Non-sclerotic Hippocampus Research Articles

5 Combining Neurophysiology and Behavioral Measures to Identify Biomarkers of Clinical and Preclinical Hippocampus-Dependent Memory Dysfunction

Objective:Memory is a critical piece of the human experience and impairments in neural memory networks can have devastating consequences for the affected person. A subtype of memory, episodic memory generates context for the present based on past experience and allows us to make predictions about the future. Episodic memories become stable fixtures through long-term memory consolidation. It is believed that consolidation of episodic memory requires a dynamic interplay between connected hippocampal-cortical networks, mainly during sleep. Sleep oscillations, slow oscillations and thalamocortical spindles, coupled with hippocampal sharp wave ripples (SWR) is proposed to be mechanistically involved in establishing the crucial cortical-subcortical dialog. The current study aimed to determine alterations in typical sleep oscillations and oscillation coupling in patients with and without structural hippocampal damage and correlate them with neuropsychological measures believed to be sensitive to hippocampal dysfunction, i.e., Rey Auditory Verbal Learning Task (RAVLT) and Verbal Paired Associates (VPA-II).Participants and Methods:We used intracranial electroencephalography (iEEG) in 14 patients with epilepsy to directly record hippocampal and neocortical oscillations and neuropsychological measures obtained prior to implantation. Half of the participants were diagnosed with mesial temporal sclerosis (MTS) in the left hippocampus and healthy tissue in the right hippocampus. The other half did not have MTS and had either mesial temporal epilepsy without MTS or extra-temporal seizures. We analyzed hippocampal SWR output from both hippocampi and characterized neocortical slow oscillations and spindles and their coupling for each participant. We correlated electrophysiological data with behavioral results of neuropsychological testing in order to characterize the clinical relevance.Results:SWR analysis revealed significant differences in the frequency, t(7639) = 15.52, p>.001, p > .001), amplitude, t(7664) = -23.93, p > .001, and waveforms (p > .001) of SWR in the sclerotic versus healthy hippocampi. Patients with a sclerotic hippocampus but relatively preserved verbal memory scores (RAVLT, VPA-II) showed increased SWR amplitudes in the contralateral hippocampus compared to patients with low verbal memory scores. Additionally, we found differences between hemispheres in phase amplitude coupling of SWRs to spindles and SOs (p > 0.001). Results of our correlational analysis were variable and dependent upon additional factors, such as age of onset and diagnosis duration.Conclusions:Results from this work will aid in establishing a criterion for characterizing a relationship between subcortical and cortical oscillations as they relate to memory performance. Besides aiding our understanding of the neural mechanisms underpinning memory consolidation this will ideally help with developing neurophysiological biomarkers that may predict possible memory decline in resective or ablative neurosurgery absent of structural lesion. In addition, this work may potentially provide first evidence of a neurophysiological biomarker directly recorded from the human hippocampus to support possible reorganization of memory functioning in the non-sclerotic hippocampus.

Volumetric changes in amygdala and entorhinal cortex and their relation to memory impairment in patients with medial temporal lobe epilepsy with visually normal MR imaging findings

To explore the relation between parahippocampal structures, such as the amygdala and the entorhinal cortex (EC), with verbal and nonverbal memory in patients with medial temporal lobe epilepsy (MTLE) with visually normal MR imaging findings by volumetric measurements using magnetic resonance imaging (MRI). Thirty-six consecutive patients with MTLE presenting a non-sclerotic hippocampus though visual inspection were assessed by MRI to measure the volumes of the hippocampus, amygdale and EC, and by using the clinical memory scale (CMS), a test battery for verbal and nonverbal memory, where summation of all CMS subscale scores equals the memory quotient (MQ). The correlations between MRI volumetric data (Z scores or asymmetry indexes (AI; (L-R)/(L+R)), "L" and "R" refer to the left and right volumes of each structure, respectively), clinical variables and memory scale scores were analyzed using a principal component regression model. Volumetric MRI revealed significant differences between the volumes of the hippocampus, EC, and right amygdala, but no differences in the volume of the left amygdala between the controls and the patients group. The patients group performed significantly worse in MQ (p < 0.01), the associate memory test (p < 0.01), directed memory test (p < 0.05), and the nonsense graphical recognition test (p < 0.05) compared to the control group. The asymmetry of the amygdala negatively correlated to verbal paired associates' recall and nonsense graphical recognition. The direct memory was positively related to the volume of the EC. The volumetric asymmetry of the amygdala contributes to either verbal or nonverbal memory impairment in MTLE patients. Verbal memory may correlate with the volume of the EC.

