Fine Spike Timing in Hippocampal-Prefrontal Ensembles Predicts Poor Encoding and Underlies Behavioral Performance in Healthy and Malformed Brains.

Spatial working memory (SWM) is a central cognitive process during which the hippocampus and prefrontal cortex (PFC) encode and maintain spatial information for subsequent decision-making. This occurs in the context of ongoing computations relating to spatial position, recall of long-term memory, attention, among many others. To establish how intermittently presented information is integrated with ongoing computations we recorded single units, simultaneously in hippocampus and PFC, in control rats and those with a brain malformation during performance of an SWM task. Neurons that encode intermittent task parameters are also well modulated in time and incorporated into a functional network across regions. Neurons from animals with cortical malformation are poorly modulated in time, less likely to encode task parameters, and less likely to be integrated into a functional network. Our results implicate a model in which ongoing oscillatory coordination among neurons in the hippocampal-PFC network describes a functional network that is poised to receive sensory inputs that are then integrated and multiplexed as working memory. The background temporal modulation is systematically altered in disease, but the relationship between these dynamics and behaviorally relevant firing is maintained, thereby providing potential targets for stimulation-based therapies.

Defective Reelin/Dab1 signaling pathways associated with disturbed hippocampus development of homozygous yotari mice.

Homozygous Dab1 yotari mutant mice, Dab1yot (yot/yot) mice, have an autosomal recessive mutation of Dab1 and show reeler-like phenotype including histological abnormality of the cerebellum, hippocampus, and cerebral cortex. We here show abnormal hippocampal development of yot/yot mice where granule cells and pyramidal cells fail to form orderly rows but are dispersed diffusely in vague multiplicative layers. Possibly due to the positioning failure of granule cells and pyramidal cells and insufficient synaptogenesis, axons of the granule cells did not extend purposefully to connect with neighboring regions in yot/yot mice. We found that both hippocampal granule cells and pyramidal cells of yot/yot mice expressed proteins reactive with the anti-Dab1 antibody. We found that Y198- phosphorylated Dab1 of yot/yot mice was greatly decreased. Accordingly the downstream molecule, Akt was hardly phosphorylated. Especially, synapse formation was defective and the distribution of neurons was scattered in hippocampus of yot/yot mice. Some of neural cell adhesion molecules and hippocampus associated transcription factors of the neurons were expressed aberrantly, suggesting that the Reelin-Dab1 signaling pathway seemed to be importantly involved in not only neural migration as having been shown previously but also neural maturation and/or synaptogenesis of the mice. It is interesting to clarify whether the defective neural maturation is a direct consequence of the dysfunctional Dab1, or alternatively secondarily due to the Reelin-Dab1 intracellular signaling pathways.

Incomplete hippocampal inversion and epilepsy: A systematic review and meta-analysis.

OBJECTIVE: Incomplete hippocampal inversion (IHI) is a relatively frequent radiological finding at visual inspection in both epilepsy and healthy controls, but its clinical significance is unclear. Here, we systematically retrieve and assess the association between epilepsy and IHI using a meta-analytic approach. Additionally, we estimate the prevalence of IHI in patients with malformation of cortical development (MCD). METHODS: We systematically searched two databases (Embase and PubMed) to identify potentially eligible studies from their inception to December 2019. For inclusion, studies were population-based, case-control, observational studies reporting on epilepsy and IHI. The risk of developing epilepsy in IHI (estimated with odds ratio [ORs]) and the frequency of IHI among patients with MCD are provided. RESULTS: We screened 3601 records and assessed eligibility of 2812 full-text articles. The final material included 13 studies involving 1630 subjects. Seven studies (1329 subjects: 952 epileptic and 377 nonepileptic) were included for the estimation of the risk of developing epilepsy in the presence of IHI. The estimated OR of active epilepsy in IHI was 1.699 (95% confidence interval = 0.880-3.281), with moderate heterogeneity across studies (I2  = 71%). Seven studies (591 patients) provided information about the frequency of IHI in MCD. Up to one third of patients with MCD (27.9%) presented coexistent IHI. SIGNIFICANCE: The present findings confirm that IHI is commonly observed in patients with MCD especially in periventricular nodular heterotopia or polymicrogyria. However, the estimated OR indicates overall weak increased odds of epilepsy in people with IHI, suggesting that the presence of isolated IHI cannot be considered a strong independent predictor for epilepsy development. Clear-cut neuroradiological criteria for IHI and advanced postprocessing analyses on structural magnetic resonance imaging scans are recommended to highlight differences between epileptogenic and nonepileptogenic IHI.

