Language processing within the human medial temporal lobe

Although the hippocampal formation is essential for verbal memory, it is not fully understood how it contributes to language comprehension. We recorded event-related potentials (ERPs) directly from two substructures of the medial temporal lobe (MTL), the rhinal cortex and the hippocampus proper, while epilepsy patients listened to sentences that either were correct or contained semantic or syntactic violations. Semantic violations elicited a large negative ERP response peaking at approximately 400 ms in the rhinal cortex. In contrast, syntactically incorrect sentences elicited a negative deflection of 500-800 ms in the hippocampus proper. The results suggest that functionally distinct aspects of integration in language comprehension are supported by different MTL structures: the rhinal cortex is involved in semantic integration, whereas the hippocampus proper subserves processes of syntactic integration. An analysis of phase synchronization within the gamma band between rhinal and hippocampal recording sites showed that both of the above-mentioned ERP components were preceded by an increase of phase synchronization. In contrast to these short phasic increases of phase synchronization in both violation conditions, correct sentences were associated with a long-lasting synchronization in a late time window, possibly reflecting the integration of semantic and syntactic information as required for normal comprehension.     

Functional differentiation within the medial temporal lobe in the rat

The structures that comprise the medial temporal lobe (MTL) have been implicated in learning and memory. The question of primary concern in the present research was whether the group of anatomically related structures (hippocampus, subiculum, presubiculum/parasubiculum, entorhinal cortex, perirhinal/postrhinal cortex) are involved in mediating a similar memory process or whether the individual structures are differentially involved in memory processes and/or in handling various types of information. A series of five experiments were carried out that involved selectively lesioning the main MTL structures and testing each animal on radial-maze tasks and procedures that provided measures of two different memory processes (reference memory, working memory) and the utilization of two kinds of information (spatial, nonspatial). The structures were found to differ functionally, with the hippocampus and the presubiculum/parasubiculum being especially involved in processing spatial information, and the perirhinal/postrhinal cortex having a specific role in remembering information over a brief time period (working memory). Lesions of the entorhinal cortex failed to affect consistently either memory process or type of information handled, but they did result in impairments in learning the complex spatial discrimination requiring reference memory and in working memory involving nonspatial information. The pattern of behavioral impairments resulting from damage to these discrete MTL structures suggests that several of the structures make unique contributions to learning and memory.     

Category-specificity in the human medial temporal lobe cortex

The medial temporal lobe cortex (MTLC) occupies a pivotal position at the interface between neocortical association areas and the hippocampus. It has been suggested that the MTLC contains functionally distinct regions, with perirhinal cortex (PRc) preferentially supporting object processing and posterior parahippocampal cortex (PHc) preferentially supporting encoding of spatial information. Measuring differential BOLD responsiveness to objects, scenes, and other stimulus categories, we find a double dissociation between an anterior PRc response to objects and a posterior PHc response to scene stimuli. Furthermore, an anatomical ROI based approach was undertaken in an effort to understand the response profile underlying this double dissociation. We did not see any evidence for a sharp border between putatively distinct scene-preferential and object-preferential MTLC regions. Instead, scene-preferential responsiveness was noted to drop off in a graded, linear fashion in successively anterior MTLC regions until object-preferential responsiveness emerged in anterior PRc, although objects produced above baseline responses across the anterior-posterior extent of the parahippocampal gyrus. Other stimulus categories, such as faces and words, led to above baseline activation in either a few confined regions (faces) or none at all (words). Thus, what differentiated regions along the parahippocampal gryus was the relative response to objects and scenes, not simply above baseline responses to either category. This pattern raises the possibility that posterior PHc, and anterior PRc are situated at the ends of a single organizational continuum supported by the entire length of MTLC.     

