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T L Babb

Publications and source records attributed to T L Babb.

At least 55 records · Page 3Linked to original sources

Hippocampal neuron loss and memory scores before and after temporal lobe surgery for epilepsy.

OBJECTIVE: To assess the relationship of hippocampal neuron loss to intellectual and memory measures before and after temporal lobe surgery. DESIGN: Pyramidal cell loss, as determined on the resected tissue, of hippocampal subregion CA1 correlated highest with other subregional cell loss and thus was used as the primary indicator of hippocampal neuron loss. Groups of patients with left and right temporal lobe seizures were subdivided according to degree of CA1 neuron loss. Behavioral performances of patient groups were compared before and after surgery. SETTING: Patient data were obtained from a university program of surgery for epilepsy. CASES: Twenty-five patients who had intractable epilepsy. MAIN OUTCOME MEASURES: Wechsler Adult Intelligence Scale IQ scores, verbal and nonverbal memory measures adapted from the Wechsler Memory Scale, and the Rey-Osterrieth recall score. RESULTS: Degree of hippocampal cell loss selectively related to learning of unrelated word pairs, both preoperatively and postoperatively, in patients with left but not right temporal lobe seizures. Patients with severe loss of left hippocampal neurons performed worse than those with mild-moderate neuron loss both before and after surgery. Immediate recall of logical prose did not relate to hippocampal neuron loss, although scores decreased following left temporal lobe surgery. CONCLUSION: These findings support a role for the left hippocampus in rote verbal memory, ie, learning of unrelated word pairs. Semantically complex verbal learning, ie, recall of logical prose, is more dependent on extrahippocampal temporal lobe regions. Finally, patients with severe as compared with minimal left hippocampal neuron loss may be at risk for lower memory functioning postoperatively.

Adult↗

Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model.

Previously, Mathern et al. (1992) demonstrated progressive mossy fiber (MF) sprouting in the intrahippocampal rat kainate seizure model. This study looked at the time course of EEG hyperexcitability and spontaneous seizure activity in the same in vivo model to determine if seizures were associated with MF sprouting. Results showed that animals progressed through 4 distinct EEG and behavioral phases and that in the chronic phase (greater than 90 days post kainate) MF sprouting was strongly associated with hippocampal epileptogenesis. Progressive MF sprouting into the inner molecular layer (IML) of the fascia dentata paralleled the EEG and behavioral appearance of independent hippocampal interictal epileptiform transients and chronic seizures. Hippocampi from chronic animals that demonstrated unilateral MF IML sprouting were observed to have interictal epileptiform transients and spontaneous seizures that lateralized to the hippocampus with synaptically reorganized MFs. Chronic animals with bilateral MF sprouting were observed to have bilateral independent EEG and behavioral hyperexcitability. Control animals and kainate treated animals that lacked hippocampal cell loss and MF sprouting did not show signs of chronic hippocampal EEG hyperexcitability or chronic seizures. These data support the idea that MF sprouting contributes to chronic hippocampal seizures by feedback excitation which leads to the excitability and synchronization required for a damaged hippocampus to become an epileptic focus.

Animals↗

Single mossy fiber axonal systems of human dentate granule cells studied in hippocampal slices from patients with temporal lobe epilepsy.

