Proton MR spectroscopy detects a relative decrease of N-acetylaspartate in the medial temporal lobe of patients with AD

BACKGROUND: The reduction of N-acetylaspartate (NAA) detected by proton MR spectroscopy (1H-MRS) represents a robust but unspecific marker for neuronal loss or dysfunction. OBJECTIVE: To apply 1H-MRS in two brain regions that reflect the characteristic spatial distribution of neuronal loss in AD. These regions are the medial temporal lobe (MTL), which is affected early in AD, and the primary motor and sensory cortex (central region), which is affected late in the disease and might serve as an intraindividual control region in mild to moderate disease stages. METHODS: Twenty patients and 18 volunteers underwent 1H-MRS in both brain areas. The metabolic ratios of NAA/creatine and choline/creatine were determined. Additionally, the metabolic ratios of the MTL were divided by the ratios of the central region to assess the relative change in the MTL in individual subjects. All ratios were correlated with psychometric test scores. RESULTS: A significant reduction of NAA/creatine and choline/creatine ratios was detected in the MTL of patients with AD. In the central region, no significant difference between the groups was found. NAA/creatine (MTL/central region) was reduced in patients with AD and showed a correlation with the Mini-Mental State Examination and the cognitive part of the Alzheimer Disease Assessment Scale scores. Choline/creatine (MTL/central region) did not show a significant difference between groups. CONCLUSION: Assessing the distribution of NAA/creatine reduction guided by the expected neuropathologic change can improve the role of 1H-MRS in the assessment of AD. The disease severity can be monitored by relative reduction of NAA/creatine in the MTL in comparison with an intraindividual unaffected control region.     

Novelty-related activation within the medial temporal lobes

Functional magnetic resonance imaging (fMRI) was used to examine whether (1) verbal associative encoding activates the medial temporal lobes (MTL) and related regions more than non-associative encoding, (2) verbal associative novelty is related to enhanced MTL activation, and (3) verbal item novelty is related to enhanced MTL activation and, if so, whether these activations are in different or overlapping sites. No increase in MTL activation was found during verbal associative encoding relative to non-associative encoding, although associative encoding was related to a relative increase in activation in the posterior cingulate cortex. In contrast, verbal associative novelty was found to activate the MTL and posterior cingulate cortex. Verbal item novelty did not significantly activate any brain region. The verbal associative novelty-related effect occurred despite subjects having little awareness of associative novelty. The verbal associative novelty-related activation in the MTL may be related either to unconscious novelty detection or to a priming effect at encoding. We argue that if the priming explanation is correct then this may account for our failure to observe an associative encoding MTL activation.     

Decoding representations of scenes in the medial temporal lobes

Recent theoretical perspectives have suggested that the function of the human hippocampus, like its rodent counterpart, may be best characterized in terms of its information processing capacities. In this study, we use a combination of high-resolution functional magnetic resonance imaging, multivariate pattern analysis, and a simple decision making task, to test specific hypotheses concerning the role of the medial temporal lobe (MTL) in scene processing. We observed that while information that enabled two highly similar scenes to be distinguished was widely distributed throughout the MTL, more distinct scene representations were present in the hippocampus, consistent with its role in performing pattern separation. As well as viewing the two similar scenes, during scanning participants also viewed morphed scenes that spanned a continuum between the original two scenes. We found that patterns of hippocampal activity during morph trials, even when perceptual inputs were held entirely constant (i.e., in 50% morph trials), showed a robust relationship with participants' choices in the decision task. Our findings provide evidence for a specific computational role for the hippocampus in sustaining detailed representations of complex scenes, and shed new light on how the information processing capacities of the hippocampus may influence the decision making process.     