Sequence of Abeta-protein deposition in the human medial temporal lobe

The deposition of Abeta protein (Abeta) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Abeta-deposits occurring in the course of AD, as well as for the relationship between the development of Abeta-deposition and that of neurofibrillary pathology. In the first of 4 phases of beta-amyloidosis, diffuse non-neuritic plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-beta and pre-gamma, and fleecy amyloid deposits occur in the internal entorhinal layers pri-alpha, pri-beta, pri-gamma, and in CA1. In the third phase, Abeta-deposits emerge in the molecular layer of the fascia dentata, and band-like Abeta-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Abeta-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only plaques in CA4. Diffuse plaques evolve sporadically in the external entorhinal layer pre-alpha. Parallel to the evolution of beta-amyloidosis as represented by the 4 phases, neuritic plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Abeta and the presence of neurofibrillary tangles in neurons targeting the regions where neuritic plaques evolve. Each of the different types of Abeta-deposits, including neuritic plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of beta-amyloidosis. The 4 phases in the evolution of beta-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.     

Specialization in the medial temporal lobe for processing of objects and scenes

There has been considerable debate as to whether the hippocampus and perirhinal cortex may subserve both memory and perception. We administered a series of oddity tasks, in which subjects selected the odd stimulus from a visual array, to amnesic patients with either selective hippocampal damage (HC group) or more extensive medial temporal damage, including the perirhinal cortex (MTL group). All patients performed normally when the stimuli could be discriminated using simple visual features, even if faces or complex virtual reality scenes were presented. Both patient groups were, however, severely impaired at scene discrimination when a significant demand was placed on processing spatial information across viewpoint independent representations, while only the MTL group showed a significant deficit in oddity judgments of faces and objects when object viewpoint independent perception was emphasized. These observations provide compelling evidence that the human hippocampus and perirhinal cortex are critical to processes beyond long-term declarative memory and may subserve spatial and object perception, respectively.     

Increased functional connectivity within medial temporal lobe in mild cognitive impairment

Pathology at preclinical and prodromal stages of Alzheimer's disease (AD) may manifest itself as measurable functional change in neuronal networks earlier than detectable structural change. Functional connectivity as measured using resting‐state functional magnetic resonance imaging has emerged as a useful tool for studying disease effects on baseline states of neuronal networks. In this study, we use high resolution MRI to label subregions within the medial temporal lobe (MTL), a site of early pathology in AD, and report an increase in functional connectivity in amnestic mild cognitive impairment between entorhinal cortex and subregions of the MTL, with the strongest effect in the anterior hippocampus. However, our data also replicated the effects of decreased connectivity of the MTL to other nodes of the default mode network reported by other researchers. This dissociation of changes in functional connectivity within the MTL versus the MTL's connection with other neocortical structures can help enrich the characterization of early stages of disease progression in AD. © 2012 Wiley Periodicals, Inc.     

Material specific lateralization of medial temporal lobe function: An fMRI investigation

The theory of material specific lateralization of memory function posits that left and right MTL regions are asymmetrically involved in mnemonic processing of verbal and nonverbal material respectively. Lesion and functional imaging (fMRI) studies provide robust evidence for a left MTL asymmetry in the verbal memory domain. Evidence for a right MTL/nonverbal asymmetry is not as robust. A handful of fMRI studies have investigated this issue but have generally utilised nonverbal stimuli which are amenable to semantic elaboration. This fMRI study aimed to investigate the neural correlates of recognition memory processing in 20 healthy young adults (mean age = 26 years) for verbal stimuli and nonverbal stimuli that were specifically designed to minimize verbalisation. Analyses revealed that the neural correlates of recognition memory processing for verbal and nonverbal stimuli were differentiable and asymmetrically recruited the left and right MTL respectively. The right perirhinal cortex and hippocampus were preferentially involved in successful recognition memory of items devoid of semantic information. In contrast, the left anterior hippocampus was preferentially involved in successful recognition memory of stimuli which contained semantic meaning. These results suggest that the left MTL is preferentially involved in mnemonic processing of verbal/semantic information. In contrast, the right MTL is preferentially involved in visual/non‐semantic mnemonic processing. We propose that during development, the left MTL becomes specialised for verbal mnemonic processing due to its proximity with left lateralised cortical language processing areas while visual/non‐semantic mnemonic processing gets ‘crowded out’ to become predominantly, but not completely, the domain of the right MTL. Hum Brain Mapp 37:933–941, 2016. © 2015 Wiley Periodicals, Inc .     