Evaluation of Hippocampal Function in Temporal Lobe Epilepsy: Spatial Bayesian Variable Selection and Grouping the Regression Coefficient in Multilevel Functional Magnetic Resonance Imaging Data Analysis.

Background: A pre-surgical evaluation of cognitive functions in patients with mesial temporal lobe epilepsy (mTLE) is critical. The limitations of the usual brain analysis model were resolved by the spatial Bayesian variable selection (SBVS) method. An Ising and Dirichlet Process (Ising-DP) model considers SBVS and the grouping of a large number of voxels. The present study aimed to identify brain areas involved in episodic memory in patients with right mTLE and controls via the Ising-DP model. The model was extended to include between-subject factors (BSFs), and the results were compared with other classical methods. Methods: The present cross-sectional study was conducted on 15 patients with right mTLE and 20 controls in Tehran, Iran, in 2018. During functional magnetic resonance imaging, the subjects were tested with the face-encoding memory task, followed by a recognition memory test. The participants demographic factors such as age, sex, marital status, area of residence, and years of schooling were considered to comprise BSFs. The independent t test, the chi-square test, and the correlation test were conducted using the SPSS software (version 20.0). The image processing was carried out using SPM (version 12.0) and MATLAB (version R2014a). Results: The Ising-DP model appropriately (R2=0.642) detected activated hippocampal areas. The model adjusted for BSFs indicated a better fit by the significant effect of age (P((γ]>0.91), sex (P[γ]>0.87), and years of schooling (P[γ]>0.89). The heat maps exhibited decreased activation in the right hippocampal region in the patients compared with the controls (P<0.0001). Right hippocampal activity had a significant positive correlation with the recognition memory test in the mTLE group (r=0.665) and the control group (r=0.593). Conclusion: The Ising-DP model was sufficiently sensitive to detect activated areas in our patients with right mTLE during the face-encoding memory task. Since the model adjusted for BSFs improved sensitivity, we recommend the use of more detailed BSFs such as seizure history in future research.

Activation of the G Protein-Coupled Estrogen Receptor (GPER) Increases Neurogenesis and Ameliorates Neuroinflammation in the Hippocampus of Male Spontaneously Hypertensive Rats.

It is known that spontaneously hypertensive rats (SHR) present a marked encephalopathy, targeting vulnerable regions such as the hippocampus. Abnormalities of the hippocampus of SHR include decreased neurogenesis in the dentate gyrus (DG), partial loss of neurons in the hilus of the DG, micro and astrogliosis and inflammation. It is also known that 17ß-estradiol (E2) exert neuroprotective effects and prevent hippocampal abnormalities of SHR. The effects of E2 may involve a variety of mechanisms, including intracellular receptors of the ERα and ERß subtypes or membrane-located receptors, such as the G protein-coupled estradiol receptor (GPER). We have now investigated the protective role of GPER in SHR employing its synthetic agonist G1. To accomplish this objective, 5 month-old male SHR received 150 µg/day of G1 during 2 weeks. At the end of this period, we analyzed neuronal progenitors by staining for doublecortin (DCX), and counted the number of glial fibrillary acidic protein (GFAP)-labeled astrocytes and Iba1-stained microglial cells by computerized image analysis. We found that G1 activation of GPER increased DCX+ cells in the DG and reduced GFAP+ astrogliosis and Iba1+ microgliosis in the CA1 region of hippocampus. We also found that the high expression of proinflammatory makers IL1ß and cyclooxygenase 2 (COX2) of SHR was decreased after G1 treatment, which correlated with a change of microglia phenotype from the activated to a resting morphology. Additionally, G1 treatment increased the anti-inflammatory factor TGFß in SHR hippocampus. Altogether, our results suggest that activation of GPER plays a neuroprotective role on the encephalopathy of SHR, an outcome resembling E2 effects but avoiding secondary effects of the natural hormone.

Shared hippocampal abnormalities in sporadic temporal lobe epilepsy patients and their siblings.