Previous histological and immunocytochemical studies suggest that reorganization of the dentate granule cell axons, the mossy fibers, can occur in epileptic human hippocampus (Sutula et al., 1989; Houser et al., 1990; Babb et al., 1991) and in animal models of epilepsy (Tauck and Nadler, 1985; Sutula et al., 1988; Cronin et al., 1992). However, neuroanatomical analyses of the trajectory and morphology of reorganized axons are not yet available. The present study was conducted to investigate single dentate granule cell axonal systems in human epileptic hippocampus. Individual mossy fibers were directly visualized by injecting a tracer (biocytin or Lucifer yellow) intracellularly in hippocampal slices prepared from temporal lobes that were surgically removed from patients for treatment of intractable epilepsy. Two major arborization patterns were identified: (1) the parent axons extended to and coursed through the hilus toward CA3, leaving collaterals along their paths in the hilus (N = 19 neurons); (2) in addition to the aforementioned axonal system, collateral(s) branched from the parent axon near the soma and projected to the granule cell layer and molecular layer, forming an aberrant axonal pathway (N = 9 neurons). These aberrant collaterals bore large boutons similar to those of the hilar axons and formed extensive plexuses in the granule cell layer and/or in the molecular layer. The summed length of collaterals in the granular/molecular layers was 1110.8 microns on average, which was one-fourth of the total summed length of the mossy fibers (3698.5 microns on average). The size of the somata in neurons that had aberrant collaterals was significantly larger than that of neurons without such collaterals (p < 0.025). In four cases, filopodium-like fine processes were present near the axon hillock and proximal parts of the parent axon, suggesting that the aberrant collateral formation might be an ongoing process in these tissues. The lack of control slices from normal living human hippocampus makes it difficult to assess to what extent the present findings are epilepsy associated. However, the presence of aberrant mossy fiber collaterals in the hippocampi used in the present study has been confirmed by Timm's staining and/or dynorphin immunohistochemistry in comparison with nonepileptic autopsy material, indicating its relation to epilepsy (Babb et al., 1991, 1992). At present, there seems to be a consensus that the projection of mossy fiber collaterals to the supragranular layer is a rare occurrence in normal rats (Lorento de Nó, 1934; Claiborne et al., 1986; Seress et al., 1991; present study), normal monkeys (Seress et al., 1991), and normal humans (Houser et al., 1990).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Seizure outcome following standard temporal lobectomy: correlation with hippocampal neuron loss and extrahippocampal pathology.

The authors reviewed 149 patients who underwent standard anterior temporal lobectomies for intractable complex partial epilepsy with a mean follow-up period of 5 years. Quantitative analyses of hippocampal neuron loss showed that all patients had some cell loss compared to control hippocampi obtained at autopsy. The average hippocampal cell loss was categorized as severe (greater than 30% of autopsy control levels) or mild. Analysis of hippocampal and extrahippocampal pathologies showed that in 109 cases (73%, the hippocampal lesion group) hippocampal cell loss was mild in 17 cases (16%) and severe in 92 cases (84%); in the remaining 40 cases (27%, the extrahippocampal structural lesion group) hippocampal cell loss was mild in 24 cases (60%) and severe in 16 (40%). The first index of surgical outcome was worthwhile seizure reduction, which occurred in 94 cases (86%) with mild or severe hippocampal lesions and in 33 cases (82%) with extrahippocampal pathology. In the hippocampal lesion group, worthwhile seizure reduction occurred in 90% of cases with severe and in only 65% of cases with mild hippocampal cell loss (p = 0.015). In the extrahippocampal pathology group, worthwhile seizure was not statistically different, whether hippocampal cell loss was severe (94% of cases) or mild (75% of cases). The second index of surgical outcome was the occurrence of residual seizures in the patients with worthwhile seizure reduction, which would indicate remaining epileptogenic tissue. In the hippocampal lesion group, the incidence of residual seizures was not statistically different whether hippocampal cell loss was severe (24% of cases) or mild (45% of cases). However, in the extrahippocampal pathology group, residual seizures occurred in 53% of cases with severe cell loss (dual pathology) but in only 11% of cases with mild cell loss (p = 0.025). Worthwhile seizure reduction can be predicted by the presence of either severe hippocampal cell loss or an extrahippocampal structural lesion. However, residual seizures more frequently follow in cases with a combination of both (extrahippocampal pathology associated with severe hippocampal cell loss, or dual pathology), suggesting that epileptogenic tissue more likely extends outside the boundaries of a standard temporal lobectomy.

Adult↗

Functional connections in the human temporal lobe. II. Evidence for a loss of functional linkage between contralateral limbic structures.

