Extrahippocampal Temporal Lobe Research Articles

Decreased levels of active uPA and KLK8 assessed by [111 In]MICA-401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy.

Urokinase-type plasminogen activator (uPA) and kallikrein-related peptidase 8 (KLK8) are serine proteases that contribute to extracellular matrix (ECM) remodeling after brain injury. They can be labelled with the novel radiotracer [111 In]MICA-401. As the first step in exploring the applicability of [111 In]MICA-401 in tracing the mechanisms of postinjury ECM reorganization in vivo, we performed in vitro and ex vivo studies, assessing [111 In]MICA-401 distribution in the brain in two animal models: kainic acid-induced status epilepticus (KASE) and controlled cortical impact (CCI)-induced traumatic brain injury (TBI). In the KASE model, in vitro autoradiography with [111 In]MICA-401 was performed at 7 days and 12 weeks post-SE. To assess seizure burden, rats were monitored using video-electroencephalography (EEG) for 1 month before the 12-week time point. In the CCI model, in vitro autoradiography was performed at 4 days and ex vivo autoradiography at 7 days post-TBI. At 7 days post-SE, in vitro autoradiography revealed significantly decreased [111 In]MICA-401 binding in hippocampal CA3 subfield and extrahippocampal temporal lobe (ETL). In the chronic phase, when animals had developed spontaneous seizures, specific binding was decreased in CA3 and CA1/CA2 subfields of hippocampus, dentate gyrus, ETL, and parietal cortex. Of interest, KASE rats with the highest frequency of seizures had the lowest hippocampal [111 In]MICA-401 binding (r = -0.76, p ≤ 0.05). Similarly, at 4 days post-TBI, in vitro [111 In]MICA-401 binding was significantly decreased in medial and lateral perilesional cortex and ipsilateral dentate gyrus. Ex vivo autoradiography at 7 days post-TBI, however, revealed increased tracer uptake in perilesional cortex and hippocampus, which was likely related to tracer leakage due to blood-brain barrier (BBB) disruption. Strong association of reduced [111 In]MICA-401 binding with seizure burden in the KASE model suggests that analysis of reduced levels of active uPA/KLK8 represents a novel biomarker candidate to be explored as a biomarker for epilepsy severity. However, limited BBB permeability of [111 In]MICA-401 currently limits its application in vivo.

Emotional arousal impairs association-memory: Roles of amygdala and hippocampus

Emotional arousal is well-known to enhance memory for individual items or events, whereas it can impair association memory. The neural mechanism of this association memory impairment by emotion is not known: In response to emotionally arousing information, amygdala activity may interfere with hippocampal associative encoding (e.g., via prefrontal cortex). Alternatively, emotional information may be harder to unitize, resulting in reduced availability of extra-hippocampal medial temporal lobe support for emotional than neutral associations. To test these opposing hypotheses, we compared neural processes underlying successful and unsuccessful encoding of emotional and neutral associations. Participants intentionally studied pairs of neutral and negative pictures (Experiments 1–3). We found reduced association-memory for negative pictures in all experiments, accompanied by item-memory increases in Experiment 2. High-resolution fMRI (Experiment 3) indicated that reductions in associative encoding of emotional information are localizable to an area in ventral-lateral amygdala, driven by attentional/salience effects in the central amygdala. Hippocampal activity was similar during both pair types, but a left hippocampal cluster related to successful encoding was observed only for negative pairs. Extra-hippocampal associative memory processes (e.g., unitization) were more effective for neutral than emotional materials. Our findings suggest that reduced emotional association memory is accompanied by increases in activity and functional coupling within the amygdala. This did not disrupt hippocampal association-memory processes, which indeed were critical for successful emotional association memory formation.

