Extrahippocampal Structures Research Articles

The effect of hippocampal subfield damage on rapid temporal integration through statistical learning and associative inference

IntroductionThe hippocampus (HPC) supports integration of information across time, often indexed by associative inference (AI) and statistical learning (SL) tasks. In AI, an indirect association between stimuli that never appeared together is inferred, whereas SL involves learning item relationships by extracting regularities across experiences. A recent model of hippocampal function (Schapiro et al., 2017) proposes that the HPC can support temporal integration in both paradigms through its two distinct pathways. MethodsWe tested this models’ predictions in four patients with varying degrees of bilateral HPC damage and matched healthy controls, with two patients with complementary damage to either the monosynaptic or trisynaptic pathway. During AI, participants studied overlapping paired associates (AB, BC) and their memory was tested for premise pairs (AB) and for inferred pairs (AC). During SL, participants passively viewed a continuous picture sequence that contained an underlying structure of triplets that later had to be recognized. ResultsBinomial distributions were used to calculate above chance performance at the individual level. For AI, patients with focal HPC damage were impaired at inference but could correctly infer pairs above chance once premise pair acquisition was equated to controls; however, the patient with HPC and cortical damage showed severe impairment at recalling premise and inferred pairs, regardless of accounting for premise pair performance. For SL, none of the patients performed above chance, but notably neither did most controls. ConclusionsAssociative inference of indirect relationships can be intact with HPC damage to either hippocampal pathways or the HPC more broadly, provided premise pairs can first be formed. Inference may remain intact through residual HPC tissue supporting premise pair acquisition, and/or through extra-hippocampal structures supporting inference at retrieval. Clear conclusions about hippocampal contributions to SL are precluded by low performance in controls, which we caution is not dissimilar to previous amnesic studies using the same task. This complicates interpretations of studies claiming necessity of hippocampal contributions to SL and warrants the use of a common and reliable task before conclusions can be drawn.

Verbal fluency discrepancies as a marker of the prehippocampal stages of Alzheimer's disease.

Prior to evidence of episodic memory decline, a lengthy preclinical phase of Alzheimer's disease (AD) exists characterized by the build-up of tau pathology within extrahippocampal structures. Semantic memory, also impaired in AD, has been linked to degradation within these earliest affected areas. This study aimed to assess the utility of performance discrepancies between letter and category verbal fluency tasks to detect neuronal loss in brain regions affected very early by AD. Whole-brain voxel-based morphometry was used to assess the neural correlates of semantic processing in three patient groups: two groups of mild cognitive impairment (MCI) patients split into mildly (n = 58) and moderately (n = 53) affected and a mild AD dementia group (n = 71). Discrepancies between the level of impairment on the semantic category fluency test and nonsemantic letter fluency test were calculated for each participant and included in regression models measuring the relationship between semantic memory and whole-brain gray matter volume. Patients at all disease stages demonstrated a loss of the normal semantic advantage in fluency tests, showing significantly greater impairments in category relative to letter fluency. Discrepancy scores in mild MCI correlated strongly with the structural integrity of the anterior medial temporal lobes. Correlations in more severely affected groups were weaker and more widespread. Semantic memory appears a useful indicator of even the earliest stages of medial temporal damage in AD. With advancing disease severity, the discrepancy index loses its focal anatomical association, reinforcing its value as an early marker of incipient decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Dendritic reorganization in the hippocampus, anterior temporal lobe, and frontal neocortex of lithium-pilocarpine induced Status Epilepticus (SE)

Status Epilepticus (SE) is a distributed network disorder, which involves the hippocampus and extra-hippocampal structures. Epileptogenesis in SE is tightly associated with neurogenesis, plastic changes and neural network reorganization facilitating hyper-excitability. On the other hand, dendritic spines are known to be the excitatory synapse in the brain. Therefore, dendritic spine dynamics could play an intricate role in these network alterations. However, the exact reason behind these structural changes in SE are elusive. In the present study, we have investigated the aforementioned hypothesis in the lithium-pilocarpine treated rat model of SE. We have examined cytoarchitectural and morphological changes using hematoxylin-eosin and Golgi-Cox staining in three different brain regions viz. CA1 pyramidal layer of the dorsal hippocampus, layer V pyramidal neurons of anterior temporal lobe (ATL), and frontal neocortex of the same animals. We observed macrostructural and layer-wise alteration of the pyramidal layer mainly in the hippocampus and ATL of SE rats, which is associated with sclerosis in the hippocampus. Sholl analysis exhibited partial dendritic plasticity in apical and basal dendrites of pyramidal cells as compared to the saline-treated weight-/age-matched control group. These findings indicate that region-specific alterations in dendritogenesis may contribute to the development of independent epileptogenic networks in the hippocampus, ATL, and frontal neocortex of SE rats.

