Quantification of subfield pathology in hippocampal sclerosis: A systematic review and meta-analysis

BackgroundThe utility of MRI-based hippocampal subfield volumetry as a diagnostic test for hippocampal sclerosis (HS) is based on the hypothesis that specific hippocampal subfields are differentially affected in HS. While qualitative studies suggest selective involvement of certain hippocampal subfields in this condition, whether quantifiable differences exist remains unclear. Neuronal density measurement is the most widely used technique for measuring subfield pathological change in HS. Therefore, a systematic review and meta-analysis of studies reporting neuronal densities in temporal lobe epilepsy was performed in order to quantify subfield pathology in hippocampal sclerosis.MethodsStudies were identified by searching the Medline and Embase databases using the search terms: cell count, hippocampus, and epilepsy. Of the 192 studies identified by the literature search, seven met all inclusion and exclusion criteria. Random effects meta-analyses were performed, comparing: (i) neuronal densities in control (n = 121) versus HS (n = 371) groups for subfields CA1-4; and (ii) amount of neuronal loss in HS between subfields CA1-4.ResultsStatistically significant neuronal loss was observed comparing HS to control groups in all subfields CA1-4 (p < 0.001 for all comparisons). Significantly greater neuronal loss was demonstrated in HS comparing CA1 versus CA2 (p < 0.001), CA3 (p = 0.005), and CA4 (p = 0.003). Greater pyramidal cell loss was also demonstrated in CA3 relative to the CA2 subfield (p = 0.003). No significant differences were identified comparing CA2 and CA4 (p = 0.39); or comparing CA3 and CA4 (p = 0.64).ConclusionsHS is characterized by pathology in all hippocampal subfields. Quantifiable differences exist in the involvement of specific hippocampal subfields in HS. Neuronal loss is greatest in CA1, intermediate in CA3 and CA4, and least in CA2. Further studies are required to determine if this pattern can be detected using in vivo MRI.     

Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus

While it is clear that acute hippocampal injury or status epilepticus increases the production of new neurons in the adult dentate gyrus (DG), the effects of chronic epilepsy on dentate neurogenesis are unknown. We hypothesize that epileptogenic changes and spontaneous recurrent motor seizures (SRMS) that ensue after hippocampal injury or status epilepticus considerably decrease dentate neurogenesis. We addressed this issue by quantifying the number of cells that are positive for doublecortin (DCX, a marker of new neurons) in the DG of adult F344 rats at 16 days and 5 months after an intracerebroventricular kainic acid (ICV KA) administration or after graded intraperitoneal KA (IP KA) injections, models of temporal lobe epilepsy (TLE). At early post-KA administration, the injured hippocampus exhibited increased dentate neurogenesis in both models. Conversely, at 5 months post-KA administration, the chronically epileptic hippocampus demonstrated severely declined neurogenesis, which was associated with considerable SRMS in both KA models. Additionally, stem/progenitor cell proliferation factors, FGF-2 and IGF-1, were decreased in the chronically epileptic hippocampus. Interestingly, the overall decrease in neurogenesis and the extent of SRMS were greater in rats receiving IP KA than rats receiving ICV KA, suggesting that the extent of neurogenesis during chronic TLE exhibits an inverse relationship with SRMS. These results provide novel evidence that chronic TLE is associated with extremely declined dentate neurogenesis. As fraction of newly born neurons become GABA-ergic interneurons, declined neurogenesis may contribute to the increased seizure-susceptibility of the DG in chronic TLE. Likewise, the hippocampal-dependent learning and memory deficits observed in chronic TLE could be linked at least partially to the declined neurogenesis.     

Impact of hippocampal subfield histopathology in episodic memory impairment in mesial temporal lobe epilepsy and hippocampal sclerosis