OBJECTIVE: To examine the shared familial contribution to hippocampal and extrahippocampal morphological abnormalities in patients with sporadic temporal lobe epilepsy (TLE) and their unaffected siblings. METHODS: We collected clinical, electrophysiological, and T1-weighted magnetic resonance imaging (MRI) data of 18 sporadic patients with TLE without lesions other than hippocampal sclerosis (12 right, 6 left), their 18 unaffected full siblings, and 18 matched healthy volunteers. We compared between-group differences in cortical thickness and volumes of five subcortical areas (hippocampus, amygdala, thalamus, putamen, and pallidum). We determined the subregional extent of hippocampal abnormalities using surface shape analysis. All our imaging results were corrected for multiple comparisons using random field theory. RESULTS: We detected smaller hippocampal volumes in patients (right TLE: median right hippocampus 1.92 mL, interquartile range [IQR] 1.39-2.62, P < .001; left TLE: left hippocampus 2.05 mL, IQR 1.99-2.33, P = .01) and their unaffected siblings (right hippocampus 2.65 mL, IQR 2.32-2.80, P < .001; left hippocampus 2.39 mL, IQR 2.18-2.53, P < .001) compared to healthy controls (right hippocampus 2.94 mL, IQR 2.77-3.24; left hippocampus 2.71 mL, IQR 2.37-2.89). Surface shape analysis showed that patients with TLE had bilateral subregional atrophy in both hippocampi (right > left). Similar but less-pronounced subregional atrophy was detected in the right hippocampus of unaffected siblings. Patients with TLE had reduced cortical thickness in bilateral premotor/prefrontal cortices and the right precentral gyrus. Siblings did not show abnormalities in cortical or subcortical areas other than the hippocampus. SIGNIFICANCE: Our results demonstrate a shared vulnerability of the hippocampus in both patients with TLE and their unaffected siblings, pointing to a contribution of familial factors to hippocampal atrophy. This neuroimaging trait could represent an endophenotype of TLE, which might precede the onset of epilepsy in some individuals.

Looking for indicative magnetic resonance imaging signs of hippocampal developmental abnormalities in patients with mesial temporal lobe epilepsy and healthy controls.

OBJECTIVE: To evaluate the frequency of qualitative features for hippocampal developmental abnormalities (HiDeA) definition on magnetic resonance imaging (MRI) in mesial temporal lobe epilepsy (MTLE) patients and healthy controls, highlighting which were more sensitive and specific to the epileptic syndrome. METHODS: We enrolled 93 healthy controls and 187 MTLE patients. Among patients, 133 were MRI-negative and 54 had hippocampal sclerosis (HS). Two blinded, trained investigators defined HiDeA if three signs were present, including at least one of the following: (1) globular hippocampal shape (HCS), (2) verticalized collateral sulcus, and (3) medial positioning of hippocampus (HCP). After evaluating the prevalence of HiDeA in MTLE and controls, we assessed the frequency of each sign. Then, we classified differences in type or number of HiDeA diagnostic features, calculating their sensitivity and specificity. Fisher exact test was used to assess statistical significance. RESULTS: HiDeA was detected in 36 of 187 MTLE cases (19.25%) and in eight of 93 (8.6%) controls. In particular, HiDeA was present in 25 of 133 (18.8%) patients with MRI-negative MTLE. Among all visual criteria here considered, HCS showed higher sensitivity both in the MRI-negative MTLE group (88%) and in the HS-MTLE group (91%). HCP, thickened subiculum, and reduction of the upper horizontal portion of the parahippocampal gyrus (HCTH) signs demonstrated a 100% specificity in both groups. In healthy controls, HCS was confirmed to have the highest sensitivity (100%), whereas HCP showed the highest specificity (98.8%). All these criteria were statistically associated with HiDeA. Electroencephalographic focus was concordant with the HiDeA side in 52.2% of MTLE patients. An association was not found among signs of HiDeA and treatment responsiveness. SIGNIFICANCE: We identified characteristic signs of HiDeA, such as HCTH or HCP, differentiating HiDeA features between MTLE and healthy controls. The identification of sensitive and, more importantly, specific criteria of HiDeA could be helpful to make a more confident visual diagnosis.

Hippocampal abnormalities and seizures: a 16-year single center review of sudden unexpected death in childhood, sudden unexpected death in epilepsy and SIDS.