Positron emission tomography correlations in and beyond medial temporal lobes

This article discusses the potential usefulness of brain/ behavior correlational analyses in functional neuroimaging studies of memory, and how such analyses can illuminate the role of medial temporal lobes (MTL) and the hippocampus in episodic and declarative memory processes such as encoding and retrieval. Reanalysis of the results of four previously reported positron emission tomography (PET) studies yielded evidence of both positive and negative between-subjects correlations between recognition-memory accuracy and regional blood flow. The sites of these correlations were in MTL regions as well as in other cortical and subcortical areas, including frontal lobes (Brodmann areas 6, 9, 10, 11, and 47), temporal lobes (BAs 21, 22, and 38), insula, fusiform gyrus, and cuneus/precuneus. These findings were discussed with respect to issues such as localization of the correlation sites, the distinction between brain sites revealed by brain/cognition correlational analyses ("how" sites) and those yielded by cognitive subtraction methods ("what" sites), the tendency of the "how" sites in MTL to occur in the left hemisphere, the tendency of other "how" sites to occur in one or the other hemisphere, rather than bilaterally, and the meaning and "reality" of both brain/behavior correlations and task-related activations. Because of the known incidence of false-positives, all neuroimaging data, including those involving the localization of "what" and "how" memory sites in MTL and other brain regions, need to be interpreted cautiously, and findings of individual studies should not be overinterpreted.     

Absence of sleep spindles in human medial and basal temporal lobes

All-night recordings from subdural electrocorticographic (ECoG) electrodes on the human medial and basal temporal lobes were analysed to examine spindling activities during sleep. Subjects were three males and three females who were candidates for neurosurgical treatments of partial epilepsy. Subdural electrodes were attached to the medial and basal temporal lobe cortices, allowing ECoG and electroencephalogram from the scalp vertex (Cz EEG) to be recorded simultaneously during all night sleep. In one case, subdural electrodes were attached also on the parietal lobe. Fast Fourier transformation (FFT) analyses were performed on the ECoG and Cz EEG signals. No organized sleep spindles or sigma band (12-16 Hz) peaks in FFT power spectra were observed from the medial or basal temporal lobes of the non-epileptogenic hemispheres during non-rapid eye movement (NREM) sleep. In a case with parietal electrodes, organized spindle bursts were observed in parietal signals synchronized with Cz spindles. Although delta band (0.3-3 Hz) power from both the medial and basal temporal lobes fluctuated across each night as expected, sigma activity changed little. However, 14 Hz oscillatory bursts were observed in the medial basal temporal lobe of epileptogenic hemisphere in two cases and bilaterally in one case during not only NREM sleep but rapid eye movement (REM) sleep and wakefulness. From the present study we conclude that sleep spindle activities are absent in the medial and basal temporal lobes. Fourteen Hz oscillatory bursts observed from the medial or basal temporal lobe in some cases were not considered to be sleep spindles since they also appeared during REM sleep and wakefulness. These waveforms could have originated due to epileptic pathology, since they frequently appeared in epileptic regions.     

Associative encoding of pictures activates the medial temporal lobes

It remains unresolved whether the medial temporal lobe activations found in recent neuroimaging studies are mediated by novelty detection alone, by specific kinds of encoding or consolidation operations, or both. This study attempted to see whether associative encoding or consolidation is sufficient to cause such activation by matching for novelty across conditions. Using single-photon emission computer tomography (SPECT) (with Tc^99mHMPAO), we compared the activation patterns produced by the associative encoding and the perceptual matching of novel complex scenes in 10 normal subjects using both statistical parametric mapping (SPM) and a regions-of-interest (ROI) approach. During the encoding condition, significant activations were detected in the left hippocampal/parahippocampal region, the left cingulate cortex, and the right prefrontal cortex, using both statistical techniques. Additionally, activation was found in the right cingulate cortex, and a trend towards activation was found in the right hippocampal/parahippocampal region using the ROI approach. In contrast, no medial temporal activations were found during the matching condition, which produced bilateral occipito-parietal and right posterior inferior parietal (supramarginal gyrus) activations. These results not only confirm that the associative encoding and/or consolidation of complex scenes is partially mediated by medial temporal lobe structures, but also demonstrate, for the first time, that associative encoding/consolidation is sufficient to produce such an activation. The implications of the high degree of consistency revealed by the results of the SPM and ROI comparison are discussed. Hum. Brain Mapping 6:85–104, 1998. © 1998 Wiley-Liss, Inc.     

Dissociable correlates of recollection and familiarity within the medial temporal lobes

Regions in the medial temporal lobes (MTL) have long been implicated in the formation of new memories for events, however, it is unclear whether different MTL subregions support different memory processes. Here, we used event-related functional magnetic resonance imaging (fMRI) to examine the degree to which two recognition memory processes-recollection and familiarity-were supported by different MTL subregions. Results showed that encoding activity in the rhinal cortex selectively predicted familiarity-based recognition, whereas, activity in the hippocampus and posterior parahippocampal cortex selectively predicted recollection. Collectively, these results support the view that different subregions within the MTL memory system implement unique encoding processes that differentially support familiarity and recollection.     