ObjectiveThe objective of the study was to analyze preoperative visual and verbal episodic memories in a homogeneous series of patients with mesial temporal lobe epilepsy (MTLE) and unilateral hippocampal sclerosis (HS) submitted to corticoamygdalohippocampectomy and its association with neuronal cell density of each hippocampal subfield.MethodsThe hippocampi of 72 right-handed patients were collected and prepared for histopathological examination. Hippocampal sclerosis patterns were determined, and neuronal cell density was calculated. Preoperatively, two verbal and two visual memory tests (immediate and delayed recalls) were applied, and patients were divided into two groups, left and right MTLE (36/36).ResultsThere were no statistical differences between groups regarding demographic and clinical data. Cornu Ammonis 4 (CA4) neuronal density was significantly lower in the right hippocampus compared with the left (p = 0.048). The groups with HS presented different memory performance — the right HS were worse in visual memory test [Complex Rey Figure, immediate (p = 0.001) and delayed (p = 0.009)], but better in one verbal task [RAVLT delayed (p = 0.005)]. Multiple regression analysis suggested that the verbal memory performance of the group with left HS was explained by CA1 neuronal density since both tasks were significantly influenced by CA1 [Logical Memory immediate recall (p = 0.050) and Logical Memory and RAVLT delayed recalls (p = 0.004 and p = 0.001, respectively)]. For patients with right HS, both CA1 subfield integrity (p = 0.006) and epilepsy duration (p = 0.012) explained Complex Rey Figure immediate recall performance. Ultimately, epilepsy duration also explained the performance in the Complex Rey Figure delayed recall (p < 0.001).SignificanceCornu Ammonis 1 (CA1) hippocampal subfield was related to immediate and delayed recalls of verbal memory tests in left HS, while CA1 and epilepsy duration were associated with visual memory performance in patients with right HS.     

Urokinase-type plasminogen activator regulates neurodegeneration and neurogenesis but not vascular changes in the mouse hippocampus after status epilepticus

Expression of urokinase-type plasminogen activator (uPA) is increased after brain injury, suggesting that, like in cancer tissue, uPA plays roles in brain remodeling. Here we injured brain with intrahippocampal kainic acid (KA) injection in adult Wt and uPA?/? mice. At 20 days post-injury, uPA?/? mice had more severe loss of contralateral pyramidal (p < 0.05) and hilar neurons (p < 0.05) than Wt mice. The number of doublecortin (DCX)-positive newly born neurons was also reduced in uPA?/? mice as compared to Wt (p < 0.01). No difference was observed in granule cell dispersion or distribution of DCX-positive neurons in the dentate gyrus. uPA deficiency did not affect the total length of hippocampal blood vessels or vessel density. No differences were observed in the severity of status epilepticus or consequent epilepsy between the genotypes. These data indicate that uPA deficiency can unfavorably modulate both delayed neurodegeneration and neurogenesis but has little effect on post-injury neuronal migration and vascular density. Our results favor the idea that elevated uPA during the post-injury phase is neuroprotective.     

Distribution of regional gray matter abnormalities in a pediatric population with temporal lobe epilepsy and correlation with neuropsychological performance

ObjectiveThe goals of the work described here were to determine if hippocampal and extrahippocampal atrophy in children with temporal lobe epilepsy (TLE) follows a pattern similar to that in adult patients, and to assess the clinical and neuropsychological relevance of regional brain atrophy in pediatric TLE.MethodsChildren with symptomatic TLE (n = 14: 9 with mesial TLE due to hippocampal atrophy and 5 with TLE due to neocortical lesions), healthy children (n = 14), and 9 adults with mesial temporal lobe epilepsy (MTLE) were compared using voxel-based morphometry (VBM) of brain magnetic resonance imaging (MRI). The children underwent a comprehensive neuropsychological battery.ResultsChildren with MTLE with unilateral hippocampal atrophy (n = 9) exhibited a significant reduction in gray matter in the hippocampus ipsilateral to the seizure origin and significant atrophy in the ipsilateral cingulate gyrus and contralateral middle frontal lobe. Children with TLE (n = 14) exhibited a significant reduction in the gray matter of the ipsilateral hippocampus and parahippocampal gyrus. There was a correlation between gray matter volume in children with TLE and scores on several neuropsychological tests. Atrophy in pediatric patients with MTLE was less extensive than that in adults, and involved the hippocampi and the frontal cortex.ConclusionsSimilar to adult MTLE, pediatric MTLE is associated with hippocampal and extrahippocampal cell loss. However, children display less intense quantifiable gray matter atrophy, which affects predominantly frontal lobe areas. There was a significant association between volume of gray matter in medial temporal and frontal regions and scores on neuropsychological tests. In childhood, TLE and the concomitant cognitive/behavior disturbances are the result of a damaged neural network.     