Neural networks involving the medial temporal structures in temporal lobe epilepsy.

OBJECTIVES: In a previous study using the averaged coherence technique to study interactions between medial/limbic and lateral/neocortical regions, we observed that epileptogenic networks in temporal lobe epilepsy seizures (TLES) could be divided into 4 subtypes, i.e. medial (M), medial-lateral (ML), lateral-medial (LM), and lateral (L). In the ML and LM subtypes, medial structures and the anterior temporal neocortex are co-activated at the onset of seizures. However, using this approach, we were unable to determine the direction of coupling and may have overlooked non-linear variations in interdependency. The purpose of the present study using non-linear regression for analysis of stereoelectroencephalographic (SEEG) signal pairs was to measure the degree and direction of coupling between medial and neocortical areas during TLES in patients with the M, ML, and LM subtypes. METHODS: Eighteen patients with drug-resistant TLEs who underwent SEEG recording were studied. We used a non-linear correlation method as a measure of the degree and the direction of coupling on SEEG signal pairs. Patients with pure lateral TLEs were not studied. We analyzed the functional coupling between 3 regions of the temporal lobe: the anterior temporal neocortex, the amygdala, and the anterior hippocampus. A physiological model of EEG generation was used to validate the non-linear quantification method and assess its applicability to real SEEG signals. RESULTS: Results are first based on a physiological model of EEG data in which both degree and direction of coupling are explicitly represented, thus allowing construction of the neural systems inside which causality relationships are controlled and generation of multichannel EEG signals from these systems. These signals provide an objective way of studying the performance of non-linear regression analysis on real signals.In medial networks (10 patients), the ictal discharge is limited to the medial limbic structures and may propagate secondarily to the cortex. Quantified results demonstrated no significant coupling between medial and lateral structures at the beginning of the seizures. Conversely, almost constant unidirectional or bidirectional coupling was observed between hippocampus and amygdala.In medial-lateral (5 patients) and lateral-medial (3 patients) networks, the initial ictal discharge includes both limbic and neocortical regions. A rapid "tonic" discharge is observed over the temporal neocortex at the onset of seizure. Quantitative analysis showed an initial increase in the non-linear correlation coefficient between neocortex and medial structures. Quantification of the coupling direction demonstrated influence of medial over lateral structures (medial-lateral) or of the lateral neocortex over medial structures (lateral-medial). CONCLUSIONS: These results confirm the existence of several generic and organized networks involving the medial structures during TLE seizures.     

Normal eye tracking is associated with abnormal morphology of medial temporal lobe structures in schizophrenia.

Eye tracking and brain morphology assessed by magnetic resonance imaging were examined in 48 patients in their first episode of schizophrenia and in 15 normal controls. Schizophrenic patients showed higher rates of eye tracking dysfunction and more abnormal brain morphology involving the lateral ventricles, medial temporal lobe (MTL) structures and the frontal-parietal cortex than controls. Enlargement of the lateral ventricles and global rating of abnormal brain morphology were significantly more prevalent in male schizophrenics than female schizophrenics. These findings indicate that abnormalities in a variety of brain regions are present in some schizophrenics during the period shortly after the first hospitalization and could not be a function of treatment or chronic illness. We found no relation between abnormal eye tracking and any single feature of abnormal brain morphology. However, normal eye tracking was significantly associated with MTL abnormalities in schizophrenics, reflecting an inverse association between quality of eye tracking and degree of abnormality in MTL structures. These results suggest that abnormal eye tracking is not mediated by the same processes that lead to structural brain anomalies in schizophrenia.     

