe sclerosis.

1. Medial temporal lobe sclerosis is a common pathological finding in patients with medically intractable temporal lobe epilepsy. This disease is characterized by extensive cell loss in the hilus and the hippocampal CA1 and CA3 cell fields in addition to synaptic reorganization throughout the dentate gyrus. 2. The dentate granule cells from hippocampal slices of patients diagnosed with medial temporal lobe sclerosis exhibit reduced synaptic inhibition with concommitant hyperexcitability. These physiological changes were studied relative to the hippocampi of patients with temporal lobe tumors in which the cell loss and synaptic reorganization are not seen. 3. We attempted to determine if this disinhibition was because of changes in the postsynaptic sensitivity to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by studying the responses to exogenously applied transmitter. As in rodents, the GABA responses in human dentate granule cells studied at the resting membrane potential were depolarizing and were mediated primarily by GABAA receptors. In many cases, these depolarizing GABA responses could trigger action potentials. Thus in some situations, GABA could act as an excitatory neurotransmitter. 4. We found that GABAA receptor-mediated responses in the sclerotic hippocampi were approximately 80% longer than in the comparison population. This difference was not because of changes in either the GABA reversal potential or the GABA-induced conductance change. The data support the hypothesis that the GABA transport system is impaired in sclerotic tissue: application of the GABA uptake inhibitor NNC711 (a tiagibine derivative) greatly prolonged the GABA responses in the tumor-related temporal lobe epilepsy tissue, but had little effect on the sclerotic tissue.

Action Potentials↗
PubMed1995

Seizure localization and pathology following head injury in patients with uncontrolled epilepsy.

We studied seizure localization and surgical pathology in 25 patients who developed intractable complex partial seizures following head trauma. All patients underwent an extensive presurgical evaluation that included MRI, neuropsychological evaluation, and surface EEG monitoring, and 21 had intracranial EEG monitoring. Seizures were successfully localized in nine patients; all nine underwent a surgical procedure and are seizure-free. Six of these patients had a mesial temporal lobe seizure focus, of whom five had a pathologic diagnosis of mesial temporal sclerosis. All five patients who developed mesial temporal sclerosis sustained their head injury at or before age 5 years. The three remaining patients whose seizures were successfully localized had neocortical foci and circumscribed radiographic abnormalities, which were presumed to be secondary to head trauma, and all had successful surgical resections of the epileptogenic focus. The remaining 16 patients sustained later trauma, and all had successful surgical resections of the epileptogenic focus. The remaining 16 patients sustained later trauma and did not have a focal MRI lesion, and their seizures were not adequately localized. We conclude that as a group, seizure foci secondary to head trauma are difficult to localize accurately, and this should deter surgical intervention. There was an association between early head injury (ie, at or before age 5 years) and mesial temporal sclerosis, and this association aided seizure localization and successful surgical intervention. Therefore, under the right circumstances, trauma can be a suitable historical element in the profile of patients in whom epilepsy surgery is successful.

Adolescent↗
PubMed1995

The anatomy of epileptic auras: focal pathology and surgical outcome.

An aura is generally understood to be the beginning of a seizure. Yet, following successful surgery for intractable epilepsy, patients may have persistent auras even though they are otherwise seizure free. Ninety patients with intractable seizures and auras underwent resective surgery. Forty-three patients had hippocampal sclerosis and 47 had temporal or extratemporal lesions such as glial tumors or vascular malformations. The semiology of the auras was found to have value in localization but not lateralization of the pathology. Epigastric auras as well as gustatory and olfactory auras were significantly more frequent in patients with hippocampal sclerosis than in those with temporal or extratemporal lesions. Auras of vertigo or dizziness were most frequent in patients with extratemporal pathology. There was a significant difference between the pathology groups in the efficacy of resection in eliminating the auras. Of the patients with hippocampal sclerosis who were rendered seizure free, 18.9% had persistent auras, whereas only one (2.6%) of the patients with temporal or extratemporal lesions who were rendered seizure free had persistent auras. These findings suggest that for patients with hippocampal sclerosis an anatomical dissociation between seizure and aura may occur, whereas this dissociation is not present in patients with lesions. Patients suspected of having hippocampal sclerosis should be counseled preoperatively as to the significant likelihood of persistent auras even if seizures are successfully abolished.

Brain Diseases↗
PubMed1995

Functional magnetic resonance imaging of sensory and motor cortex: comparison with electrophysiological localization.

Functional magnetic resonance (MR) imaging was performed using a 1.5-tesla MR system to localize sensorimotor cortex. Six neurologically normal subjects were studied by means of axial gradient-echo images with a motor task and one or more sensory tasks: 1) electrical stimulation of the median nerve; 2) continuous brushing over the thenar region; and 3) pulsed flow of compressed air over the palm and digits. An increased MR signal was observed in or near the central sulcus, consistent with the location of primary sensory and motor cortex. Four patients were studied using echo planar imaging sequences and motor and sensory tasks. Three patients had focal refractory seizures secondary to a lesion impinging on sensorimotor cortex. Activation seen on functional MR imaging was coextensive with the location of the sensorimotor area determined by evoked potentials and electrical stimulation. Functional MR imaging provides a useful noninvasive method of localization and functional assessment of sensorimotor cortex.