Brain-wide interactions during hippocampal sharp wave ripples

During periods of disengagement from the environment, transient population bursts, known as sharp wave ripples (SPW-Rs), occur sporadically. While numerous experiments have characterized the bidirectional relationship between SPW-Rs and activity in chosen brain areas, the topographic relationship between different segments of the hippocampus and brain-wide target areas has not been studied at high temporal and spatial resolution. Yet, such knowledge is necessary to infer the direction of communication. We analyzed two publicly available datasets with simultaneous high-density silicon probe recordings from across the mouse forebrain. We found that SPW-Rs coincide with a transient brain-wide increase in functional connectivity. In addition, we show that the diversity in SPW-R features, such as their incidence, magnitude, and intrahippocampal topography in the septotemporal axis, are correlated with slower excitability fluctuations in cortical and subcortical areas. Further, variations in SPW-R features correlated with the timing, sign, and magnitude of downstream responses with large-amplitude SPW-Rs followed by transient silence in extrahippocampal structures. Our findings expand on previous results and demonstrate that the activity patterns in extrahippocampal structures depend both on the intrahippocampal topographic origin and magnitude of hippocampal SPW-Rs.

Long-term seizure dynamics are determined by the nature of seizures and the mutual interactions between them

The seemingly random and unpredictable nature of seizures is a major debilitating factor for people with epilepsy. An increasing body of evidence demonstrates that the epileptic brain exhibits long-term fluctuations in seizure susceptibility, and seizure emergence seems to be a consequence of processes operating over multiple temporal scales. A deeper insight into the mechanisms responsible for long-term seizure fluctuations may provide important information for understanding the complex nature of seizure genesis. In this study, we explored the long-term dynamics of seizures in the tetanus toxin model of temporal lobe epilepsy. The results demonstrate the existence of long-term fluctuations in seizure probability, where seizures form clusters in time and are then followed by seizure-free periods. Within each cluster, seizure distribution is non-Poissonian, as demonstrated by the progressively increasing inter-seizure interval (ISI), which marks the approaching cluster termination. The lengthening of ISIs is paralleled by: increasing behavioral seizure severity, the occurrence of convulsive seizures, recruitment of extra-hippocampal structures and the spread of electrographic epileptiform activity outside of the limbic system. The results suggest that repeated non-convulsive seizures obey the ‘seizures-beget-seizures’ principle, leading to the occurrence of convulsive seizures, which decrease the probability of a subsequent seizure and, thus, increase the following ISI. The cumulative effect of repeated convulsive seizures leads to cluster termination, followed by a long inter-cluster period. We propose that seizures themselves are an endogenous factor that contributes to long-term fluctuations in seizure susceptibility and their mutual interaction determines the future evolution of disease activity.

Transient cortical diffusion restriction in children immediately after prolonged febrile seizures.