The vulnerability of calretinin-containing hippocampal interneurons to temporal lobe epilepsy

This review focuses on the vulnerability of a special interneuron type—the calretinin (CR)-containing interneurons—in temporal lobe epilepsy (TLE). CR is a calcium-binding protein expressed mainly by GABAergic interneurons in the hippocampus. Despite their morphological heterogeneity, CR-containing interneurons form a distinct subpopulation of inhibitory cells, innervating other interneurons in rodents and to some extent principal cells in the human. Their dendrites are strongly connected by zona adherentiae and presumably by gap junctions both in rats and humans. CR-containing interneurons are suggested to play a key role in the hippocampal inhibitory network, since they can effectively synchronize dendritic inhibitory interneurons. The sensitivity of CR-expressing interneurons to epilepsy was discussed in several reports, both in animal models and in humans. In the sclerotic hippocampus the density of CR-immunopositive cells is decreased significantly. In the non-sclerotic hippocampus, the CR-containing interneurons are preserved, but their dendritic tree is varicose, segmented, and zona-adherentia-type contacts can be less frequently observed among dendrites. Therefore, the dendritic inhibition of pyramidal cells may be less effective in TLE. This can be partially explained by the impairment of the CR-containing interneuron ensemble in the epileptic hippocampus, which may result in an asynchronous and thus less effective dendritic inhibition of the principal cells. This phenomenon, together with the sprouting of excitatory pathway axons and enhanced innervation of principal cells, may be involved in seizure generation. Preventing the loss of CR-positive cells and preserving the integrity of CR-positive dendrite gap junctions may have antiepileptic effects, maintaining proper inhibitory function and helping to protect principal cells in epilepsy.

Conditional downregulation of brain- derived neurotrophic factor and tyrosine kinase receptor B blocks epileptogenesis in the human temporal lobe epilepsy hippocampus

Brain-derived neurotrophic factor (BDNF) has been implicated as a potential therapeutic target in temporal lobe epilepsy (TLE). However, whether BDNF exerts an epileptogenic or antiepileptogenic function remains controversial. BDNF/tyrosine kinase receptor B (trkB) expression levels were comparatively assessed in the hippocampal tissue of TLE patients with (HS group) and without hippocampal sclerosis (non-HS group) as well as from non-epileptic controls. Immunohistochemistry and immunoblot analysis revealed a marked increase in BDNF/trkB expression in the dentate gyrus and CA3 regions of HS and non-HS groups. The lack of any differences in expression levels was observed between HS and non-HS patients. Meanwhile, treatment with VPA (Valproic acid, anti-epileptic drug) resulted in a significant down-regulation of BDNF/trkB protein expression in sclerotic and non-sclerotic hippocampus (P < 0.001). In contrast, no marked change was noticed in VPA-untreated and OA-treated groups (sodium octanoate). These results suggest that the up-regulation of BDNF/trkB pathway might be at least in part responsible for the epileptogenesis.

Postoperative Recovery of Hippocampal Contralateral Diffusivity in Medial Temporal Lobe Epilepsy

To search for a recovery after surgery of mean diffusivity (MD) values in the contralateral nonsclerotic hippocampus of patients with medial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS). Twenty-four MTLE patients (12 right-sided and 12 left-sided MTLE) and 36 healthy volunteers were investigated using diffusion tensor imaging. A region-of-interest approach was used to measure pre- and postoperative interictal hippocampal MD values in patients. Diffusion abnormalities in contralateral nonsclerotic hippocampus recovered after surgery (p<0.0001). A subgroup of 14 patients exhibited a clear increase in MD values whereas the remaining 10 patients were stable. No significant difference was found between the two subgroups for each of the electroclinical data studied including early postoperative outcome, all patients being either seizure free or with rare persistent auras. This finding suggests that diffusion abnormalities in contralateral hippocampus may represent a functional mechanism linked to the active epileptic process.