Lacosamide in patients with temporal lobe epilepsy: An observational multicentric open-label study

PurposeThe aim of this study was to evaluate the efficacy and tolerability of lacosamide (LCM) both as add-on therapy and monotherapy in patients with temporal lobe epilepsy (TLE) based on an observational, prospective, multicenter study.MethodsWe enrolled 100 patients (mean age: 43.4 ± 12.53 years, 57 females) with nonlesional TLE and TLE with hippocampal sclerosis (HS) that did not respond to the first drug and who were referred to epilepsy centers of the University of Catanzaro, University of Palermo, IRCSS Neuromed of Pozzilli, and Otto-von-Guericke University of Magdeburg. In this open-label, multicenter trial, patients were initiated on oral LCM as add-on therapy to first AED monotherapy or as a later add-on to two concomitant AEDs. Seizure frequency changes and adverse events were recorded for at least six months after LCM was added.ResultsFourteen patients dropped out because of positive MRI findings other than HS. Patients received LCM at 200–400 mg/day. Fifty-eight out of these 86 patients with seizures that were previously drug-resistant had reduced seizure frequency after introduction of LCM. Forty-five out of 86 patients were classified as responders (12 were seizure-free, 33 achieved a reduction > 50%). Interestingly, five patients out of 86 achieved seizure freedom for at least one year and progressively switched to monotherapy with LCM, and all five remained seizure-free at follow-up (6–48 months).ConclusionsOur results may suggest that LCM at doses of 200 to 400 mg/day reduces seizure frequency in adults with TLE regardless of the presence of HS, and that it may be considered as a first add-on treatment for patients with pharmacoresistant TLE.     

Is ‘burned-out hippocampus’ syndrome a distinct electro‐clinical variant of MTLE-HS syndrome?

AimTo study the clinical, electrophysiological and imaging characteristics of patients with unilateral mesial temporal lobe epilepsy (MTLE) with contralateral ictal onset on scalp EEG, viz. ‘burned-out hippocampus’ syndrome (MTLE-BHS).MethodsMTLE-BHS was defined as TLE with unilateral hippocampal sclerosis (HS) without any dual pathology on MRI and contralateral ictal onset on scalp EEG, unlike in classical hippocampal sclerosis (HS). Consecutive “MTLE-BHS” patients evaluated at our Centre for Comprehensive Epilepsy Care from January 2005 to July 2014 were studied. Twenty-five cases of classic MTLE-HS operated during the same period were also analyzed for comparison.ResultsSeventeen patients were diagnosed to have MTLE-BHS. Mean age of seizure onset was 9.5 ± 7.7 years and the mean duration of epilepsy was18.2 ± 7.3 years. Epigastric aura was more common in MTLE-HS and fear, secondary generalized seizures and temporal polar changes on MRI were more prevalent in the MTLE-BHS subgroup. In the latter group, five (29%) exhibited seizure semiology and 2 (12%) had interictal discharges discordant to the side of MTS. Eight (47%) patients in the MTLE-BHS sub-group had normal medial temporal volume on Scheltens scale. Eight patients among MTLE-BHS underwent surgery (4 following intracranial monitoring that localized to the side of HS) with Engel class I outcome at 1 year follow-up in 6 and Engel class II outcome in 2.ConclusionAttenuation of ipsilateral fast ictal rhythms on scalp EEG as well as neocortical changes are likely to be deterministic factors for MTLE-BHS as opposed to the severity of hippocampal atrophy. Considering good post-operative outcomes, intracranial monitoring for surgical selection is not mandatory in MTLE-BHS despite discordant semiology and ictal onset, in the presence of inter-ictal, functional imaging and neuropsychology data concordant to the side of HS.     

Interictal serum brain-derived neurotrophic factor level reflects white matter integrity,epilepsy severity,and cognitive dysfunction in chronic temporal lobe epilepsy

ObjectiveMost patients with temporal lobe epilepsy (TLE) have epileptic foci originating from the medial temporal lobe, particularly the hippocampus. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor mainly expressed in the hippocampus, though it is not known whether the circulating level of BDNF reflects cognitive performance or white matter structural changes in chronic TLE.MethodsThirty-four patients with TLE and 22 healthy controls were enrolled for standardized cognitive tests, diffusion tensor imaging, and serum BDNF measurement. The patients were further divided into a subgroup with unilateral TLE (n = 23) and a subgroup with bilateral TLE (n = 11) for clinical and neuroimaging comparisons.ResultsThere were significantly lower BDNF levels in the patients with TLE compared with the controls, with significance contributed mainly from the subgroup with bilateral TLE, which also had more frequent seizures. The BDNF levels correlated with epilepsy duration (σ = − 0.355; p = 0.040) and fractional anisotropy (FA) in the left temporal lobe, left thalamus, and right hippocampus. Using a regression model, BDNF level predicted verbal memory score. Further, design fluency scores were predicted by serum BDNF level via the interactions with left temporal FA.ConclusionsSerum BDNF levels reflected longer epilepsy duration, impaired white matter integrity, and poor cognitive function in patients with chronic TLE.     