Little is known about acute febrile status epilepticus-induced injury of extrahippocampal structures. To clarify the presence and clinical significance of acute extrahippocampal injuries, we performed diffusion-weighted imaging (DWI) in children immediately after prolonged febrile seizure (PFS). We performed a retrospective cohort study in children younger than 6 years old who visited one of two hospitals due to PFSs between January 2013 and October 2018. PFS was defined as a febrile seizure that persisted for 15min or longer. We collected brain DWI data within 6h of the end of PFS. When the initial DWI detected an abnormality, a follow-up DWI was performed a few days later. The study population consisted of 101 patients with PFSs. DWI was performed within 6h in 51 patients, while the remaining 50 patients did not undergo imaging because of good recovery of consciousness. Restricted cortical diffusion was evident in 9 (18%) patients on initial DWI. All of them underwent DWI within 100min after PFS. Restricted cortical diffusion was associated with male sex, asymmetrical PFS symptoms, and a shorter duration between the end of the seizure and DWI, but was not associated with seizure duration. All cortical abnormalities had resolved on follow-up DWI of these patients within 72h after the initial imaging, but ipsilateral hippocampal hyperintensity appeared in one patient. All 9 patients with restricted cortical diffusion were finally diagnosed with PFS and discharged without sequelae. Some children with PFSs exhibit transient restricted diffusion in the regional cortex on DWI performed immediately after the end of PFS. These transient diffusion changes were not associated with unfavorable epileptic sequelae or neuroimaging in the short-term.

P2‐443: ASSOCIATION BETWEEN SUBFIELD VOLUMES OF THE MEDIAL TEMPORAL LOBE AND NEUROPSYCHOLOGICAL ASSESSMENTS

Neuropsychological assessments and neuroimaging are routinely combined in clinical practice to diagnose dementia represented by Alzheimer's disease (AD). The Montreal Cognitive Assessment (MoCA) is reported to be more suitable than the Mini-Mental State Examination (MMSE) for screening mild cognitive impairment (MCI) and mild AD. On the other hand, attention to the subfield volumes of the medial temporal lobe has recently been considered important for the differential diagnosis and early detection of AD. The aim of this study was to uncover which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits in neuropsychological assessment scores in patients with MCI and AD. We recruited from our institute 31 Japanese patients—14 with amnestic MCI and 17 with probable AD, with a clinical dementia rating (CDR) of 0.5 and 1, respectively—and 50 healthy elderly individuals with a CDR of 0. All participants underwent magnetic resonance imaging and neuropsychological assessments with the MMSE, Wechsler Memory Scale-Revised Logical Memory I and II, and Japanese version of the MoCA (MoCA-J). With adjustment for age and sex, we performed partial correlation analysis of the neuropsychological assessment scores with the subfield volumes of the medial temporal lobe measured by software-mediated automatic segmentation of hippocampal subfields using high-resolution T1-and T2-weighted images. Compared with normal controls, patients with MCI and AD showed subfield volume reductions in cornu ammonis (CA) 1, CA2, Brodmann area (BA) 35, BA36, the dentate gyrus (DG), the subiculum, and the entorhinal cortex (ERC). All participants showed high correlation coefficients (above 0.6) between neuropsychological assessment scores and subfield volumes in CA1, the DG, the subiculum, the ERC, and BA36. In patients with MCI and AD, the MoCA-J showed higher correlations than the MMSE with subfield volumes in CA1, the DG, the subiculum, and the ERC. These results suggest that the combination of the in vivo analysis of subfield morphometry of the medial temporal lobe with the MoCA-J paradigm provides important insights into whether changes within specific subfields are related to the cognitive profile in MCI and AD.

Association between subfield volumes of the medial temporal lobe and cognitive assessments

Cognitive assessments and neuroimaging are routinely combined in clinical practice to diagnose dementia represented by Alzheimer's disease (AD). The Montreal Cognitive Assessment (MoCA) is reported to be more suitable than the Mini-Mental State Examination (MMSE) for screening mild cognitive impairment (MCI) and mild AD. On the other hand, attention to the subfield volumes of the medial temporal lobe has recently been considered important for the differential diagnosis and early detection of AD. The aim of this study was to uncover which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits in cognitive assessment scores in patients with MCI and AD. We recruited from our institute 31 Japanese patients—14 with amnestic MCI and 17 with probable AD, with a clinical dementia rating (CDR) of 0.5 and 1, respectively—and 50 healthy elderly individuals with a CDR of 0. All participants underwent magnetic resonance imaging and cognitive assessments with the MMSE, Wechsler Memory Scale-Revised Logical Memory I and II, and Japanese version of the MoCA (MoCA-J). With adjustment for age and sex, we performed partial correlation analysis of the cognitive assessment scores with the subfield volumes of the medial temporal lobe measured by software-mediated automatic segmentation of hippocampal subfields using high-resolution T1-and T2-weighted images. Compared with normal controls, patients with MCI and AD showed subfield volume reductions in cornu ammonis (CA) 1, CA2, Brodmann area (BA) 35, BA36, the dentate gyrus (DG), the subiculum, and the entorhinal cortex (ERC). All participants showed high correlation coefficients (above 0.6) between cognitive assessment scores and subfield volumes in CA1, the DG, the subiculum, the ERC, and BA36. In patients with MCI and AD, the MoCA-J showed higher correlations than the MMSE with subfield volumes in CA1, the DG, the subiculum, and the ERC. These results suggest that the combination of the in vivo analysis of subfield morphometry of the medial temporal lobe with the MoCA-J paradigm provides important insights into whether changes within specific subfields are related to the cognitive profile in MCI and AD.