High-frequency oscillations recorded in human medial temporal lobe during sleep

The presence of fast ripple oscillations (FRs, 200-500 Hz) has been confirmed in rodent epilepsy models but has not been observed in nonepileptic rodents, suggesting that FRs are associated with epileptogenesis. Although studies in human epileptic patients have reported that both FRs and ripples (80-200 Hz) chiefly occur during non-rapid eye movement sleep (NREM), and that ripple oscillations in human hippocampus resemble those found in nonprimate slow wave sleep, quantitative studies of these oscillations previously have not been conducted during polysomnographically defined sleep and waking states. Spontaneous FRs and ripples were detected using automated computer techniques in patients with medial temporal lobe epilepsy during sleep and waking, and results showed that the incidence of ripples, which are thought to represent normal activity in animal and human hippocampus, was similar between epileptogenic and nonepileptogenic temporal lobe, whereas rates of FR occurrence were significantly associated with epileptogenic areas. The generation of both FRs and ripples showed the highest rates of occurrence during NREM sleep. During REM sleep, ripple rates were lowest, whereas FR rates remained elevated and were equivalent to rates observed during waking. The predominance of FRs within the epileptogenic zone not only during NREM sleep, but also during epileptiform-suppressing desynchronized episodes of waking and REM sleep supports the view that FRs are the product of pathological neuronal hypersynchronization associated with seizure-generating areas.     

Identification of the human medial temporal lobe regions on magnetic resonance images

The medial temporal lobe (MTL) plays a key role in learning, memory, spatial navigation, emotion, and social behavior. The improvement of noninvasive neuroimaging techniques, especially magnetic resonance imaging, has increased the knowledge about this region and its involvement in cognitive functions and behavior in healthy subjects and in patients with various neuropsychiatric and neurodegenerative disorders. However, cytoarchitectonic boundaries are not visible on magnetic resonance images (MRI), which makes it difficult to identify precisely the different parts of the MTL (hippocampus, amygdala, temporopolar, perirhinal, entorhinal, and posterior parahippocampal cortices) with imaging techniques, and thus to determine their involvement in normal and pathological functions. Our aim in this study was to define neuroanatomical landmarks visible on MRI, which can facilitate the examination of this region. We examined the boundaries of the MTL regions in 50 post‐mortem brains. In eight cases, we also obtained post‐mortem MRI on which the MTL boundaries were compared with histological examination before applying them to 26 in vivo MRI of healthy adults. We then defined the most relevant neuroanatomical landmarks that set the rostro‐caudal limits of the MTL structures, and we describe a protocol to identify each of these structures on coronal T1‐weighted MRI. This will help the structural and functional imaging investigations of the MTL in various neuropsychiatric and neurodegenerative disorders affecting this region. Hum Brain Mapp 35:248–256, 2014. © 2012 Wiley Periodicals, Inc.     

Parametric fMRI analysis of visual encoding in the human medial temporal lobe

A number of functional brain imaging studies indicate that the medial temporal lobe system is crucially involved in encoding new information into memory. However, most studies were based on differences in brain activity between encoding of familiar vs. novel stimuli. To further study the underlying cognitive processes, we applied a parametric design of encoding. Seven healthy subjects were instructed to encode complex color pictures into memory. Stimuli were presented in a parametric fashion at different rates, thus representing different loads of encoding. Functional magnetic resonance imaging (fMRI) was used to assess changes in brain activation. To determine the number of pictures successfully stored into memory, recognition scores were determined afterwards. During encoding, brain activation occurred in the medial temporal lobe, comparable to the results obtained by others. Increasing the encoding load resulted in an increase in the number of successfully stored items. This was reflected in a significant increase in brain activation in the left lingual gyrus, in the left and right parahippocampal gyrus, and in the right inferior frontal gyrus. This study shows that fMRI can detect changes in brain activation during variation of one aspect of higher cognitive tasks. Further, it strongly supports the notion that the human medial temporal lobe is involved in encoding novel visual information into memory.     