Reduced Pumilio-2 expression in patients with temporal lobe epilepsy and in the lithium–pilocarpine induced epilepsy rat model

ObjectiveDrosophila Pumilio (Pum), a homolog of mammalian Pum2, plays an important role in translational regulation in the central nervous system (CNS), particularly for dendrite outgrowth and neuronal excitability. We investigated the expression pattern and cellular distribution of Pum2 in patients with drug-refractory temporal lobe epilepsy (TLE) and rats with lithium chloride–pilocarpine-induced epilepsy.MethodsReal-time quantitative PCR (RT-qPCR), Western blot, immunohistochemistry, and double-labeled immunofluorescence were utilized to determine the expression level and distribution of Pum2 in temporal neocortex tissues from patients with intractable TLE (n = 20) and patients with severe head trauma (n = 20) in addition to the hippocampus and adjacent cortex of rats with lithium chloride–pilocarpine-induced TLE and controls.ResultsPum2 was expressed in the cell bodies and dendrites of neurons but did not colocalize with glial fibrillary acidic protein-positive astrocytes or propidium iodide (PI) in nuclei. The expression of Pum2 was significantly reduced in patients and rats with TLE in comparison to controls (P < 0.05).ConclusionPum2 expression was less in patients with TLE and a rodent model of epilepsy, suggesting that decreased expression of Pum2 may be involved in the pathogenesis of TLE.     

T2 hyperintense signal in patients with temporal lobe epilepsy with MRI signs of hippocampal sclerosis and in patients with temporal lobe epilepsy with normal MRI

BackgroundIncreased MRI T2 signal is commonly present not only in the hippocampus but also in other temporal structures of patients with temporal lobe epilepsy (TLE), and it is associated with histological abnormalities related to the epileptogenic lesion.ObjectiveThis study aimed to verify the distribution of T2 increased signal in temporal lobe structures and its correlations with clinical characteristics of TLE patients with (TLE-HS) or without (TLE-NL) MRI signs of hippocampal sclerosis.MethodsWe selected 203 consecutive patients: 124 with TLE-HS and 79 with TLE-NL. Healthy controls (N = 59) were used as a comparison group/comparative group. T2 multiecho images obtained via a 3-T MRI were evaluated with in-house software. T2 signal decays were computed from five original echoes in regions of interest in the hippocampus, amygdala, and white matter of the anterior temporal lobe. Values higher than 2 standard deviations from the mean of controls were considered as abnormal.ResultsT2 signal increase was observed in the hippocampus in 78% of patients with TLE-HS and in 17% of patients with TLE-NL; in the amygdala in 13% of patients with TLE-HS and in 14% of patients with TLE-NL; and in the temporal lobe white matter in 22% of patients with TLE-HS and in 8% of patients with TLE-NL. Group analysis demonstrated a significant difference in the distribution of the T2 relaxation times of the hippocampus (ANOVA, p < 0.0001), amygdala (p = 0.003), and temporal lobe white matter (p < 0.0001) ipsilateral to the epileptogenic zone for patients with TLE-HS compared with controls but only for the amygdala (p = 0.029) and temporal lobe white matter (ANOVA, p = 0.025) for patients with TLE-NL compared with controls. The average signal from the hippocampus ipsilateral to the epileptogenic zone was significantly higher in patients with no family history of epilepsy (two-sample T-test, p = 0.005).ConclusionIncreased T2 signal occurs in different temporal structures of patients with TLE-HS and in patients with TLE-NL. The hippocampal hyperintense signal is more pronounced in patients without family history of epilepsy and is influenced by earlier seizure onset. These changes in T2 signal may be associated with structural abnormalities related to the epileptogenic zone or to the nature of the initial precipitating injury in patients with TLE.     