Less means more: The magnitude of synaptic plasticity along the hippocampal dorso-ventral axis is inversely related to the expression levels of plasticity-related neurotransmitter receptors.

The dorsoventral axis of the hippocampus exhibits functional differentiations with regard to (spatial Vs emotional) learning and information retention (rapid encoding Vs long‐term storage), as well as its sensitivity to neuromodulation and information received from extrahippocampal structures. The mechanisms that underlie these differentiations remain unclear. Here, we explored neurotransmitter receptor expression along the dorsoventral hippocampal axis and compared hippocampal synaptic plasticity in the CA1 region of the dorsal (DH), intermediate (IH) and ventral hippocampi (VH). We observed a very distinct gradient of expression of the N‐methyl‐D‐aspartate receptor GluN2B subunit in the Stratum radiatum (DH< IH< VH). A similar distribution gradient (DH< IH< VH) was evident in the hippocampus for GluN1, the metabotropic glutamate receptors mGlu1 and mGlu2/3, GABAB and the dopamine‐D1 receptor. GABAA exhibited the opposite expression relationship (DH > IH > VH). Neurotransmitter release probability was lowest in DH. Surprisingly, identical afferent stimulation conditions resulted in hippocampal synaptic plasticity that was the most robust in the DH, compared with IH and VH. These data suggest that differences in hippocampal information processing and synaptic plasticity along the dorsoventral axis may relate to specific differences in the expression of plasticity‐related neurotransmitter receptors. This gradient may support the fine‐tuning and specificity of hippocampal synaptic encoding.

Mapping the structural and functional network architecture of the medial temporal lobe using 7T MRI.

Medial temporal lobe (MTL) subregions play integral roles in memory function and are differentially affected in various neurological and psychiatric disorders. The ability to structurally and functionally characterize these subregions may be important to understanding MTL physiology and diagnosing diseases involving the MTL. In this study, we characterized network architecture of the MTL in healthy subjects (n = 31) using both resting state functional MRI and MTL-focused T2-weighted structural MRI at 7 tesla. Ten MTL subregions per hemisphere, including hippocampal subfields and cortical regions of the parahippocampal gyrus, were segmented for each subject using a multi-atlas algorithm. Both structural covariance matrices from correlations of subregion volumes across subjects, and functional connectivity matrices from correlations between subregion BOLD time series were generated. We found a moderate structural and strong functional inter-hemispheric symmetry. Several bilateral hippocampal subregions (CA1, dentate gyrus, and subiculum) emerged as functional network hubs. We also observed that the structural and functional networks naturally separated into two modules closely corresponding to (a) bilateral hippocampal formations, and (b) bilateral extra-hippocampal structures. Finally, we found a significant correlation in structural and functional connectivity (r = 0.25). Our findings represent a comprehensive analysis of network topology of the MTL at the subregion level. We share our data, methods, and findings as a reference for imaging methods and disease-based research.