High-resolution multi-voxel pattern analysis of category selectivity in the medial temporal lobes

Although the parahippocampal cortex (PHc) is known to be critical for memory formation, little is known about what is encoded by this area. Using multi-voxel pattern analysis of high-resolution functional magnetic resonance imaging (MRI) data, we examined responses to blocks of categorically coherent stimuli and found that patterns of activity in PHc were selective for not only scenes, but also for other nonspatial object categories (e.g., faces and toys). This pattern of results was also found in the parahippocampal place area (PPA), indicating that this region is not sensitive exclusively to scenes. In contrast, neither the hippocampus nor perirhinal cortex (PRc) were found to be selective for category information. The results indicate that regions within the medial temporal lobe may support distinct functions, and that the PHc appears to be particularly sensitive to category-level information.     

Apraxia and the parietal lobes

The widely held belief in a central role of left parietal lesions for apraxia can be traced back to Liepmann's model of a posterior to anterior stream converting mental images of intended action into motor execution. Although this model has undergone significant changes, its modern descendants still attribute the parietal contribution to the existence of mental representations of intended movements which precede and direct their motor execution. They predict that pantomime of tool use should be particularly vulnerable to parietal lesions. A review of clinical studies contradicts these assumptions: The impact of parietal lobe damage on pantomime of tool use is inconstant if not absent altogether. The domains of action which are most affected by left parietal damage are the imitation of meaningless gestures and, although probably only in the context of additional more widespread brain damage, actual use of tools and objects.I hypothesize that imitation of meaningless gestures and use of tool and objects depend on left parietal lobe integrity because of their demands on categorical apprehension of spatial relationships between multiple objects or between multiple parts of objects. For use of tools and objects the spatial relationships are between the hand, the tool, its recipient, and the material it acts upon. Categorical apprehension concentrates on features of these relations which determine mechanical interactions. For imitation of meaningless gestures, categorical apprehension of demonstrated gesture results in “body part coding” which reduces the visual appearance of the demonstrated gestures to simple spatial relationships between a limited set of discrete body parts. The hypothesis that the role of the left parietal lobe in apraxia concerns categorical apprehension of spatial relationships fits well with more general theories of parietal lobe function and hemisphere asymmetries.     

Interaction of medial temporal lobe atrophy and white matter hyperintensities in AD

The authors investigated the interaction between medial temporal lobe (MTL) atrophy and white matter hyperintensities (WMH) in Alzheimer disease (AD). They measured the MTL and WMH on MRI in 58 AD patients and 28 controls. MTL atrophy was associated with an increased risk of AD (OR = 6.2), but there was no significant association between WMH and AD. Moreover, there was an interaction between MTL and WMH (p = 0.045). These results suggest that vascular and Alzheimer-type pathology act in synergy in the clinical syndrome of AD.     

A comparative study of the different N-acetylaspartate measures of the medial temporal lobe in Alzheimer's disease

OBJECTIVE: To investigate group differences and correlations and to determine the sensitivity and specificity of different measures of the neuronal marker N-acetylaspartate (NAA) in the medial temporal lobe of Alzheimer's Disease (AD) patients. METHODS: The metabolic ratio NAA/creatine (Cr), the absolute concentration of NAA referenced against brain tissue (BT) water and NAA multiplied with the amount of BT in the proton magnetic resonance spectroscopy (1H-MRS) voxel were assessed in patients and healthy controls with a single-voxel 1H-MRS protocol. RESULTS: All measures were significantly lower in AD patients compared with controls. NAA/Cr and NAA correlated weakly, and there was no correlation of NAA with the amount of BT in the voxel. The highest specificity (87%) at a sensitivity of 80% was observed for NAA multiplied with the amount of BT in the voxel. There was no correlation of the MMSE with any of the NAA parameters. Conclusions: NAA/Cr does not reflect NAA concentration very well. NAA is not correlated with brain atrophy. The BT volume in the 1H-MRS voxel in combination with the concentration of NAA discriminates AD from healthy controls sufficiently.     