Right medial temporal lobe structures particularly impact early stages of affective picture processing

Human vision prioritizes emotional stimuli. This is reflected in stronger electrocortical activation in response to emotional than neutral stimuli, measurable on the surface of the head. Feedback projections from brain structures deep within the medial temporal lobes (mTLs), in particular the amygdala, are thought to give rise to this phenomenon, although causal evidence is rare. Given the many pathways involved in visual processing, the influence of mTL structures could be restricted to specific time windows. Therefore, we delineate the temporal dynamics of the impact of right mTL structures on affective picture processing, investigating event‐related potentials (ERPs) in 19 patients (10 female) with right mTL resections and 19 individually matched healthy participants, while they viewed negative and neutral scenes. Groups differed significantly at early‐ and mid‐latency processing stages. Patients with right mTL resection, unlike controls, showed no (P1: 90–140 ms) or marginal (N1: 170–220 ms) emotion modulation. At mid‐latency (early posterior negativity: 220–370 ms), emotion modulation over the ipsi‐resectional right hemisphere was smaller in patients than in controls, but groups did not differ over the left hemisphere. During late parietal positivities (400–650 ms and 650–900 ms), both groups had similar emotion modulation. Our results demonstrate that right mTL structures attenuate particularly early processing of affectively negative scenes. This is theoretically consistent with an initial amygdala‐dependent feedforward sweep in visual emotion processing whose absence is successively compensated. Findings specify the impact of right mTL structures on emotional picture processing and highlight the value of time‐resolved measures in affective neuroscience.

We have compared event‐related potential correlates of affective picture processing in 19 patients with right temporal lobe resections including the amygdala and individually matched healthy controls. Our results show that particularly early processing stages (P1, ipsi‐resectional N1 and early posterior negativity) are impaired by the resections, whereas late positivities are largely intact. These findings constrain theories on the role of medial temporal lobe structures in visual affective stimulus processing.     

Involvement of medial pulvinar thalamic nucleus in human temporal lobe seizures

PURPOSE: Several animal studies suggest that the thalamus might be involved in the maintenance and propagation of epileptic seizures. However, electrophysiologic evidence for this implication in human partial epileptic seizures is still lacking. Considering the rich and reciprocal connectivity of the medial pulvinar (PuM) with the temporal lobe, we evaluated a potential participation of this thalamic nucleus in temporal lobe epilepsy (TLE). METHODS: The electrophysiologic activity of PuM was recorded during stereoelectroencephalographic exploration of spontaneous temporal lobe seizures in 14 patients referred for presurgical assessment of refractory TLE. RESULTS: We recorded PuM ictal activity in 80% of the 74 seizures that we analyzed. This activity was characterized by rhythmic slow-waves or rhythmic spikes (RSW-RS) or both or by low-voltage fast activity (LVFA) in 64% and 36% of seizures, respectively. RSW-RS occurred mostly in seizures arising from mesiotemporal structures, whereas LVFA was more frequently observed in seizures of neocortical origin. In the 15 seizures without PuM ictal activity, spreading of the seizure outside the onset zone never occurred, whereas it did in 78% of seizures with PuM ictal involvement. Discharge propagation was systematic when PuM involvement corresponded to LVFA, whatever the seizure onset zone was, whereas it represented only 66% of the seizures when PuM exhibited RSW-RS. CONCLUSIONS: This study shows that ictal changes in PuM activity are frequently observed during temporal lobe seizures and suggests that this thalamic nucleus might participate in their propagation.     

The human medial temporal lobe processes online representations of complex objects

There has been considerable debate as to whether structures in the medial temporal lobe (MTL) support both memory and perception, in particular whether the perirhinal cortex may be involved in the perceptual discrimination of complex objects with a large number of overlapping features. Similar experiments testing the discrimination of blended images have obtained contradictory findings, and it remains possible that reported deficits in object perception are due to subtle learning in controls, but not patients. To address this issue, a series of trial-unique object "oddity" tasks, in which subjects selected the odd stimulus from a visual array, were administered to amnesic patients with either selective bilateral damage to the hippocampus or more extensive damage to MTL regions, including the perirhinal cortex. Whereas patients with damage limited to the hippocampus performed similarly to controls on all conditions, patients with perirhinal damage were significantly impaired when the task required discrimination between objects with a large number of features in common. By contrast, when the same stimuli could be discriminated using simple visual features, patients with perirhinal damage performed normally. These results are consistent with a theoretical view which holds that rostral inferotemporal cortical regions, including perirhinal cortex, represent the complex conjunctions of stimulus features necessary for both perception and memory of objects.     