Epilepsy duration impacts on brain glucose metabolism in temporal lobe epilepsy: Results of voxel-based mapping

Objective[¹⁸F]Fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) is a valuable method for detecting focal brain dysfunction associated with epilepsy. Evidence suggests that a progressive decrease in [¹⁸F]FDG uptake occurs in the epileptogenic cortex with an increase in the duration of epilepsy. In this study, our aim was to use statistical parametric mapping (SPM) to test the validity of this relationship in a retrospective study of patients with temporal lobe epilepsy (TLE).Methods[¹⁸F]FDG-PET scans of 46 adult patients with pharmacoresistant unilateral TLE (25 RTLE and 21 LTLE) were subjected to SPM analysis.ResultsForty-six patients were diagnosed with nonlesional TLE, 16 of whom had hippocampal sclerosis (HS). The average duration of epilepsy was 17.4 ± 12.3 years (3–46 years), <5 years in 10 patients and ?10 years in 30 patients. Visual analysis of [¹⁸F]FDG-PET scans revealed hypometabolism in the epileptogenic temporal cortex in 31 (67%) patients. After SPM analysis of all [¹⁸F]FDG-PET images, hypometabolism was unilateral and reported in lateral and mesial structures of the epileptogenic temporal cortex in addition to the ipsilateral fusiform and middle occipital gyrus. Subsequent analysis revealed that temporal lobe hypometabolism was present only in patients with longer epilepsy duration (?10 years) in parahippocampal gyrus, uncus, and middle and superior temporal gyrus (P < 0.05 corrected). Epilepsy duration was inversely correlated with decreased glucose uptake in the inferior temporal gyrus, hippocampus, and parahippocampal gyrus of the epileptogenic temporal cortex (P < 0.05). Age at seizure onset did not affect the correlation between epilepsy duration and glucose uptake except in the inferior temporal gyrus (P < 0.05).ConclusionVoxel-based mapping supports the assertion that glucose hypometabolism of the epileptogenic temporal lobe cortex and other neighboring cortical regions increases with longer epilepsy duration in TLE.     

Major depressive disorder as a predictor of a worse seizure outcome one year after surgery in patients with temporal lobe epilepsy and mesial temporal sclerosis

PurposeThe association between pre-surgical psychiatric disorders (PDs) and worse seizure outcome in patients with refractory epilepsy submitted to surgery has been increasingly recognized in the literature. The present study aimed to verify the impact of pre- and post-surgical PD on seizure outcome in a series of patients with refractory temporal lobe epilepsy and mesial temporal sclerosis (TLE–MTS).MethodData from 115 TLE–MTS patients (65 females; 56.5%) who underwent cortico-amygdalohippocampectomy (CAH) were analyzed. Pre- and post-surgical psychiatric evaluations were performed using DSM-IV and ILAE criteria. The outcome subcategory Engel IA was considered as corresponding to a favorable prognosis. A multivariate logistic regression model was applied to identify possible risk factors associated with a worse seizure outcome.ResultsPre-surgical PDs, particularly major depressive disorder (MDD), anxiety and psychotic disorders, were common, being found in 47 patients (40.8%). Fifty-six patients (48.7%) were classified as having achieved an Engel IA one year after CAH. According to the logistic regression model, the presence of pre-surgical MDD (OR = 5.23; p = 0.003) appeared as the most important risk factor associated with a non-favorable seizure outcome.ConclusionAlthough epilepsy surgery may be the best treatment option for patients with refractory TLE–MTS, our findings emphasize the importance of performing a detailed psychiatric examination as part of the pre-surgical evaluation protocol.     

Functional substrate for memory function differences between patients with left and right mesial temporal lobe epilepsy associated with hippocampal sclerosis