The relevance of hippocampal subfield integrity and clock drawing test performance for the diagnosis of Alzheimer’s disease and mild cognitive impairment

Objectives: The clock drawing test (CDT) is one of the worldwide most used screening tests for Alzheimer’s disease (AD). MRI studies have identified temporo-parietal regions being involved in CDT impairment. However, the contributions of specific hippocampal subfields and adjacent extrahippocampal structures to CDT performance in AD and mild cognitive impairment (MCI) have not been investigated so far. It is unclear whether morphological alterations or CDT score, or a combination of both, are able to predict AD.Methods: 38 AD patients, 38 MCI individuals and 31 healthy controls underwent neuropsychological assessment and MRI at 3 Tesla. FreeSurfer 5.3 was used to perform hippocampal parcellation. We used a collection of statistical methods to better understand the relationship between CDT and hippocampal formation. We also tested the clinical feasibility of this relationship when predicting AD.Results: Impaired CDT performance in AD was associated with widespread atrophy of the cornu ammonis, presubiculum, and subiculum, whereas MCI subjects showed CDT-related alterations of the CA4-dentate gyrus and subiculum. CDT correlates in AD and MCI showed regional and quantitative overlap. Importantly, CDT score was the best predictor of AD.Conclusions: Our findings lend support for an involvement of different hippocampal subfields in impaired CDT performance in AD and MCI. CDT seems to be more efficient than subfield imaging for predicting AD.

Hippocampal formation alterations differently contribute to autobiographic memory deficits in mild cognitive impairment and Alzheimer's disease

Autobiographical memory (AM) is part of declarative memory and includes both semantic and episodic aspects. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. Previous MRI studies in AD patients have showed that deficits in semantic and episodic AM are associated with hippocampal alterations. However, the question which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits of AM in individuals with mild cognitive impairment (MCI) and AD patients has not been investigated so far. Hundred and seven participants (38 AD patients, 38 MCI individuals and 31 healthy controls [HC]) underwent MRI at 3 Tesla. AM was assessed with a semi-structured interview (E-AGI). FreeSurfer 5.3 was used for hippocampal parcellation. Semantic and episodic AM scores were related to the volume of 5 hippocampal subfields and cortical thickness in the parahippocampal and entorhinal cortex. Both semantic and episodic AM deficits were associated with bilateral hippocampal alterations. These associations referred mainly to CA1, CA2-3, presubiculum, and subiculum atrophy. Episodic, but not semantic AM loss was associated with cortical thickness reduction of the bilateral parahippocampal and enthorinal cortex. In MCI individuals, episodic, but not semantic AM deficits were associated with alterations of the CA1, presubiculum and subiculum. Our findings support the crucial role of CA1, presubiculum, and subiculum in episodic memory. The present results implicate that in MCI individuals, semantic and episodic AM deficits are subserved by distinct neuronal systems.

Frequency of Penile-Vaginal Intercourse is Associated with Verbal Recognition Performance in Adult Women.

Previous studies have identified a number of factors that contribute to improved cognitive function, and to memory function specifically, in cognitively normal individuals. One such factor, frequency of penile-vaginal intercourse (PVI), has been reported in a number of animal studies to be advantageous to memory for previously presented objects by increasing neurogenesis in the dentate gyrus of the hippocampus. However, studies investigating the potential benefits of frequent PVI on memory function in young women are to the best of our knowledge absent from the literature. The current study thus investigated whether the self-reported frequency of sexual intercourse was related to memory function in healthy female college students. To determine whether variation in PVI would be associated with memory performance, we asked 78 heterosexual women aged 18-29years to complete a computerized memory paradigm consisting of abstract words and neutral faces. Results showed that frequency of PVI was positively associated with memory scores for abstract words, but not faces. Because memory for words depends to a large extent on the hippocampus, whereas memory for faces may rely to a greater extent on surrounding extra-hippocampal structures, our results appear to be specific for memory believed to rely on hippocampal function. This may suggest that neurogenesis in the hippocampus is higher in those women with a higher frequency of PVI, in line with previous animal research. Taken together, these results suggest that PVI may indeed have beneficial effects on memory function in healthy young women.

Discrimination performance in aging is vulnerable to interference and dissociable from spatial memory.