High-resolution fMRI investigation of the medial temporal lobe

The medial temporal lobe (MTL) is critical for declarative memory formation. Several theories of MTL function propose functional distinctions between the different structures of the MTL, namely the hippocampus and the surrounding cortical areas. Furthermore, computational models and electrophysiological studies in animals suggest distinctions between the subregions of the hippocampus itself. Standard fMRI resolution is not sufficiently fine to resolve activity on the scale of hippocampal subregions. Several approaches to scanning the MTL at high resolutions have been made, however there are limitations to these approaches, namely difficulty in conducting group-level analyses. We demonstrate here techniques for scanning the MTL at high resolution and analyzing the high-resolution fMRI data at the group level. To address the issue of cross-participant alignment, we employ the ROI-LDDMM alignment technique, which is demonstrated to result in smaller alignment errors when compared with several other common normalization techniques. Finally, we demonstrate that the pattern of activation obtained in the high-resolution functional data is similar to that obtained at lower resolution, although the spatial extent is smaller and the percent signal change is greater. This difference in the pattern of activation may be due to less partial volume sampling in the high-resolution data, resulting in more accentuated regions of activation.     

Functional disconnectivity of the medial temporal lobe in Asperger's syndrome.

BACKGROUND: Autistic spectrum disorders (ASD) are neurodevelopmental conditions that may be caused by abnormal connectivity between brain regions constituting neurocognitive networks for specific aspects of social cognition. METHODS: We used three-way multidimensional scaling of regionally parcellated functional magnetic resonance imaging (fMRI) data to explore the hypothesis of abnormal functional connectivity in people with ASD. Thirteen high-functioning individuals with Asperger's syndrome and 13 healthy volunteers were scanned during incidental processing of fearful facial expressions. RESULTS: Using permutation tests for inference, we found evidence for significant abnormality of functional integration of amygdala and parahippocampal gyrus (p < .05, false discovery rate [FDR] corrected) in people with Asperger's syndrome. There were less salient abnormalities in functional connectivity of anterior cingulate, inferior occipital, and inferior frontal cortex, but there was no significant difference between groups in whole brain functional connectivity. CONCLUSIONS: We conclude there is evidence that functional connectivity of medial temporal lobe structures specifically is abnormal in people with Asperger's syndrome during fearful face processing.     

Suppression of gamma activity in the human medial temporal lobe by sevoflurane anesthesia

We have reported the presence of continuous gamma (30-150 Hz) activity in the human medial temporal lobe (MTL). Since the MTL is involved in learning and memory, we speculated that MTL gamma activity is related to such higher brain functions. It is thus of interest to learn how this activity changes during different states of consciousness. In this study, we recorded electrocorticographic (ECoG) activity directly from the surface of the MTL after various doses of sevoflurane anesthesia. Five epileptic patients underwent electrode placement operations in which electrodes were attached to the surfaces of the MTL and the basal temporal lobe (BTL). Immediately following the operation ECoG was recorded from each patient under four concentrations of sevoflurane anesthesia (1.5, 2.0, 2.5 and 3.0%). Fast Fourier Transform (FFT) analysis was performed on the MTL ECoGs. Under the lowest sevoflurane concentration, MTL gamma activity was observed in all patients. However, gamma activity was progressively suppressed by increased concentrations of sevoflurane, in a dose-dependent manner. Sevoflurane has been known to reduce neuronal excitability in the rat hippocampus in vitro, probably by changing GABAergic inhibition. The reduction of MTL gamma in the present study may be the result of such a mechanism. Although memory function was not tested in this study, the amount of MTL gamma activity may be related to residual memory function during anesthesia.