Sudden Unexpected Death in Childhood (SUDC) is the unexplained death of children aged between 1 and 18 years old. Hippocampal abnormalities have previously been described in Sudden Unexpected Death in Epilepsy (SUDEP) and it is possible that SUDC shares similar pathogenic mechanisms with SUDEP. Our aim was to determine the prevalence of hippocampal abnormalities, history of seizures and demographic features in our caseload of SUDC, SUDEP and SIDS cases. A review of post-mortem reports from 2003 to 2018 was carried out to identify cases of SUDC, SUDEP and SIDS. Histological evidence of hippocampal abnormalities, patient demographics (age, gender), sleeping position, and past medical history (history of seizures and illness 72 hours prior to death) were recorded. Statistical analysis was performed to compare the three groups. 48 SUDC, 18 SUDEP and 358 SIDS cases were identified. Hippocampal abnormalities associated with temporal lobe epilepsy were found in 44.4% of SUDC cases. 5/15 SUDC cases with a history of seizures demonstrated hippocampal abnormalities. SUDC cases were also more likely to be found prone compared to SIDS cases. In comparison with SIDS, both SUDC and SUDEP cases were more likely to demonstrate hippocampal abnormalities (SUDC: (OR = 9.4, 95% CI: 3.1-29.1, p < 0.001; SUDEP: OR = 35.4, 95% CI: 8.3-151.5, p < 0.001). We found a potential link between hippocampal abnormalities and epileptic seizures in SUDC. A concerted effort should be directed towards consistent sampling and standardized description of the hippocampus and clinical correlation with a history of seizures/epilepsy in postmortem reports.

C-Terminal Region Truncation of RELN Disrupts an Interaction with VLDLR, Causing Abnormal Development of the Cerebral Cortex and Hippocampus.

We discovered a hypomorphic reelin (Reln) mutant with abnormal cortical lamination and no cerebellar hypoplasia. This mutant, RelnCTRdel, carries a chemically induced splice-site mutation that truncates the C-terminal region (CTR) domain of RELN protein and displays remarkably distinct phenotypes from reeler The mutant does not have an inverted cortex, but cortical neurons overmigrate and invade the marginal zone, which are characteristics similar to a phenotype seen in the cerebral cortex of Vldlrnull mice. The dentate gyrus shows a novel phenotype: the infrapyramidal blade is absent, while the suprapyramidal blade is present and laminated. Genetic epistasis analysis showed that RelnCTRdel/Apoer2null double homozygotes have phenotypes akin to those of reeler mutants, while RelnCTRdel/Vldlrnull mice do not. Given that the receptor double knock-out mice resemble reeler mutants, we infer that RelnCTRdel/Apoer2null double homozygotes have both receptor pathways disrupted. This suggests that CTR-truncation disrupts an interaction with VLDLR (very low-density lipoprotein receptor), while the APOER2 signaling pathway remains active, which accounts for the hypomorphic phenotype in RelnCTRdel mice. A RELN-binding assay confirms that CTR truncation significantly decreases RELN binding to VLDLR, but not to APOER2. Together, the in vitro and in vivo results demonstrate that the CTR domain confers receptor-binding specificity of RELN. SIGNIFICANCE STATEMENT: Reelin signaling is important for brain development and is associated with human type II lissencephaly. Reln mutations in mice and humans are usually associated with cerebellar hypoplasia. A new Reln mutant with a truncation of the C-terminal region (CTR) domain shows that Reln mutation can cause abnormal phenotypes in the cortex and hippocampus without cerebellar hypoplasia. Genetic analysis suggested that CTR truncation disrupts an interaction with the RELN receptor VLDLR (very low-density lipoprotein receptor); this was confirmed by a RELN-binding assay. This result provides a mechanistic explanation for the hypomorphic phenotype of the CTR-deletion mutant, and further suggests that Reln mutations may cause more subtle forms of human brain malformation than classic lissencephalies.

Early Predictors of Drug-Resistant Epilepsy Development after Convulsive Status Epilepticus.