ObjectiveLittle is known about the functional substrate for memory function differences in patients with left or right mesial temporal lobe epilepsy (mTLE) associated with hippocampal sclerosis (HS) from an electrophysiological perspective. To characterize these differences, we hypothesized that hippocampal theta connectivity in the resting-state might be different between patients with left and right mTLE with HS and be correlated with memory performance.MethodsResting-state hippocampal theta connectivity, identified via whole-brain magnetoencephalography, was evaluated. Connectivity and memory function in 41 patients with mTLE with HS (left mTLE = 22; right mTLE = 19) were compared with those in 46 age-matched healthy controls and 28 patients with focal cortical dysplasia (FCD) but without HS.ResultsConnectivity between the right hippocampus and the left middle frontal gyrus was significantly stronger in patients with right mTLE than in patients with left mTLE. Moreover, this connectivity was positively correlated with delayed verbal recall and recognition scores in patients with mTLE. Patients with left mTLE had greater delayed recall impairment than patients with right mTLE and FCD. Similarly, delayed recognition performance was worse in patients with left mTLE than in patients with right mTLE and FCD. No significant differences in memory function between patients with right mTLE and FCD were detected. Patients with right mTLE showed significantly stronger hippocampal theta connectivity between the right hippocampus and left middle frontal gyrus than patients with FCD and left mTLE.ConclusionOur results suggest that right hippocampal–left middle frontal theta connectivity could be a functional substrate that can account for differences in memory function between patients with left and right mTLE. This functional substrate might be related to different compensatory mechanisms against the structural hippocampal lesions in left and right mTLE groups. Given the positive correlation between connectivity and delayed verbal memory function, hemispheric-specific hippocampal–frontal theta connectivity assessment could be useful as an electrophysiological indicator of delayed verbal memory function in patients with mTLE with HS.     

Long-term accelerated forgetting of verbal and non-verbal information in temporal lobe epilepsy

IntroductionWe investigated whether pre-surgical patients with temporal lobe epilepsy (TLE) forget verbal and non-verbal material faster than healthy controls over retention intervals of an hour and 6 weeks, and whether any observed memory loss was associated with structural changes to the hippocampus and/or seizure frequency.MethodsA mixed factorial design compared the performance of 27 patients with TLE and 22 healthy control participants, matched for IQ, age and gender, on tests of story recall and complex figure recall at three delays: immediate, 1 h and 6 weeks. Performance of the patient and control groups was matched at the immediate delay, which enabled comparisons of forgetting rate over the longer delays.ResultsWe found that TLE can affect the acquisition and retention of new memories over a relatively short delay of 1 h. This deficit was associated with structural hippocampal abnormality, with a material-specific effect that was particularly evident for the verbal task. We also found evidence of accelerated long-term forgetting in both patient groups, for the verbal and non-verbal tasks. It was demonstrated most strongly on the verbal task by the patients with right lateralized hippocampal sclerosis whose verbal recall was normal at the 1-h delay. Accelerated long-term forgetting was not associated with hippocampal pathology, but was associated with the frequency of epileptic seizures.DiscussionThe findings from the verbal task in particular provide evidence consistent with an extended period of memory consolidation that can be disrupted by both left and right TLE. The material-specific effects at the 1-h delay only, suggest that the initial consolidation of verbal and non-verbal, information depends on the integrity of the left and right hippocampus, respectively.     

Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus

Doublecortin (DCX), a microtubule-associated phosphoprotein, has been recently utilized as a marker of newly born neurons in the adult dentate gyrus (DG). Nonetheless, it is unknown whether DCX exclusively labels newly formed neurons, as certain granule cells with the phenotype of differentiated neurons express DCX. We addressed the authenticity of DCX as a marker of new neurons in the adult DG by quantifying cells that are positive for 5'-bromodeoxyuridine (BrdU), DCX and both BrdU and DCX in hippocampal tissues of adult rats treated with daily injections of BrdU for 12 consecutive days. We provide new evidence that neurons visualized with DCX immunostaining in the adult rat DG are new neurons that are predominantly born during the 12 days before euthanasia. This is confirmed by the robust expression of BrdU in 90% of DCX-positive neurons in the DG of animals injected with BrdU for 12 days. Furthermore, DCX expression is specific to newly generated healthy neurons, as virtually all DCX-positive cells express early neuronal antigens but lack antigens specific to glia, undifferentiated cells or apoptotic cells. As DCX expression is also robust in the dendrites, DCX immunocytochemistry of thicker sections facilitates quantification of the dendritic growth in newly born neurons. Thus, both absolute number and dendritic growth of new neurons that are generated in the adult DG over a 12-day period can be quantified reliably with DCX immunostaining. This could be particularly useful for analysing changes in dentate neurogenesis in human hippocampal tissues as a function of ageing or neurodegenerative diseases.     