In a previous investigation of functional limbic pathways in the human mesial temporal lobe, we found evidence for strong connections between ipsilateral mesial temporal structures, but none for contralateral functional connections (Wilson et al. 1990). In the present study, we focused specifically upon the question of functional commissural linkages between these structures by systematic stimulation of a total of 390 electrode placements in 74 epileptic patients with temporal lobe depth electrodes implanted for surgical diagnosis. Eight standard electrode placement regions were targeted: amygdala, entorhinal cortex, anterior, middle and posterior hippocampus, subicular cortex, middle parahippocampal gyrus, and posterior parahippocampal gyrus. Three to six electrodes were implanted bilaterally in each patient, and each electrode was individually stimulated while recording from all the other sites. Out of the 390 electrodes stimulated, 78% were effective in evoking clear responses in adjacent ipsilateral structures, and 75% of 581 ipsilateral recording sites were responsive to stimulation. Only one of the stimulated electrode sites was effective in evoking responses in contralateral recording sites, and only two of 511 contralateral recording sites were responsive to that stimulation. The effective stimulation site was in presubicular cortex, and the responsive contralateral recording sites were in entorhinal and presubicular cortices. Response to this stimulation site was intermittent and variable in latency. The relative ease of obtaining functional verification of significant ipsilateral anatomical pathways in the human limbic system, and the sharply contrasting difficulty of functionally activating commissural pathways to contralateral limbic sites are discussed in the context of decreases in hippocampal contribution to commissural pathways in the primate brain compared to sub-primate mammals, and the significance of this change to normal limbic system function as well as to mechanisms of seizure spread in epilepsy.

Amygdala↗

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.

Animals↗

Physiologic properties of human dentate granule cells in slices prepared from epileptic patients.

The neurophysiological properties of human dentate granule cells were studied in hippocampal slices prepared from patients undergoing surgical treatment for medically intractable temporal lobe epilepsy. In 24 neurons which were morphologically identified as dentate granule cells by intracellular staining with biocytin, there were 2 types of synaptic responses to perforant path stimulation: one showed an EPSP-IPSP sequence (n = 10) and the other showed prolonged EPSPs without accompanying hyperpolarizing IPSPs (n = 14). The prolonged EPSPs were markedly retarded by the application of an NMDA receptor antagonist, APV. Membrane properties of neurons showing the different classes of synaptic responses were similar in resting membrane potential (pooled average: -56.2 mV +/- 0.94 SEM) and spike amplitude (pooled average: 65.2 mV +/- 1.69 SEM). However, membrane resistance tended to be lower in neurons with prolonged EPSPs (31.8 M omega +/- 2.63 SEM) than in neurons that showed EPSP-IPSP responses (40.2 +/- 4.33) (P less than 0.05, Fisher). No spontaneous and/or evoked burst firing was observed. These data provide fuller information on the neurophysiological properties of human dentate granule cells in surgically resected epileptogenic hippocampus, implicating a role of NMDA receptor activation in human temporal lobe epilepsy.

Action Potentials↗

Bilateral pathological damage in temporal lobe epilepsy.

Patients with drug-refractory temporal lobe epilepsy can be treated successfully with surgical resection of one temporal lobe, especially when the resection includes the hippocampus. Although intrahippocampal recordings usually localize seizure onsets to one hippocampus, there are bilaterally-independent interictal spikes, occasional contralateral seizure onsets and post-resection seizures that implicate contralateral damage and epileptogenicity. Post-mortem non-quantified studies of both hippocampi in epileptics have revealed incidences of bilateral hippocampal sclerosis, mostly being asymmetric. The present paper reports on two post-mortem cases of bilateral, asymmetric cell loss in patients with physiologically-verified hippocampal epilepsy. In one patient the damage was severe bilaterally, but only slightly greater damage in one hippocampus. In the second patient, damage in one hippocampus was as severe as in the first patient; however the contralateral hippocampus appeared undamaged. However, cell counts revealed losses of over 30% in three different hippocampal subregions, indicating a mild form of asymmetric bilateral damage in patient two.

Adult↗

Surgical treatment of limbic epilepsy associated with extrahippocampal lesions: the problem of dual pathology.

