Loss of memory for auditory-spatial associations following unilateral medial temporal-lobe damage

The goal of the present experiment was to determine the role of medial temporal-lobe structures in episodic memory of auditory-spatial associations. By using a two-alternative forced choice paradigm in which an association between eight different sounds and their spatial location must be recognized, learning abilities over 10 learning sessions were tested in 19 patients who had undergone a right or a left medial temporal-lobe resection for the relief of intractable seizures as well as in nine normal control participants. The data demonstrated that significant learning took place over the successive sessions for all the participants. In addition, the results showed that patients with left but not right medial temporal-lobe lesion were impaired in this learning task as compared to normal participants, suggesting the predominant implication of left medial temporal-lobe structures in auditory-spatial associative learning. The predominant role of left hemisphere structures in this memory task could be explained by a spatial categorical coding, which was enhanced by the use of eight loud-speakers. This result also suggests that the ability to store an episodic event associated with a rich spatial (or temporal) context depends on the left medial temporal-lobe structures. Thus, this finding provides an interesting parallel with data obtained in the visual modality by documenting for the first time the role of the left medial temporal-lobe in episodic learning of auditory-spatial associations

Effect of unilateral temporal lobe resection on short-term memory for auditory object and sound location

To investigate auditory spatial and nonspatial short-term memory, a sound location discrimination task and an auditory object discrimination task were used in patients with medial temporal lobe resection. The results showed a double dissociation between the side of the medial temporal lobe lesion and the nature of the auditory discrimination deficits, suggesting that right and left temporal lobe structures are differently involved in auditory spatial and nonspatial short-term memory

Increased DJ-1 expression under oxidative stress and in Alzheimer's disease brains

Mutations in the DJ-1 gene have been linked to autosomal recessive familial Parkinson's disease. To understand the function of DJ-1, we determined the DJ-1 expression in both zebrafish and post mortem human brains. We found that DJ-1 was expressed early during zebrafish development and throughout adulthood. Knock down (KD) of DJ-1 by injection of morpholino did not cause dramatic morphologic alterations during development, and no loss of dopaminergic neurons was observed in embryos lacking DJ-1. However, DJ-1 KD embryos were more susceptible to programmed cell death. While a slight reduction in staining for islet-1 positive neurons was observed in both DJ-1 KD and H2O2 treated embryos, the number of apoptotic cells was significantly increased in both KD and H2O2 treated embryos. Interestingly, DJ-1 expression was increased in brains of zebrafish under conditions of oxidative stress, indicating that DJ-1 is a part of stress-responsive machinery. Since oxidative stress is one of the major contributors to the development of Alzheimer's disease (AD), we also examined DJ-1 expression in AD brains. Using DJ-1 specific antibodies, we failed to detect a robust staining of DJ-1 in brain tissues from control subjects. However, DJ-1 immunoreactivity was detected in hippocampal pyramidal neurons and astrocytes of AD brains. Therefore, our results strongly suggest that DJ-1 expression is not necessary during zebrafish development but can be induced in zebrafish exposed to oxidative stress and is present in human AD brains

Spatial and non-spatial auditory short-term memory in patients with temporal-lobe lesion

Primate auditory systems are divided into at least two different pathways. One refers to objects and the other deals with localization. To investigate auditory spatial and non-spatial short-term memory, we tested patients with unilateral medial temporal lobe lesions including the pole in two tasks involving either sound localization discrimination or auditory object discrimination. The results showed that both left and right temporal lobe lesions impaired spatial short-term memory whereas only lesions on the right affected non-spatial short-term memory. By contrast, the same patients were able to perform the tasks when short interstimulus intervals were used suggesting that short-term memory deficits can not be ascribed to difficulties in perception. These findings document, for the first time, in a neurological population, the functional dissociation between spatial and non-spatial auditory short-term memory that seem to depend on separate neural circuits within the medial temporal lobe

Cardiac investigations in sudden unexpected death in DEPDC5-related epilepsy

Objective: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP. Methods: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5c/−), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures. Results: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic–ECG records on Depdc5c/− mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia. Interpretation: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies. ANN NEUROL 2022;91:101–11

Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations

open14siMutations in the sodium-activated potassium channel gene KCNT1 have been associated with nonlesional sleep-related hypermotor epilepsy (SHE). We report the co-occurrence of mild malformation of cortical development (mMCD) and KCNT1 mutations in four patients with SHE. Focal cortical dysplasia type I was neuropathologically diagnosed after epilepsy surgery in three unrelated MRI-negative patients, periventricular nodular heterotopia was detected in one patient by MRI. Our findings suggest that KCNT1 epileptogenicity may result not only from dysregulated excitability by controlling Na+K+ transport, but also from mMCD. Therefore, pathogenic variants in KCNT1 may encompass both lesional and nonlesional epilepsies.openRubboli G.; Plazzi G.; Picard F.; Nobili L.; Hirsch E.; Chelly J.; Prayson R.A.; Boutonnat J.; Bramerio M.; Kahane P.; Dibbens L.M.; Gardella E.; Baulac S.; Moller R.S.Rubboli, G.; Plazzi, G.; Picard, F.; Nobili, L.; Hirsch, E.; Chelly, J.; Prayson, R. A.; Boutonnat, J.; Bramerio, M.; Kahane, P.; Dibbens, L. M.; Gardella, E.; Baulac, S.; Moller, R. S

The GABBR1 locus and the G1465A variant is not associated with temporal lobe epilepsy preceded by febrile seizures

BACKGROUND: Polymorphism G1465A in the GABBR1 gene has been suggested as a risk factor for non-lesional temporal lobe epilepsy (TLE); however, this genetic association study has not been independently replicated. We attempted to replicate this study in our cohort of patients with TLE. Furthermore, we also analyzed the coding sequence of this gene and searched for disease-causing mutations. METHODS: We included 120 unrelated individuals with TLE that was preceded by febrile seizures (FS) who did not have any evidence of structural lesions suggesting secondary epilepsy. 66 individuals had positive family history of TLE epilepsy and 54 were sporadic. Each patient was genotyped for the presence of G1465A polymorphism. All exons of the GABBR1 gene were screened by single strand confirmation polymorphism method. Genotypes were compared with two independent matched control groups. RESULTS: We detected two A alleles of the G1465A polymorphism in one homozygous control subject (0.87% of all alleles) and one A allele in a patient with TLE (0.45%, not significant). Other detected polymorphisms in coding regions had similar frequencies in epilepsy patients and control groups. No disease causing mutations in the GABBR1 gene were detected in patients with sporadic or familial TLE. CONCLUSION: Our results indicate that TLE preceded by FS is not associated with the polymorphisms or mutations in the GABBR1 gene, including the G1465A polymorphism. The proportion of TLE patients with FS in the original study, reporting this positive association, did not differ between allele A negative and positive cases. Thus, our failure to reproduce this result is likely applicable to all non-lesional TLE epilepsies

Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Objective: Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme. Methods: Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients. Results: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa =.65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases. Significance: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype–phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype–phenotype diagnosis in the near future