Multiple hippocampal transections for intractable hippocampal epilepsy: Seizure outcome

PurposeThe purpose of this study was to evaluate the seizure outcomes after transverse multiple hippocampal transections (MHTs) in 13 patients with intractable TLE.MethodsThirteen patients with normal memory scores, including 8 with nonlesional hippocampi on MRI, had temporal lobe epilepsy (TLE) necessitating depth electrode implantation. After confirming hippocampal seizure onset, they underwent MHT. Intraoperative monitoring was done with 5–6 hippocampal electrodes spaced at approximately 1-cm intervals and spike counting for 5–8 min before each cut. The number of transections ranged between 4 and 7. Neuropsychological assessment was completed preoperatively and postoperatively for all patients and will be reported separately.ResultsDuration of epilepsy ranged between 5 and 55 years. There were no complications. Intraoperatively, MHT resulted in marked spike reduction (p = 0.003, paired t-test). Ten patients (77%) are seizure-free (average follow-up was 33 months, range 20–65 months) without medication changes. One of the 3 patients with persistent seizures had an MRI revealing incomplete transections, another had an additional neocortical seizure focus (as suggested by pure aphasic seizures), and the third had only 2 seizures in 4 years, one of which occurred during antiseizure medication withdrawal. Verbal and visual memory outcomes will be reported separately. Right and left hippocampal volumes were not different preoperatively (n = 12, p = 0.64, Wilcoxon signed-rank test), but the transected hippocampal volume decreased postoperatively (p = 0.0173).ConclusionsMultiple hippocampal transections provide an effective intervention and a safe alternative to temporal lobectomy in patients with hippocampal epilepsy.     

Reduced microglial immunoreactivity for endogenous NMDA receptor agonist quinolinic acid in the hippocampus of schizophrenia patients

Postmortem and positron emission tomography studies have indicated the pathophysiological involvement of microglial cells in schizophrenia. We hypothesized that the microglial production of quinolinic acid (QUIN), an endogenous N-methyl-d-aspartate receptor (NMDAR) agonist, may be linked to the previously described glutamatergic deficits in the hippocampus of schizophrenia patients.We performed a semi-quantitative assessment of QUIN-immunoreactive microglial cells in schizophrenia patients and matched controls in the CA1, CA2/3, and dentate gyrus (DG) area of the posterior hippocampal formation. Complementary immunostaining of the commonly used microglial surface marker HLA-DR was performed in adjacent histological sections.Fewer QUIN-immunoreactive microglial cells were observed in the CA1 hippocampal subregion of schizophrenia patients compared to controls (left p = 0.028, right p = 0.018). No significant diagnosis-dependent changes were observed in the CA2/3 and DG regions. These results were controlled for potential confounds by age, duration of disease, autolysis time, psychotropic medication, and hippocampal volume. No diagnosis-related differences were observed for the overall density of microglial cells (HLA-DR expression).Our findings suggest that reduced microglial QUIN content in the hippocampal CA1 region is associated with schizophrenia. We hypothesize that this association may contribute to impaired glutamatergic neurotransmission in the hippocampus of schizophrenia patients.     

Effects of prenatal binge-like ethanol exposure and maternal stress on postnatal morphological development of hippocampal neurons in rats

BackgroundAlcohol is one of the most commonly used drugs of abuse negatively affecting human health and it is known as a potent teratogen responsible for fetal alcohol syndrome (FAS), which is characterized by cognitive deficits especially pronounced in juveniles but ameliorating in adults. Searching for the potential morphological correlates of these effects, in this study, we compared the course of developmental changes in the morphology of principal hippocampal neurons in fetal-alcohol (A group), intubated control (IC group), and intact control male rats (C group) over a protracted period of the first two postnatal months.MethodsEthanol was administered to the pregnant Wistar dams intragastrically, throughout gestation days (GD) 7–20, at a total dose of 6 g/kg/day resulting in the mean blood alcohol concentration (BAC) of 246.6 ± 40.9 mg/dl. Ten morphometric parameters of Golgi-stained hippocampal neurons (pyramidal and granule) from CA1, CA3, and DG areas were examined at critical postnatal days (PD): at birth (PD1), at the end of the brain growth spurt period (PD10), in juveniles (PD30), and in young adults (PD60).ResultsDuring postnatal development, the temporal pattern of morphometric changes was shown to be region-dependent with most significant alterations observed between PD1-30 in the CA region and between PD10-30 in the DG region. It was also parameter-dependent with the soma size (except for CA3 pyramids), number of primary dendrites, dendrite diameter, dendritic tortuosity and the branch angle demonstrating little changes, while the total dendritic field area, dendritic length, number of dendritic bifurcations, and spine density being highly increased in all hippocampal regions during the first postnatal month. Moderate ethanol intoxication and the maternal intubation stress during gestation, showed similar, transient effects on the neuron development manifested as a smaller soma size in granule cells, reduced dendritic parameters and lower spine density in pyramidal neurons at PD1. Full recovery from these effects took place within the first 10 postnatal days.ConclusionsThis study showed regional and temporal differences in the development of different morphometric features of principal hippocampal neurons in intact subjects over a protracted 2-months postnatal period. It also demonstrated an overlap in the effects of a moderate fetal ethanol intoxication and a mild maternal stress produced by the intragastric intubation, a commonly used method of ethanol administration to the pregnant dams. Fast recovery from the adverse effects on the soma size, dendritic arborization and spines density observed at birth indicates towards the fetal ethanol/stress induced developmental retardation.     