BACKGROUND: Drug-resistant epilepsy (DRE) is a common and serious consequence of convulsive status epilepticus (CSE). Little is known on the early prediction of DRE development after CSE. Our aim was to identify independent DRE predictors in patients with CSE. METHODS: One hundred and forty consecutive patients identified with CSE in a tertiary academic hospital between March 2008 and January 2015 were reviewed. Demographics, clinical features, serum albumin neuroimaging, and electroencephalogram characteristics were collected and analyzed. Independent predictors of DRE were identified using multivariate logistic regression. The receiver operating characteristic (ROC) curve was used to quantify the predictive validity of all the risk factors. RESULTS: After a median 62-month observation period, 91 patients were enrolled into this study. Thirty-seven (40.7%) patients did not have DRE, 22 (24.2%) developed DRE, and 32 (35.2%) were dead. History of epilepsy (OR 9.17, 95% CI 1.77-49.22, p = 0.010), status epilepticus duration ≥24 h (OR 4.82, 95% CI 1.04-22.37, p = 0.044), and cortical or hippocampal abnormalities on neuroimaging (OR 9.49, 95% CI 1.90-47.50, p = 0.006) were independent predictors of DRE after CSE. A combination of these 3 variables yielded an area under the ROC curve of 0.77 (0.65-0.89). CONCLUSIONS: History of epilepsy, longer SE duration, and cortical or hippocampal abnormalities on neuroimaging are early predictors for the development of DRE after CSE. Further studies are needed to assess whether a more aggressive treatment will reduce the likelihood of DRE development in these high-risk patients.

Influence of the location and type of epileptogenic lesion on scalp interictal epileptiform discharges and high-frequency oscillations.

OBJECTIVE: To increase the diagnostic power of scalp electroencephalography (EEG) by investigating whether lesion type and location influence the morphology of interictal epileptic discharges (IEDs) and the likelihood that IEDs and high-frequency oscillations (HFOs) are present. METHODS: We studied EEG activity in epilepsy patients with lesional epilepsy. Lesions were classified by type and by location (region and depth). We marked a maximum of 50 IEDs during deep non-rapid eye movement sleep. IEDs were identified as spikes or sharp waves with or without slow waves, or bursts of spikes or sharp waves with or without slow waves. We analyzed HFOs in the studies showing at least 50 IEDs. RESULTS: In 192 scalp EEG studies, the differences in the percentage of studies showing IEDs in each depth-related group were not statistically significant, whereas HFOs (55 studies) predominated in patients exhibiting superficial lesions (p<0.001). Sharp waves, as predominant pattern, were more prevalent in hippocampal abnormalities (p < 0.001), whereas bursts predominated in patients with malformations of cortical development (p < 0.001). SIGNIFICANCE: The depth of the lesion does not influence the presence of IEDs, as one might expect, but it influences that of HFOs. This is explained as follows. HFOs are generated in the epileptogenic region, do not propagate, and hence are only visible on scalp EEG with superficial lesions. IEDs can result from a nearby focus or propagate from a deep generator and are therefore equally present with deep, intermediate, and superficial lesions. Additionally, IED morphology provides information in determining the lesion type.

Hippocampal malformation associated with sudden death in early childhood: a neuropathologic study: Part 2 of the investigations of The San Diego SUDC Research Project.

PURPOSE: Sudden unexplained death in childhood (SUDC), while rare, accounts for an important fraction of unexpected deaths in children >1 year of age. Previously we reported an association between febrile seizures, hippocampal maldevelopment, and sudden, unexpected deaths in young children (1-6 years), termed "hippocampal maldevelopment associated with sudden death (HMASD)." Here, we characterize in greater detail the hippocampal pathology in a large cohort of cases (n = 42) of this entity, and attempt to define possible new entities responsible for sudden, unexplained death in young children without HMASD/febrile seizure phenotypes. METHODS: We performed comparative analysis on cases, which we classified in a cohort of 89 sudden and unexpected deaths as HMASD, explained deaths, SUDC with febrile seizure phenotype (SUDC-FS) but without hippocampal pathology, and SUDC (without hippocampal pathology or febrile seizure phenotype). RESULTS: The frequency of each subgroup was: HMASD 48% (40/83); SUDC 27% (22/83); SUDC-FS 18% (15/83); explained 7% (6/83). HMASD was characterized clinically by sudden, sleep-related death, term birth, and discovery in the prone position. Key morphologic features of HMASD were focal granule cell bilamination of the dentate gyrus with or without asymmetry and/or malrotation of the hippocampus, associated with significantly increased frequencies of 11 other developmental abnormalities. We identified no other distinct phenotype in the unexplained categories, except for an association of febrile seizures without hippocampal maldevelopment. CONCLUSIONS: HMASD is a distinct clinicopathologic entity characterized by a likely developmental failure of neuronal migration in the dentate gyrus. Future research is needed to determine the causal role of HMASD in sudden death in early childhood.