Diffusion tensor imaging in medial temporal lobe epilepsy with hippocampal sclerosis

Interictal diffusion imaging studies in patients with medial temporal lobe epilepsy (MTLE) accompanied by hippocampal sclerosis (HS) have shown an increased diffusivity in the epileptogenic hippocampus. In this study, we wanted to explore the whole brain in order to determine if MTLE could have an impact on the organization and the architecture of a large cerebral network and to identify clinical factors that could mediate diffusion abnormalities. Diffusion tensor imaging (DTI) and statistical parametric mapping of the entire brain were performed in 35 well-defined MTLE patients and in 36 healthy volunteers. SPM analyses identified three abnormal areas: an increased diffusivity was detected in the epileptic hippocampus and the ipsilateral temporal structures associated with a decreased anisotropy along the temporal lobe, a decreased diffusivity was found in the contralateral non-sclerotic hippocampus, the amygdala, and the temporal pole, and finally, a decreased anisotropy was noted ipsilaterally in posterior extratemporal regions. Duration of epilepsy, age at onset, and the frequency of generalized tonic–clonic seizures or partial complex seizures did not correlate with the presence of diffusion abnormalities. Region of interest analysis in the hippocampus/parahippocampus demonstrated a correlation between lower ipsilateral diffusivity values and occurrence of epigastric aura and between higher anisotropy values in both hemispheres and history of febrile seizures. In conclusion, this study showed that diffusion abnormalities are not restricted to the pathologic hippocampus and involve a larger network. This pattern may indirectly reflect the epileptogenic network and may be interpreted as a cause or a consequence of epilepsy.

Abnormalities in hippocampi remote from the seizure focus: a T2 relaxometry study.

The aim of this study was to determine whether partial epilepsy is associated with abnormalities in hippocampi that are not the primary seizure focus. As hippocampal T2 relaxometry is useful for identifying abnormalities that are not obvious on visual assessment of MRI, this was the method employed. Of 457 consecutive children and young adults from whom T2 relaxometry data were obtained, 96 had well characterized partial epilepsy and were enrolled, along with 27 control subjects. The patients were divided on the basis of clinical, video-EEG and visual MRI assessment into three groups: (i) those with temporal lobe epilepsy (TLE) and mesial temporal sclerosis (MTS) (MTS-TLE); (ii) lesional TLE (l-TLE); or (iii) extratemporal epilepsy (ETE). There was a significant and similar prolongation of T2 relaxation time identified in hippocampi remote from the seizure focus in all patient groups when compared with control subjects. In the non-sclerotic hippocampus of patients with MTS, T2 relaxation time was prolonged by a mean of 3.3 ms [95% confidence interval (CI), 0.8-5.9 ms; P = 0.01], patients with l-TLE had prolongation of T2 relaxation time by a mean of 4.3 ms (95% CI, 1.8-7.1 ms; P = 0.001) and those with ETE had prolongation of T2 relaxation time by a mean of 3.7 ms (95% CI, 1.6-6.6 ms; P = 0.006) compared with control subjects after adjustment for age. Unsurprisingly, in patients with MTS-TLE, T2 relaxation time in the sclerotic hippocampus was prolonged by a mean of 19 ms (95% CI = 14.6-22.4 ms; P < 0.001). The similarity in the extent of prolongation of T2 relaxation time in hippocampi that are not the primary epileptogenic focus, the wide variety of structural associations and the varied sites of epileptogenic foci, considered together, suggest that the abnormalities are likely to be caused by ongoing seizure activity rather than by underlying aetiology or site of epileptogenic focus.

Mini-Review: Morphological changes in the human epileptogenic hippocampus

The availability of surgical tissue from epilepsy patients and the development of different animal models have increased our knowledge about the morphological changes in the epileptogenic brain. In this review we focus on the main morphopathological changes in the hippocampus from patients with temporal lobe epilepsy. The pathological substrate most frequently found in patients, suffering from temporal lobe epilepsy is hippocampal sclerosis. The sclerotic hippocampus is characterized by neuronal degeneration, astrogliosis, and granule cell dispersion. Even temporal lobe epilepsy patients with a non-sclerotic hippocampus suffer from neuronal cell loss. Another important hallmark of the sclerotic hippocampus is the presence of mossy fibre sprouts in the supragranular region of the dentate gyrus. This so called “mossy fibre” sprouting was only observed in the sclerotic hippocampus, and corresponded to the degree of hippocampal sclerosis. Moreover, the demonstration of actively sprouting mossy fibres in the sclerotic hippocampus, indicates that the process of mossy fibre sprouting is still an active, on-going process in the sclerotic hippocampus, even though these patients have suffered from seizures for many years. This active mossy fibre sprouting could potentially further aggravate the process of neuronal degeneration and astrogliosis. Therefore, it seems important to surgically remove the sclerotic hippocampal tissue in patients with temporal lobe epilepsy as early as possible.