T2 relaxometry improves detection of non-sclerotic epileptogenic hippocampus

ObjectThe use of T2 relaxometry was investigated to detect non-sclerotic epileptogenic abnormality of the hippocampus in presurgical evaluation of temporal lobe epilepsy (TLE). MethodsThis prospective study included 30 patients who underwent hippocampectomy as part of surgical treatment of refractory TLE. Ten patients had structural epileptogenic lesions in the extra-hippocampal temporal lobe. Twelve patients underwent intracranial electroencephalography (iEEG) study before surgery. Visual assessment of atrophy and increased T2 signal intensity, volumetry, and T2 relaxometry of hippocampus were performed pre-operatively using 3T magnetic resonance imaging, and compared with the neuropathological findings and iEEG findings. Magnetic resonance imaging of 30 age- and sex-matched healthy controls was used to establish normal values, which were defined as z score within 2. ResultsVisual assessment, volumetry, and T2 relaxometry detected hippocampal abnormalities on the surgical side in 16 (53%), 16 (53%), and 26 (87%) patients, respectively. Hippocampal volume loss was always associated with prolonged T2 relaxation time, and supported by histopathological diagnosis of HS in all cases except one. Hippocampal abnormality was detected only by T2 relaxometry in nine patients (30%). Pathological diagnosis of these cases included mild HS in one, microdysgenesis in one, and granule cell pathology in three. Four patients with normal hippocampal volume and T2 relaxation time had no HS or granule cell pathology. Prolonged T2 relaxation time was associated with medial temporal seizure onset in iEEG (p<0.05). ConclusionsT2 relaxometry improves the detection of non-sclerotic epileptogenic abnormality of the hippocampus.

Hippocampal contributions to recollection in retrograde and anterograde amnesia

Lesions restricted to the hippocampal formation and/or extended hippocampal system (hippocampal formation, fornix, mammillary bodies, and anterior thalamic nuclei) can disrupt conscious recollection in anterograde amnesia, while leaving familiarity-based memory relatively intact. Familiarity may be supported by extra-hippocampal medial temporal lobe (MTL) structures. Within-task dissociations in recognition memory best exemplify this distinction in anterograde amnesia. The authors report for the first time comparable dissociations within recognition memory in retrograde amnesia. An amnesic patient (A.D.) with bilateral fornix and septal nuclei lesions failed to recognize details pertaining to personal past events only when recollection was required, during recognition of episodic details. His intact recognition of generic and semantic details pertaining to the same events was ascribed to intact familiarity processes. Recollective processes in the controls were reflected by asymmetrical Receiver's Operating Characteristic curves, whereas the patient's Receiver's Operating Characteristic was symmetrical, suggesting that his inferior recognition performance on episodic details was reliant on familiarity processes. Anterograde and retrograde memories were equally affected, with no temporal gradient for retrograde memories. By comparison, another amnesic person (K.C.) with extensive MTL damage (involving extra-hippocampal MTL structures in addition to hippocampal and fornix lesions) had very poor recognition and no recollection of either episodic or generic/semantic details. These data suggest that the extended hippocampal system is required to support recollection for both anterograde and retrograde memories, regardless of their age.

Lesión de las cortezas extrahipocampales del lóbulo temporal medial: descripción de un caso

The cortex of medial temporal lobe is a group of different allocortical fields which included the hippocampal formation (dentate gyrus, hippocampus proper, and subicular complex) and extrahippocampal cortices (entorhinal, perirhinal, and parahippocampal). It is widely accepted that both of them play an important role in memory process. In humans, several reports indicates that damage to the hippocampus alone would lead to a clinically significant amnesia; when the injuries are more extensive others cognitive disorders, as those related to visual sphere, make worse the clinic picture, and some of these cases were reported as associative visual agnosias. Nevertheless, although evidence from animal studies points to the importance of the extrahippocampal medial temporal lobe cortices in order to recognise visual stimuli, such involvement has not been demonstrated in humans.A 44 year-old male who consulted us because they had lost about of '80% of his vision' after a stroke. Ophthalmological examination was entirely within normal limits, but neuropsychological test put in evidence difficulties in the visuo-verbal naming, discrimination of superposed images, recognition of faces and, mainly, in the test of immediate and deferred visual memory. Anterograde memory impairment was also revealed. Magnetic resonance imaging showed a lesion of left entorhinal, perirhinal and parahippocampal cortices.We suggest, in relation to anatomical evidences, that isolation of hippocampus is responsible for symptomatollogy of our patient.