The authors present their review of 178 patients who underwent en bloc temporal lobectomies as surgical treatment for intractable epilepsy. Hippocampal cell density was quantitatively analyzed and the histology of the anterior temporal lobe was reviewed. Fifty-four patients (30.3%) had evidence of extrahippocampal lesions in addition to neuronal cell loss within the hippocampus (the dual pathology group). The pattern of cell loss was analyzed in the remaining 124 cases (69.7%) with no extrahippocampal pathology, and compared with that of the dual pathology group and a control group of four nonepileptic patients. Hippocampal cell loss was found in almost all epileptic patients compared to the control group. Severe cell loss greater than 30% of control values was found in 88.7% of patients without extrahippocampal lesions, but in only 51.8% of patients with dual pathology. The difference between these two groups was statistically significant (p less than 0.001). In the dual pathology group, lesions of different pathology had a significant relationship with the degree of hippocampal cell loss: all 12 patients with glioma had mild cell loss, whereas all 13 patients with heterotopia were associated with severe cell loss. Severity of hippocampal cell loss was also analyzed in relation to seizure history: a prior severe head injury was associated with severe cell loss. Other factors such as seizure duration, secondary generalization, or family history of seizures were not associated with hippocampal damage. Dual pathology may produce a combination of neocortical and temporolimbic epilepsies that warrants a precise definition of the true epileptogenic area prior to surgical treatment.

Adolescent↗

Functional connections in the human temporal lobe. I. Analysis of limbic system pathways using neuronal responses evoked by electrical stimulation.

Connections in the human mesial temporal lobe were investigated using brief, single pulses of electrical stimulation to evoke field potential responses in limbic structures of 74 epileptic patients. Eight specific areas within these structures were stereotactically targeted for study, including amygdala, entorhinal cortex, presubiculum, the anterior, middle and posterior levels of hippocampus and the middle and posterior levels of parahippocampal gyrus. These sites were studied systematically in order to quantitatively assess the response characteristics and reliability of responses evoked during stimulation of pathways connecting the areas. Specific measures included response probability, amplitude, latency and conduction velocities. The results are assumed to be representative of typical human limbic pathways since all recordings were made interictally and response probabilities across sites were not found to differ significantly between non-epileptogenic vs. identified epileptogenic regions. Field potentials ranging in amplitude from less than 0.1 to greater than 6.0 mV were evoked ipsilaterally, with mean onset latencies and conduction velocities ranging from 4.4 ms and 3.64 m/s in the perforant pathway connecting entorhinal cortex to anterior hippocampus to 24.8 ms and 0.88 m/s in the pathway connecting the amygdala and middle hippocampus. Stimulation of presubiculum and entorhinal cortex were most effective in evoking widespread responses in adjacent limbic recording sites, whereas posterior parahippocampal gyrus appeared functionally separated from other limbic sites since its probability of influencing ipsilateral sites was significantly lower than any other area. It was particularly noteworthy that stimulation did not evoke responses in any sites in contralateral hippocampal formation; even though a large number of sites were tested with bilateral implantation of homotopic electrodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

Sprouting of GABAergic and mossy fiber axons in dentate gyrus following intrahippocampal kainate in the rat.

The present study examined the bilateral synaptic rearrangements of presumed gamma-aminobutyric acid (GABAergic) inhibitory axons and mossy fiber (presumed excitatory) recurrent collaterals following intrahippocampal kainic acid (KA) injection. Glutamate decarboxylase immunoreactivity (GAD-IR) was used to study inhibitory axon terminal sprouting, following 0.5 microgram KA/0.2 microliter injected unilaterally into the posterior hippocampus of rats (n = 16), with survival periods of 14, 28, and 120 days. The age-matched control animals (n = 9) received intrahippocampal 0.2 microliter saline (sham, n = 4) or no injection (normal, n = 5). To study mossy fiber synaptic rearrangements, 0.5 microgram KA/0.2 microliter volumes were injected unilaterally into the posterior hippocampus of rats (n = 10), with survival periods from 14, 28, and 120 days, and Timm sulfide-stained tissue sections were compared to age-matched sham (n = 4) or normal controls (n = 4). At 14 through 120 days after posterior KA injection, GAD-IR puncta were significantly increased in the ipsi- and contralateral inner molecular layers (IML) of the fascia dentata (FD) when compared to sham or normal controls. KA lesion also induced mossy fiber recurrent collateral sprouting into the ipsi- and contralateral FD IMLs. The loss of both the commissural and ipsilateral associational afferents to the FD apparently induced sprouting into their ipsi- and contralateral termination zones by granule cell mossy fibers and GAD-IR axons, thus establishing an abnormal circuitry near the observed pathology in the kainate model of epilepsy. Although reactive synaptogenesis of mossy fibers producing monosynaptic excitation may be one mechanism for KA epileptogenicity, the concurrent sprouting of GABAergic terminals in the same IML zone of the FD suggests that anomalous inhibitory synapses may contribute to chronic KA hippocampal hyperexcitability.