Hippocampal-dependent episodic memory and stimulus discrimination abilities are both compromised in the elderly. The reduced capacity to discriminate between similar stimuli likely contributes to multiple aspects of age-related cognitive impairment; however, the association of these behaviors within individuals has never been examined in an animal model. In the present study, young and aged F344×BN F1 hybrid rats were cross-characterized on the Morris water maze test of spatial memory and a dentate gyrus-dependent match-to-position test of spatial discrimination ability. Aged rats showed overall impairments relative to young in spatial learning and memory on the water maze task. Although young and aged learned to apply a match-to-position response strategy in performing easy spatial discriminations within a similar number of trials, a majority of aged rats were impaired relative to young in performing difficult spatial discriminations on subsequent tests. Moreover, all aged rats were susceptible to cumulative interference during spatial discrimination tests, such that error rate increased on later trials of test sessions. These data suggest that when faced with difficult discriminations, the aged rats were less able to distinguish current goal locations from those of previous trials. Increasing acetylcholine levels with donepezil did not improve aged rats’ abilities to accurately perform difficult spatial discriminations or reduce their susceptibility to interference. Interestingly, better spatial memory abilities were not significantly associated with higher performance on difficult spatial discriminations. This observation, along with the finding that aged rats made more errors under conditions in which interference was high, suggests that match-to-position spatial discrimination performance may rely on extra-hippocampal structures such as the prefrontal cortex, in addition to the dentate gyrus.

Forgetting Patterns Differentiate Between Two Forms of Memory Representation

For decades, there has been controversy about whether forgetting is caused by decay over time or by interference from irrelevant information. We suggest that forgetting occurs because of decay or interference, depending on the memory representation. Recollection-based memories, supported by the hippocampus, are represented in orthogonal patterns and are therefore relatively resistant to interference from one another. Decay should be a major source of their forgetting. By contrast, familiarity-based memories, supported by extrahippocampal structures, are not represented in orthogonal patterns and are therefore sensitive to interference. In a study in which we manipulated the postencoding task-interference level and the length of the delay between study and testing, we provide direct evidence in support of our representation theory of forgetting. Recollection and familiarity were measured using the remember/know procedure. We show that the causes of forgetting depend on the nature of the underlying memory representation, which places the century-old puzzle of forgetting in a coherent framework.

Atrophy of hippocampal subfields and adjacent extrahippocampal structures in dementia with Lewy bodies and Alzheimer's disease

The hippocampus and adjacent extrahippocampal structures are organized in distinct and specialized regions which process heterogeneous functions, including memory, and visuospatial functions. Specific alterations of the different hippocampal subfields and adjacent extrahippocampal structures could differently contribute to the pathophysiology of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Based on visual symptoms which characterize DLB patients, the hippocampal subfields and the adjacent extrahippocampal structures which are mainly involved in the visual functions could be impaired in DLB and preserved in AD. To test this hypothesis, we performed structural magnetic resonance imaging on 19 DLB, 15 AD, and 19 age-matched healthy controls. FreeSurfer's pipelines were used to perform parcellation of hippocampus and adjacent extrahippocampal structures and to assess the structural changes within each region. The cornu ammonis and subiculum were bilaterally damaged in AD and preserved in DLB. The perirhinal cortex and parahippocampus were damaged in DLB but not in AD. Our findings demonstrate that the hippocampal subfields and adjacent extrahippocampal structures were differently altered in AD and DLB. Particularly, DLB patients showed a more focused alteration of the extrahippocampal structures linked to visual functions.

Does the hippocampus keep track of time?

In the present study, we examined the role of the medial temporal lobe (MTL) in prospective time estimation at short and long timescales using a novel behavioral paradigm adapted from rodent work. Amnesic patients with MTL damage and healthy control participants estimated the duration of nature-based video clips that were either short (≤ 90 s) or long (more than 4 min). Consistent with previous work in rodents, we found that amnesic patients were impaired at making estimations for long, but not for short durations. Critically, these effects were observed in patients who had lesions circumscribed to the hippocampus, suggesting that the pattern observed was not attributable to the involvement of extra-hippocampal structures. That the MTL, and more specifically the hippocampus, is critical for prospective temporal estimation only at long intervals suggests that multiple neurobiological mechanisms support prospective time estimation.

Short-Term Memory Depends on Dissociable Medial Temporal Lobe Regions in Amnestic Mild Cognitive Impairment.