Sudden unexpected death in early childhood: general observations in a series of 151 cases: Part 1 of the investigations of the San Diego SUDC Research Project.

PURPOSE: The purpose of this study was to determine the major subcategories and clinicopathologic features of sudden unexpected death in young children in a large retrospective cohort, and to confirm the association of sudden unexplained death in children (abbreviated by us for unexplained deaths as SUDC) with hippocampal pathology and/or febrile seizures. METHODS: We undertook analysis of a retrospective cohort of 151 cases, of which 80% (121/151) were subclassified as SUDC, 11% (16/151) as explained, 7% (10/151) as undetermined, and 3% (4/151) as seizure-related. RESULTS: There were no significant differences between SUDC and explained cases in postnatal, gestational, or postconceptional age, frequency of preterm birth, gender, race, or organ weights. In contrast, 96.7% (117/121) of the SUDC group were discovered during a sleep period compared to 53.3% (8/15) of the explained group (p < 0.001), and 48.8% (59/121) of the SUDC cases had a personal and/or family history of febrile seizures compared to 6.7% (1/15) of the explained group (p < 0.001). Of the explained deaths, 56% (9/16) were subclassified as infection, 31% (5/16) cardiac, 6% (1/16) accidental, and 6% (1/16) metabolic. Two of the three cases specifically tested for cardiac channelopathies at autopsy based upon clinical indications had genetic variants in cardiac genes, one of uncertain significance. Bacterial cultures at autopsy typically revealed organisms interpreted as contaminants. Two of the four seizure-related deaths were witnessed, with two of the brains from these cases showing generalized malformations. Hippocampal anomalies, including a specific combination we termed hippocampal maldevelopment associated with sudden death, were found in almost 50% (40/83) of the SUDC and undetermined cases in which hippocampal sections were available. CONCLUSIONS: This study highlights the key role for the hippocampus, febrile seizures, and sleep in SUDC pathophysiology. It also demonstrates the role of known predisposing conditions such as cardiac channelopathies and infections in causing sudden unexpected death in childhood, and the need for improved ancillary testing and protective strategies in these cases, even when the cause of death is established at autopsy.

Hippocampal Malrotation Is Associated With Prolonged Febrile Seizures: Results of the FEBSTAT Study.

OBJECTIVE: Hippocampal malrotation is characterized by incomplete hippocampal inversion with a rounded shape and blurred internal architecture. There is still debate about whether hippocampal malrotation has pathologic significance. We present findings from the Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study on the frequency of and risk factors for hippocampal malrotation. SUBJECTS AND METHODS: FEBSTAT is a prospective multicenter study investigating the consequences of febrile status epilepticus in childhood. MRI studies of 226 patients with febrile status epilepticus were analyzed visually by two board-certified neuroradiologists blinded to clinical details and were compared with MRI studies of 96 subjects with first simple febrile seizure. Quantitative analysis of hippocampal volume was performed by two independent observers. RESULTS: Hippocampal malrotation was present in 20 of 226 (8.8%) patients with febrile status epilepticus compared with two of 96 (2.1%) control subjects (odds ratio [OR], 4.56; 95% CI, 1.05-19.92). Hippocampal malrotation was exclusively left-sided in 18 of 22 (81.8%) patients and bilateral in the remaining four patients (18.2%). There was no case of exclusively right-sided hippocampal malrotation. Hippocampal malrotation was more common in boys than in girls (OR, 6.1; 95% CI, 1.7-21.5). On quantitative volumetric MRI analysis, the left hippocampal volume was smaller in patients with hippocampal malrotation than in control subjects with simple febrile seizure (p = 0.004), and the right-to-left hippocampal volume ratio was higher in the hippocampal malrotation group than in the simple febrile seizure group (p < 0.001). CONCLUSION: Hippocampal malrotation is a developmental malformation that predominantly affects the left hippocampus in male patients and is more frequently found in children with prolonged febrile status epilepticus than in control subjects. These data provide further evidence that hippocampal malrotation represents a pathologic error in brain development rather than a normal variant.