Investigating temporal lobe contribution to confrontation naming using MRI quantitative volumetrics

Confrontation naming ability entails the operation of distinct cognitive operations and the integrity of a distributed neural network. Previous research has indicated a critical role for the left temporal lobe region in naming ability, but there is less agreement about the relative role of distinct temporal lobe regions. In the current paper, we used quantitative MR volumetrics to investigate the relative contribution of the hippocampus and extrahippocampal temporal lobe (segmented gray and white matter) volumes to confrontation naming performance in 53 patients with temporal lobe epilepsy. Findings showed (1) a stronger relationship for left temporal lobe volume than right temporal lobe volume in predicting naming performance; (2) both left temporal lobe white matter volume and left hippocampus volume contributed a significant amount of unique variance to spontaneous naming performance; and (3) left temporal lobe white matter volume but not left hippocampus volume predicted recognition naming performance.

Quantitative MR analyses of the hippocampus: Unspecific metabolic changes in aging

The age-related structural changes of the human hippocampus are not entirely understood. The goal of the present investigation was to understand better the nature of age-related hippocampal changes by a comparative MR-analysis of four complementary aspects of hippocampal integrity: total volume, metabolite concentration, neuron to glial cell ratio and amount of extracellular diffusion space for water. To that end, we applied MR-based methods of manual and computerized (voxel-based morphometry) volumetry, diffusion-weighted imaging and 1H MR spectroscopy to characterize specific age-related hippocampal effects in a group of 22 healthy old adults in comparison with a group of 13 healthy younger adults. Age-related reductions of the hippocampal N-acetyl aspartate to creatine/choline ratio together with only marginal age-related reductions in hippocampal volumes and increases in diffusion parameters suggest that the process of aging affects mainly the metabolic status of the hippocampus with little equivalent age-related changes in hippocampal cell density. The metabolic changes are unspecific as they are not restricted to the hippocampus but equally occur in measures obtained from extrahippocampal temporal lobe regions.

Voxel-based morphometry of unilateral temporal lobe epilepsy reveals abnormalities in cerebral white matter

Voxel-based morphometric (VBM) investigations of temporal lobe epilepsy have focused on the presence and distribution of gray matter abnormalities. VBM studies to date have identified the expected abnormalities in hippocampus and extrahippocampal temporal lobe, as well as more diffuse abnormalities in the thalamus, cerebellum, and extratemporal neocortical areas. To date, there has not been a comprehensive VBM investigation of cerebral white matter in nonlesional temporal lobe epilepsy. This study examined 25 lateralized temporal lobe epilepsy patients (13 left, 12 right) and 62 healthy controls in regard to both temporal and extratemporal lobe gray and white matter. Consistent with prior reports, gray matter abnormalities were evident in ipsilateral hippocampus and ipsilateral thalamus. Temporal and extratemporal white matter was affected ipsilateral to the side of seizure onset, in both left and right temporal lobe epilepsy groups. These findings indicate that chronic temporal lobe epilepsy is associated not only with abnormalities in gray matter, but also with concomitant abnormalities in cerebral white matter regions that may affect connectivity both within and between the cerebral hemispheres.

Expression and activation of caspase 3 following status epilepticus in the rat

It is in dispute whether caspase 3 contributes to status epilepticus (SE)-induced cell loss. We hypothesized that caspase 3-mediated cell death continues beyond the acute phase of SE. We induced SE with either kainic acid or electrical stimulation of the amygdala in Wistar and Sprague-Dawley rats. Caspase 3 immunohistochemistry, Western blot analysis and enzyme activity measurements were used to determine cellular localization and the time course of caspase 3 expression and activation. Immunohistochemistry indicated that caspase 3 protein expression increased following SE, peaking at 16-24 h. Cleavage of procaspase 3 to active fragments (p20-17) was detected 2-7 days after SE. Caspase 3 enzyme activity was elevated at 8 h and further increased up to 19.4-fold at 7 days following SE. Activation of caspase 3 after SE occurred in the hippocampus and the extrahippocampal temporal lobe but not in the thalamus. Caspase 3-immunoreactive cells represented only a minority of degenerating cells as assessed by Fluoro-Jade B and TUNEL staining. Analysis of double-labelled sections indicated that active caspase 3 was located in astrocytes rather than neurons or microglia. There was increased caspase 3 expression in both rat strains, and it was independent of the method used to induce SE. These data demonstrate that caspase 3 contributes to the cell death occurring within the first week after SE, but in only a small proportion of degenerating cells. These results suggest that, contrary to expectations, caspase 3 inhibitors would have only limited benefits in the treatment of SE.