Animals↗

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.

Adult↗

Surgical treatment of epilepsy: opportunities for research into basic mechanisms of human brain function.

Numerous technological developments in neurology have increased the ability to localize structural and functional abnormalities within the human brain. Such techniques have contributed to a renewed interest in resective surgical treatment for medically refractory partial seizures. Enhanced capacity to carry out detailed in vivo and in vitro measurements of neuronal activity in patients, during the course of presurgical evaluation and following surgical resection, now offers unprecedented opportunities for invasive research into normal and abnormal human cerebral function. Electrophysiological, microanatomical, biochemical and behavioral studies can be carried out without presenting undue risk or discomfort to the patient. Such research in a clinical setting presents difficulties in experimental design for the basic neuroscientist. Problems are reduced in clinical programs where diagnostic and surgical procedures are carried out in a standardized fashion according to specific protocols. The UCLA clinical protocol for anterior temporal lobectomy, based on presurgical evaluation with stereotactically implanted depth electrodes, is particularly amenable to the integration of basic research projects. This protocol and related ongoing research projects are described.

Brain Mapping↗

Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus.

The present study was designed to determine whether inhibitory neurons in human epileptic hippocampus are reduced in number, which could reduce inhibition on principal cells and thereby be a basis for seizure susceptibility. We studied the distribution of GABA neurons and puncta by using glutamate decarboxylase (GAD) immunocytochemistry (ICC) together with Nissl stains. Using quantitative comparisons of GAD-immunoreactive (GAD-IR) neurons and puncta in human epileptic hippocampus and in the normal monkey hippocampus, we found that GAD-IR neurons and puncta are relatively unaffected by the hippocampal sclerosis typical of hippocampal epilepsy where 50-90% of principal (non-GAD-IR) cells are lost. GAD-IR neurons and puncta were not significantly decreased compared with normal monkey. In 6 patients, prior in vivo electrophysiology demonstrated that the anterior hippocampus generated all seizures. The anterior and posterior hippocampus were processed simultaneously, and the counts of hippocampal GAD-IR neurons were numerically greater in anterior than in the posterior hippocampus, where no seizures were initiated. These results indicate that GABA neurons are intact in sclerotic and epileptogenic hippocampus. Computerized image analysis of puncta densities in fascia dentata, Ammon's horn, and subicular complex in epileptic hippocampi (n = 7) were not different from puncta densities in the same regions in normal monkey (n = 2). Hence, despite the significant loss of principal cells (50-90% loss) GABA terminals (GAD-IR puncta) were normal, which suggests GABA hyperinnervation of the remnant pyramidal cells and/or dendrites in human epileptic hippocampus. The apparent increase in puncta ranged from 2 (fascia dentata) to 3.3 (CA1) times normal puncta densities. These findings would suggest increased inhibition and less excitability; however, those regions were epileptogenic. We suggest that GABA terminal sprouting or hyperinnervation of the few remnant projection cells may serve to synchronize their membrane potentials so that subsequent excitatory inputs will trigger a larger population of neurons for seizure onset in the hippocampus and propagation out to undamaged regions of subiculum and neocortex.

Animals↗