Adult↗
PubMed1995

Impaired fear conditioning following unilateral temporal lobectomy in humans.

Classical fear conditioning was used in the present study as a model for investigating emotional learning and memory in human subjects with lesions to the medial temporal lobe. Animal studies have revealed a critical role for medial temporal lobe structures, particularly the amygdala, in simple and complex associative emotional responding. Whether these structures perform similar functions in humans is unknown. On both simple and conditional discrimination tasks, unilateral temporal lobectomy subjects showed impaired conditioned response acquisition relative to control subjects. This impairment could not be accounted for by deficits in nonassociative sensory or autonomic performance factors, or by differences in declarative memory for the experimental parameters. These results show that temporal lobe structures in humans, as in other mammals, are important components in an emotional memory network.

Adult↗
PubMed1995

Unplanned splenectomy--harbinger of complications.

Splenectomy alone or in combination with other major operative procedures has been implicated as the cause of excessive morbidity and mortality. We retrospectively studied 151 consecutive patients with splenectomy performed between 1985 and 1992. Subsets of patients according to indication for splenectomy were compared with a cohort of patients having elective open cholecystectomy. Morbidity with elective splenectomy (11.5%) was not significantly increased over that with elective open cholecystectomy (6.8%). Morbidity with nonelective splenectomy (40.4%) was increased when compared with that of elective splenectomy (11.5%) or with elective open cholecystectomy (6.8%). Mortality was significantly worse for nonelective (10.6%) than for elective splenectomy (1%). Nonelective splenectomy should be recognized as one event in a cascade of events leading to excessive morbidity and mortality. Splenectomy should not be implicated as the sole or primary cause of such excesses.

Adolescent↗
PubMed1995

Language-related field potentials in the anterior-medial temporal lobe: I. Intracranial distribution and neural generators.

Field potentials were recorded from intracranial electrodes in humans to study language-related processing. Subjects viewed sentences in which each word was presented successively in the center of a video monitor. Half of the sentences ended normally, while the other half ended with a semantically anomalous word. The anomalous sentence-ending words elicited a large negative field potential with a peak latency near 400 msec, which was focally distributed bilaterally in the anterior medial temporal lobe (AMTL), anterior to the hippocampus and near the amygdala. Subdural electrodes positioned near the collateral sulcus just inferior and lateral to the amygdala recorded a positive field potential at the same latency. This spatial distribution of voltage suggested that this language-sensitive field potential was generated in the neocortex near the collateral sulcus and anterior fusiform gyrus. Additional task-related field potentials were recorded in the hippocampus. The AMTL field potential at 400 msec shares characteristics with the N400 potential recorded from scalp electrodes that has been associated with semantic processing.

Action Potentials↗
PubMed1994

Hippocampal resections and the use of human tissue in defining temporal lobe epilepsy syndromes.

From the clinical perspective, a continued analysis of the hippocampus in animal models of epilepsy as well as in human material will be critical to finally understanding MTLE. Through the continued evolution of surgical feedback to our preoperative localization studies, and from our basic science studies on resected tissue, we propose that 1) the hippocampus is critical to developing medial temporal lobe excitability, and that the inhibitory hilar interneurons which suffer most during developmental injury are likely to be involved in this process; 2) the hippocampus is not the only potentially hyperexcitable medial temporal lobe structure, but seems to function (both normally and pathologically) in a recurrent loop consisting of the entorhinal cortex, amygdala, and temporal neocortices; and 3) hypotheses derived from animal model studies, and data obtained directly from analysis of human tissue can be used to refine epilepsy classifications.

Animals↗
PubMed1994

Phenytoin concentrations in the human brain: an in vivo microdialysis study.

We report the first human study of phenytoin concentration using in vivo microdialysis, which permits sampling the extracellular environment of the brain. This technique has been applied to patients undergoing intracranial electrode investigation for intractable epilepsy. By varying the rate of perfusion (from 2.5 to 0.25 microliters/min), it is possible to quantify the concentration of drug in the extracellular fluid (ECF), which reflects the concentration on the outer neuronal cell membrane. Samples were obtained from four catheters in two patients, in whom serum phenytoin (PHT) concentrations were held constant. Unbound serum concentrations were measured following ultrafiltration at 37 degrees C. In one patient, with left and right hippocampal probes, steady state ECF/unbound serum ratios were 87 and 84% respectively. In the second patient, with hippocampal and frontal probes, ECF/unbound serum ratios were 87 and 85% respectively. Flow rate for 50% maximal recovery averaged 1.65 microliters/min (1.5-1.7 microliters/min). We found that steady state ECF PHT concentrations corresponded closely to unbound serum concentrations. No differences are observed between different sites within the brain. Flow rates needed for equilibration of dialysate with the extracellular space were slower than reported for carbamazepine, but faster than those we found for carbamazepine-epoxide and valproate.

Brain↗