Neuroprotective effect of remacemide hydrochloride in a perforant pathway stimulation model of status epilepticus in the rat.

Previous studies have demonstrated that remacemide and its desglycinyl metabolite, AR-R 2495AA, reduce neuronal damage in animal models of ischemia, subarachnoid hemorrhage, and traumatic brain injury. The aim of the present study was to investigate whether remacemide hydrochloride also alleviates seizure-induced neuronal damage in a model of status epilepticus induced by the stimulation of the perforant pathway (PP) in the rat. Chronic oral remacemide treatment (3 x 25 mg/kg/day) was started either 2 days before or 2 h after the beginning of PP stimulation (2 mA, 20 Hz, 0.1 ms pulse duration for 60 min). The effects of remacemide treatment on the severity of seizures, electroencephalogram (EEG) parameters, seizure-induced neuronal damage in the temporal lobe regions, and memory impairment were compared to unstimulated and stimulated vehicle-treated controls, and carbamazepine-pre-treated (3 x 40 mg/kg/day) rats. Both remacemide and carbamazepine pretreatments, but not remacemide posttreatment, decreased pyramidal cell damage in the CA3 and CA1 subregions of the hippocampus (P < 0.05). In addition, overall neuronal damage in the extrahippocampal temporal lobe regions (the piriform cortex, entorhinal cortex, and the amygdaloid complex) was milder in remacemide-pretreated rats compared to stimulated control rats (P < 0.01). The neuroprotective effect was most evident on the side contralateral to stimulation. Remacemide or carbamazepine pretreatment had no evident effect on the number or duration of behavioral seizures during PP stimulation. Neither drug altered the spectral parameters of the baseline EEG or prevented status epilepticus-induced EEG slowing observed 2 weeks after PP stimulation. Nor did remacemide or carbamazepine treatment alleviate spatial memory impairment determined in a Morris water-maze task 2 weeks after PP stimulation. Our data provide evidence that pretreatment with remacemide has a moderate neuroprotective effect against status epilepticus-induced neuronal damage.

Widespread glucose hypometabolism in patients with hippocampal atrophy: Evaluation with 18F-fluorodeoxyglucose positron emission tomography

Positron emission tomography (PET) with 18 F-fluorodeoxyglucose was performed to measure the interictal local cerebral metabolic rate for glucose (ICMRGlc) in 18 patients observed to have hippocampal atrophy (HA) on magnetic resonance imaging (MRI). In all patients, the MRI showed unilateral atrophy of the hippocampus, and the side showing HA was ipsilateral to the EEG lateralization. PET scans were obtained in a semicoronal plane at an angle of −30 ° to the orbitomeatal line, approximately -60 ° to the long axis of the temporal lobe. The metabolic asymmetry was compared with the frequency of epileptic seizures, duration of illness, and intellectual deficit. The absolute values of ICMRGlc (mg/min/100g) in the hippocampus, extrahippocampal temporal lobe, and frontal lobe were significantly lower on the side ipsilateral to the epileptic focus than on the contralateral side. In patients with frequent seizures, there were greater asymmetry of the ICMRGlc in the extrahippocampal temporal lobe and less in the hippocampus, suggesting that the ipsilateral temporal lobe and contralateral hippocampus were affected by repeated seizures. In conclusion, in patients with presumed unilateral temporal lobe epilepsy and HA, PET studies demonstrated widespread glucose hypometabolism in extrahippocampal areas, and the semicoronal scan was useful in its evaluation.

Specificity of volumetric magnetic resonance imaging in detecting hippocampal sclerosis.