Memory loss due to transient hypoperfusion in the medial temporal lobes including hippocampus

A typical case of transient global amnesia (TGA) was investigated with single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) with 1.5-tesler scans. During the amnesic episode, a marked decrease of cerebral blood flow was observed in the areas confined to the territory of the bilateral posterior cerebral arteries including the hippocampus. After the episode, cerebral blood flow returned to normal and a circumscribed lesion was detected in the middle portion of CA 1 field of the left hippocampus. The SPECT findings prove direct evidence that the medial temporal structures are involved in the establishment of new memories, as well as in process of recalling only recently acquired memories, but not in retrieval of memories acquired long ago. The MRI findings indicate that a unilateral partial damage to CA 1 sector of the hippocampus does not develop a definite memory impairment and that high-resolution MRI study on the hippocampus is necessary in TGA patients.     

The role of recollection and familiarity in the functional differentiation of the medial temporal lobes

The components of the medial temporal lobes (MTL) receive different kinds of input. The perirhinal cortex receives primarily object/item information, the parahippocampal cortex receives contextual information, and the hippocampus receives high-level inputs that include object/item, context, and other information. Critically, the perirhinal and parahippocampal cortices have similar cytoarchitectonics, which differ considerably from that of the hippocampus and suggest that these cortices process their inputs differently from the way that the hippocampus processes its inputs. Much evidence indicates that the hippocampus is designed to rapidly bind together pattern-separated representations that support recall/recollection well. In contrast, the newer MTL cortices rapidly create poorly pattern-separated memories that support familiarity well, but recall/recollection very poorly. For over a decade, there has been disagreement about whether recall/recollection is primarily mediated by the hippocampus and familiarity by the evolutionarily newer MTL cortices or whether the MTL mediates these kinds of memory in an integrated, homogeneous fashion. Common misconceptions about familiarity, recollection, item, and associative memory are discussed as are methodological problems with MTL lesion and functional imaging research. The possible confound of familiarity with weaker memory and recollection with stronger memory is discussed and the implications of the Montaldi et al. (2006) functional Magnetic Resonance Imaging (fMRI) study, which matched memory strength between strong familiarity and recollection, finding that only recollection activated the hippocampus, are discussed. A suggestion is made about how the long-running conflict of findings in the human hippocampal lesion literature may be resolved.     

Cortical laminar thickness and column spacing in human temporal and inferior parietal lobes: intra-individual anatomical relations

Harasty, Seldon, Chan, Halliday, and Harding (2003) and Seldon (2005) have proposed a "balloon model" which suggests that myelin growth stretches the cerebral cortex, causing the cortical thickness to decrease and the columnar spacing to increase, in turn affecting the cortical capacity to differentiate afferent signals. This has been tested using temporal lobe (area TA) and inferior parietal lobule (areas PG, PF) histological specimens from human donors. The temporal and inferior parietal regions differ in ways that have never been described. Correlations between the thickness of laminae II-III and columnar spacing in lamina III within individual cytoarchitectonic areas in both hemispheres of each donor were calculated. Those in areas PG/PF are predominantly negative in both hemispheres, as predicted by the model. This is also true for the left hemisphere TA, but the right hemisphere TA shows no correlations between thickness and spacing. Comparisons of thickness and spacing between left and right hemispheres in PG/PF of each donor show no consistent direction, whereas those in TA fairly consistently show thinner laminae and wider column intervals on the left. In the left area TA, females have thinner laminae than males. Thus, intra-area predictions of the balloon model are supported in most areas, whereas the hemispheric asymmetry predictions appear to hold for TA, but not for the inferior parietal lobe.     

Cortical laminar thickness and column spacing in human temporal and inferior parietal lobes: Intra-individual anatomical relations

Harasty, Seldon, Chan, Halliday, and Harding (2003) and Seldon (2005) have proposed a “balloon model” which suggests that myelin growth stretches the cerebral cortex, causing the cortical thickness to decrease and the columnar spacing to increase, in turn affecting the cortical capacity to differentiate afferent signals. This has been tested using temporal lobe (area TA) and inferior parietal lobule (areas PG, PF) histological specimens from human donors. The temporal and inferior parietal regions differ in ways that have never been described. Correlations between the thickness of laminae II–III and columnar spacing in lamina III within individual cytoarchitectonic areas in both hemispheres of each donor were calculated. Those in areas PG/PF are predominantly negative in both hemispheres, as predicted by the model. This is also true for the left hemisphere TA, but the right hemisphere TA shows no correlations between thickness and spacing. Comparisons of thickness and spacing between left and right hemispheres in PG/PF of each donor show no consistent direction, whereas those in TA fairly consistently show thinner laminae and wider column intervals on the left. In the left area TA, females have thinner laminae than males. Thus, intra-area predictions of the balloon model are supported in most areas, whereas the hemispheric asymmetry predictions appear to hold for TA, but not for the inferior parietal lobe.     