Short-term memory (STM) has generally been thought to be independent of the medial temporal lobe (MTL) in contrast to long-term memory (LTM). Prodromal Alzheimer's disease (AD) is a condition in which the MTL is a major early focus of pathology and LTM is thought disproportionately affected relative to STM. However, recent studies have suggested a role for the MTL in STM, particularly hippocampus, when binding of different elements is required. Other work has suggested involvement of extrahippocampal MTL structures, particularly in STM tasks that involve item-level memory. We examined STM for individual objects, locations, and object-location conjunctions in amnestic mild cognitive impairment (MCI), often associated with prodromal AD. Relative to age-matched, cognitively normal controls, MCI patients not only displayed impairment on object-location conjunctions but were similarly impaired for non-bound objects and locations. Moreover, across all participants, these conditions displayed dissociable correlations of cortical thinning along the long axis of the MTL and associated cortical nodes of anterior and posterior MTL networks. These findings support the role of the MTL in visual STM tasks and the division of labor of MTL in support of different types of memory representations, overlapping with findings in LTM.

Functional interactions between dentate gyrus, striatum and anterior thalamic nuclei on spatial memory retrieval

The standard model of memory system consolidation supports the temporal reorganization of brain circuits underlying long-term memory storage, including interactions between the dorsal hippocampus and extra-hippocampal structures. In addition, several brain regions have been suggested to be involved in the retrieval of spatial memory. In particular, several authors reported a possible role of the ventral portion of the hippocampus together with the thalamus or the striatum in the persistence of this type of memory. Accordingly, the present study aimed to evaluate the contribution of different cortical and subcortical brain regions, and neural networks involved in spatial memory retrieval. For this purpose, we used cytochrome c oxidase quantitative histochemistry as a reliable method to measure brain oxidative metabolism. Animals were trained in a hidden platform task and tested for memory retention immediately after the last training session; one week after completing the task, they were also tested in a memory retrieval probe. Results showed that retrieval of the previously learned task was associated with increased levels of oxidative metabolism in the prefrontal cortex, the dorsal and ventral striatum, the anterodorsal thalamic nucleus and the dentate gyrus of the dorsal and ventral hippocampus. The analysis of functional interactions between brain regions suggest that the dorsal and ventral dentate gyrus could be involved in spatial memory retrieval. In addition, the results highlight the key role of the extended hippocampal system, thalamus and striatum in this process. Our study agrees with previous ones reporting interactions between the dorsal hippocampus and the prefrontal cortex during spatial memory retrieval. Furthermore, novel activation patterns of brain networks involving the aforementioned regions were found. These functional brain networks could underlie spatial memory retrieval evaluated in the Morris water maze task.

Certain secondary antiepileptic drugs can rescue hippocampal injury following a critical growth period despite poor anticonvulsant activity and cognitive deficits

Clinical and experimental studies have shown that many common secondary antiepileptic drugs (AEDs) are ineffective at blocking seizures in adulthood; however, some afford neuroprotection. In early development, certain AEDs cause apoptosis; however, it is unknown whether these drugs are neurotoxic to the juvenile brain following a developmentally regulated proapoptotic period and whether they alter the seizure threshold, seizure-induced neuronal vulnerability, and/or cognitive function. Lamotrigine (LTG), carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and topiramate (TPM) were systemically administered to rat pups for 7days beginning on postnatal (P) day 14 (P14), then half the animals were injected with kainate (KA) to trigger seizures, an age when the CA1 subregion becomes preferentially sensitive to status epilepticus. Histological outcome, seizure severity, and learning and memory were determined with an electroencephalograph (EEG), silver impregnation, and a water-maze swim task. None of the AEDs tested significantly attenuated behavioral or electrographic seizures. Phenytoin increased mortality, identifying a detrimental side effect of this drug. The other drugs (LTG, VPA, TPM, and CBZ) afforded different amounts of protection to the CA1 subregion but not to the CA3 subregion or extrahippocampal structures. With the exception of VPA, AED-treated animals lagged behind during swim task acquisition. All groups improved in the water-maze swim task over time, particularly on the last trials; however, the average escape latency was still impaired for TPM-treated animals and all AED+KA-treated groups. Thus, while certain AEDs demonstrated some neuroprotective effects, poor antiepileptic activity, memory impairment, and other deleterious side effects were observed with these drugs suggesting that the search for potentially more effective and tolerated agents is essential for improving clinical outcome in children and adolescents with epilepsy.