Magnetic resonance imaging (MRI)-based volumetric measurements of the hippocampal formation are useful in detecting unilateral hippocampal sclerosis (HS) in patients with temporal lobe epilepsy. In this pathologic entity, volumetric MRI analysis shows the epileptogenic structure to be atrophic when compared with the normal, nonepileptogenic side. Some authors have suggested that the radiological features of atrophy of medial temporal lobe structures are common in patients with complex partial seizures, but also are seen frequently in other seizure types and can occur even in patients without epilepsy. To determine if seizures originating in extrahippocampal sites cause gliosis, cell loss, and atrophy of medial temporal lobe structures (i.e., HS). We studied 110 patients with chronic epilepsy using volumetric MRI measurements of the hippocampal formation. Seventeen patients had pathologically proven HS, 27 patients had seizures due to extratemporal structural lesions, 15 patients had seizures caused by extrahippocampal temporal lobe lesions, 29 patients had primary generalized epilepsy, and 22 patients had secondary generalized epilepsy. All 17 patients with HS showed significantly reduced absolute hippocampal formation volumes of greater than 2 SDs below the mean of the control groups. The preoperative hippocampal formation volume measurements correlated well with the severity of HS on pathological examination. Hippocampal volumes were within the normal range in all patients with primary generalized epilepsy, secondary generalized epilepsy, extratemporal structural lesions, and extrahippocampal temporal lobe lesions. Seizures originating at extrahippocampal sites do not cause gliosis, cell loss, or atrophy of medial temporal structures. Significant reduction in hippocampal volumes is a specific marker for HS.

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

To assess the relationship of hippocampal neuron loss to intellectual and memory measures before and after temporal lobe surgery. 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. Patient data were obtained from a university program of surgery for epilepsy. Twenty-five patients who had intractable epilepsy. Wechsler Adult Intelligence Scale IQ scores, verbal and nonverbal memory measures adapted from the Wechsler Memory Scale, and the Rey-Osterrieth recall score. 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. 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.

Anatomic Temporal Lobe Resections for Temporal Lobe Epilepsy

Temporal lobe epilepsy is not a single clinicopathologic entity but a group of syndromes requiring different surgical solutions. Anatomic resections planned for the treatment of these syndromes are aimed at pathologic substrates minimizing ablation of normal tissue. Most of these procedures involve mesial and lateral temporal resections. The syndrome of mesial temporal sclerosis should be treated with resection aimed at hippocampus and the PHG, including entorhinal cortex, and at part of the amygdala. Improvement in diagnostic methods and refinement of anatomic surgical procedures that maximize resection of hippocampus resulted in excellent outcome in the treatment of patients with this syndrome. Mass lesions in patients with intractable seizures should be resected with some surrounding margins, but additional clinical studies will be required to determine the role of anatomic resections, including hippocampectomy, in the treatment of these patients. Extrahippocampal temporal lobe epilepsy is the most difficult to evaluate and treat. Tailored individualized resections based on acute or chronic EEG recordings may be required until and if discrete anatomically based syndromes can be identified in this patient population.

Operative strategy in patients with MRI-identified dual pathology and temporal lobe epilepsy

We performed a prospective study using preoperative magnetic resonance imaging to identify hippocampal formation atrophy in 15 consecutive patients with intractable partial epilepsy who had undergone a stereotactic resection of an extrahippocampal temporal lobe foreign-tissue lesion. A stereotactic lesionectomy was performed in all patients, i.e., only the imaging-defined lesion itself was resected. Hippocampal formation atrophy was identified in three of the 15 patients. Neuroimaging-detected hippocampal formation atrophy has been shown to be a reliable marker of moderate to severe mesial temporal sclerosis. All patients with hippocampal formation atrophy had an unfavorable operative outcome. Pathological examination of the hippocampus in one patient with neuroimaging-identified hippocampal formation atrophy who subsequently received an anterior temporal lobectomy revealed mesial temporal sclerosis. Nine of the 12 patients without hippocampal formation atrophy experienced a significant reduction in seizure tendency after lesionectomy. The surgically excised hippocampus in one patient without hippocampal formation atrophy who later underwent a temporal lobectomy showed no significant neuronal loss. Results of this study have modified the surgical approach taken at this institution in patients with temporal lesional epilepsy. Patients with magnetic resonance imaging-defined dual pathology now undergo a temporal lobectomy which includes resection of the hippocampus and the foreign-tissue lesion.