Zinc Deficiency Reduces Neurogenesis Accompanied by Neuronal Apoptosis Through Caspase-Dependent and -Independent Signaling Pathways

Dietary zinc deficiency may affect zinc homeostasis in the brain and lead to reductions of neurogenesis and neuronal survival. However, the mechanisms responsible for the effects of zinc deficiency on hippocampal neurogenesis and neuronal death remain obscure. In the present study, young CD-1 mice were fed with zinc-deficient diet (0.85 ppm) for 5 weeks. The vesicular zinc was reduced at CA1 and CA3 regions of the hippocampus in zinc-deficient mice. The significant decreased zinc ions was associated with a reduction in proliferating cells labeled with bromo-deoxyuridine (BrdU) and immature neurons labeled with doublecortin (DCX) immunoreactivity in the dentate gyrus of the hippocampus. The processes of DCX-positive neurons were shortened, and flexuously went through into the granular cell layer in zinc-deficient hippocampus. There was also a conspicuous increase in the number of TUNEL-positive cells in the hippocampus after zinc-deficient diet treatment. Meanwhile, the apoptosis proteins, including Fas, Fas ligand (FasL), apoptosis inducing factor (AIF), and caspase-3, were significantly activated in zinc-deficient mouse hippocampus. These data suggest that chronic treatment with zinc-deficient diet results in reduction in hippocampal neurogenesis and increases neuronal apoptosis, indicating that zinc deficiency is associated with destroying structural plasticity in the hippocampus.     

Deafferentation enhances neurogenesis in the young and middle aged hippocampus but not in the aged hippocampus

Increased neurogenesis in the dentate gyrus (DG) after brain insults such as excitotoxic lesions, seizures, or stroke is a well known phenomenon in the young hippocampus. This plasticity reflects an innate compensatory response of neural stem cells (NSCs) in the young hippocampus to preserve function or minimize damage after injury. However, injuries to the middle‐aged and aged hippocampi elicit either no or dampened neurogenesis response, which could be due to an altered plasticity of NSCs and/or the hippocampus with age. We examined whether the plasticity of NSCs to increase neurogenesis in response to a milder injury such as partial deafferentation is preserved during aging. We quantified DG neurogenesis in the hippocampus of young, middle‐aged, and aged F344 rats after partial deafferentation. A partial deafferentation of the left hippocampus without any apparent cell loss was induced via administration of Kainic acid (0.5 μg in 1.0 μl) into the right lateral ventricle of the brain. In this model, degeneration of CA3 pyramidal neurons and dentate hilar neurons in the right hippocampus results in loss of commissural axons which leads to partial deafferentation of the dendrites of dentate granule cells and CA1‐CA3 pyramidal neurons in the left hippocampus. Quantification of newly born cells that are added to the dentate granule cell layer at postdeafferentation days 4–15 using 5′‐bromodeoxyuridine (BrdU) labeling revealed greatly increased addition of newly born cells (～three fold increase) in the deafferented young and middle‐aged hippocampi but not in the deafferented aged hippocampus. Measurement of newly born neurons using doublecortin (DCX) immunostaining also revealed similar findings. Analyses using BrdU‐DCX dual immunofluorescence demonstrated no changes in neuronal fate‐choice decision of newly born cells after deafferentation, in comparison to the age‐matched naive hippocampus in all age groups. Thus, the plasticity of hippocampal NSCs to increase DG neurogenesis in response to a milder injury such as partial hippocampal deafferentation is preserved until middle age but lost at old age. © 2010 Wiley‐Liss, Inc.