Temporal lobe epilepsy in infants and children.

Clinical expression of temporal lobe seizures is different with a more diverse and more extensive etiology in infants and children than it is in adults. It is dominated by cortical dysplasia, low-grade tumors and perinatal damage. Hippocampal sclerosis, although less frequent, exists in children usually as a dual pathology associated with ipsilateral neocortical lesions. The clinical semiology of temporal seizures is more varied, and sometimes misleading. Motor features including tonic, clonic or myoclonic behaviors, and infantile spasms predominate in infants. Classical complex partial seizures with behavioral arrest and automatisms, as well as lateralizing signs are rare and occur mostly with onset after the age of two years. Interestingly, aura, emotional, and autonomic signs seem to be independent on the brain maturation process. Moreover, the neuropsychological profile varies according to age of onset and duration, lateralization of the focus and etiology. Quality of care benefits from individual cognitive assessment for memory and emotional processes.

Knockdown of the candidate dyslexia susceptibility gene homolog dyx1c1 in rodents: effects on auditory processing, visual attention, and cortical and thalamic anatomy.

The current study investigated the behavioral and neuroanatomical effects of embryonic knockdown of the candidate dyslexia susceptibility gene (CDSG) homolog Dyx1c1 through RNA interference (RNAi) in rats. Specifically, we examined long-term effects on visual attention abilities in male rats, in addition to assessing rapid and complex auditory processing abilities in male and, for the first time, female rats. Our results replicated prior evidence of complex acoustic processing deficits in Dyx1c1 male rats and revealed new evidence of comparable deficits in Dyx1c1 female rats. Moreover, we found new evidence that knocking down Dyx1c1 produced orthogonal impairments in visual attention in the male subgroup. Stereological analyses of male brains from prior RNAi studies revealed that, despite consistent visible evidence of disruptions of neuronal migration (i.e., heterotopia), knockdown of Dyx1c1 did not significantly alter the cortical volume, hippocampal volume, or midsagittal area of the corpus callosum (measured in a separate cohort of like-treated Dyx1c1 male rats). Dyx1c1 transfection did, however, lead to significant changes in medial geniculate nucleus (MGN) anatomy, with a significant shift to smaller MGN neurons in Dyx1c1-transfected animals. Combined results provide important information about the impact of Dyx1c1 on behavioral functions that parallel domains known to be affected in language-impaired populations as well as information about widespread changes to the brain following early disruption of this CDSG.

Intracranial evaluation of the epileptogenic zone in regional infrasylvian polymicrogyria.

PURPOSE: To define the relationship between the epileptogenic zone and the polymicrogyric area using intracranial electroencephalography (EEG) recordings in patients with structural epilepsy associated with regional infrasylvian polymicrogyria (PMG). METHODS: We retrospectively reviewed the medical charts, scalp, and intracranial video-EEG recordings, neuroimaging findings, and neuropsychological evaluations of four patients with refractory temporal lobe epilepsy related to PMG who consequently underwent resective surgery. KEY FINDINGS: High-resolution magnetic resonance imaging (MRI) revealed temporal lobe PMG in all cases, accompanied by hippocampal malrotation and closed lip schizencephaly in 3/4 cases, respectively. In intracranial recordings, interictal spike activity was localized within the PMG in only 2/4 and within the amygdala, hippocampus, and entorhinal cortex in all cases. In the first patient, two epileptogenic networks coexisted: the prevailing network initially involved the mesial temporal structures with spread to the anterior PMG; the secondary network successively involved the anterior part of the PMG and later the mesial temporal structures. In the second patient, the epileptogenic network was limited to the mesial temporal structures, fully sparing the PMG. In the third patient, the epileptogenic network first involved the mesial temporal structures and later the PMG. Conversely, in the last case, part of the PMG harbored an epileptogenic network that propagated to the mesial temporal structures. Consistent with these findings a favorable outcome (Engel class I in three of four patients; Engel class II in one of four) at last follow-up was obtained by a resection involving parts of the PMG cortex in three of four and anteromesial temporal lobe structures in another three of four cases. SIGNIFICANCE: Infrasylvian PMG displays a heterogeneous epileptogenicity and is occasionally and partially involved in the epileptogenic zone that commonly includes the mesial temporal structures. Our results highlight the intricate interrelations between the MRI-detectable lesion and the epileptogenic zone as delineated by intracranial recordings. Seizure freedom can be accomplished as a result of a meticulous intracranial study guiding a tailored resection that may spare part of the PMG.

Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.

Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Two identified lissencephaly genes do not account for all known cases, and additional lissencephaly syndromes have been described. An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN). The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity. RELN encodes a large (388 kD) secreted protein that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11 ), alpha3beta1 integrin and protocadherins. Although reelin was previously thought to function exclusively in brain, some humans with RELN mutations show abnormal neuromuscular connectivity and congenital lymphoedema, suggesting previously unsuspected functions for reelin in and outside of the brain.

Automatic hippocampal segmentation in temporal lobe epilepsy: impact of developmental abnormalities.

In drug-resistant temporal lobe epilepsy (TLE), detecting hippocampal atrophy on MRI is important as it allows defining the surgical target. The performance of automatic segmentation in TLE has so far been considered unsatisfactory. In addition to atrophy, about 40% of patients present with developmental abnormalities (referred to as malrotation) characterized by atypical morphologies of the hippocampus and collateral sulcus. Our purpose was to evaluate the impact of malrotation and atrophy on the performance of three state-of-the-art automated algorithms. We segmented the hippocampus in 66 patients and 35 sex- and age-matched healthy subjects using a region-growing algorithm constrained by anatomical priors (SACHA), a freely available atlas-based software (FreeSurfer) and a multi-atlas approach (ANIMAL-multi). To quantify malrotation, we generated 3D models from manual hippocampal labels and automatically extracted collateral sulci. The accuracy of automated techniques was evaluated relative to manual labeling using the Dice similarity index and surface-based shape mapping, for which we computed vertex-wise displacement vectors between automated and manual segmentations. We then correlated segmentation accuracy with malrotation features and atrophy. ANIMAL-multi demonstrated similar accuracy in patients and healthy controls (p > 0.1), whereas SACHA and FreeSurfer were less accurate in patients (p < 0.05). Surface-based analysis of contour accuracy revealed that SACHA over-estimated the lateral border of malrotated hippocampi (r = 0.61; p < 0.0001), but performed well in the presence of atrophy (|r |< 0.34; p > 0.2). Conversely, FreeSurfer and ANIMAL-multi were affected by both malrotation (FreeSurfer: r = 0.57; p = 0.02, ANIMAL-multi: r = 0.50; p = 0.05) and atrophy (FreeSurfer: r = 0.78, p < 0.0001, ANIMAL-multi: r = 0.61; p < 0.0001). Compared to manual volumetry, automated procedures underestimated the magnitude of atrophy (Cohen's d: manual: 1.68; ANIMAL-multi: 1.11; SACHA: 1.10; FreeSurfer: 0.90, p < 0.0001). In addition, they tended to lateralize the seizure focus less accurately in the presence of malrotation (manual: 64%; ANIMAL-multi: 55%, p = 0.4; SACHA: 50%, p = 0.1; FreeSurfer: 41%, p = 0.05). Hippocampal developmental anomalies and atrophy had a negative impact on the segmentation performance of three state-of-the-art automated methods. These shape variants should be taken into account when designing segmentation algorithms.

Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration.

Premutation CGG repeat expansions (55-200 CGG repeats; preCGG) within the fragile X mental retardation 1 (FMR1) gene give rise to the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), primary ovarian insufficiency and neurodevelopmental problems. Morphometric analysis of Map2B immunofluorescence reveals that neurons cultured from heterozygous female mice with preCGG repeats in defined medium display shorter dendritic lengths and fewer branches between 7 and 21 days in vitro compared with wild-type (WT) littermates. Although the numbers of synapsin and phalloidin puncta do not differ from WT, preCGG neurons possess larger puncta. PreCGG neurons display lower viability, and express elevated stress protein as they mature. PreCGG neurons have inherently different patterns of growth, dendritic complexity and synaptic architecture discernable early in the neuronal trajectory to maturation, and may reflect a cellular basis for the developmental component of the spectrum of clinical involvement in carriers of premutation alleles. The reduced viability of preCGG neurons is consistent with the mRNA toxicity and neurodegeneration associated with FXTAS.