FMRI signals associated with memory strength in the medial temporal lobes: a meta-analysis

To identify patterns of memory-related neural activity in the medial temporal lobes (MTL), a quantitative meta-analysis of 17 functional magnetic resonance imaging (fMRI) studies was performed. The analysis shows that increased activity in the hippocampus and the parahippocampal cortex predicts subsequent memory strength. During retrieval, activity in the hippocampus increases in association with strong memory. In the perirhinal cortex, increased activity predicts subsequent recognition, whether based on weak or strong memory, whereas during retrieval activity decreases below the level for misses in association with both weak and strong memory. The results are consistent with the claim that the hippocampus selectively subserves recollection, whereas adjacent structures subserve familiarity [Eichenbaum, H., Yonelinas, A., & Ranganath, C. (2007). The medial temporal lobe and recognition memory. The Annual Review of Neuroscience, 30, 123-152]. However, this conclusion depends on a specific dual-process theory of recognition memory that has been used to interpret the results. An alternative dual-process model holds that the behavioral methods used to differentiate recollection from familiarity instead separate strong memories from weak memories. When the fMRI data are interpreted in terms of the alternative theory, the fMRI results do not point to selective roles for the hippocampus or the adjacent MTL structures. The fMRI data alone cannot distinguish between these two models, so other methods are needed to resolve the issue.     

An angiographically occult arteriovenous malformation in the medial parietal lobe presenting as seizures of medial temporal lobe origin

We present an unusual case of a patient who was diagnosed with temporal lobe epilepsy and whose seizures were reduced markedly after excision of an angiographically occult arteriovenous malformation (AVM) located in the left medial parietal lobe. A 38-year-old man had complex partial seizures characterized by motionless staring with oroalimentary and behavioral automatisms since the age of 15 years. Magnetic resonance imaging (MRI) demonstrated a small lesion extending from the left posterior cingulate gyrus to the precuneus. There was no MRI evidence of mesial temporal sclerosis. Intracranial EEG recordings showed ictal onset from the left medial parietal lobe propagating to the medial temporal lobes. Clinical signs appeared when these discharges reached the temporal lobes. After excision of the lesion (which was histologically confirmed as an AVM), together with the marginal cortex, seizures were reduced significantly. Careful diagnostic evaluation of lesions such as the this one may reveal an epileptogenic lesion (zone) far from the region where scalp ictal discharges seem to arise. In our case, we hypothesize that false localization was due to propagation of ictal discharges from the parietal focus through the limbic system.     

Animacy and real‐world size shape object representations in the human medial temporal lobes

Identifying what an object is, and whether an object has been encountered before, is a crucial aspect of human behavior. Despite this importance, we do not yet have a complete understanding of the neural basis of these abilities. Investigations into the neural organization of human object representations have revealed category specific organization in the ventral visual stream in perceptual tasks. Interestingly, these categories fall within broader domains of organization, with reported distinctions between animate, inanimate large, and inanimate small objects. While there is some evidence for category specific effects in the medial temporal lobe (MTL), in particular in perirhinal and parahippocampal cortex, it is currently unclear whether domain level organization is also present across these structures. To this end, we used fMRI with a continuous recognition memory task. Stimuli were images of objects from several different categories, which were either animate or inanimate, or large or small within the inanimate domain. We employed representational similarity analysis (RSA) to test the hypothesis that object‐evoked responses in MTL structures during recognition‐memory judgments also show evidence for domain‐level organization along both dimensions. Our data support this hypothesis. Specifically, object representations were shaped by either animacy, real‐world size, or both, in perirhinal and parahippocampal cortex, and the hippocampus. While sensitivity to these dimensions differed across structures when probed individually, hinting at interesting links to functional differentiation, similarities in organization across MTL structures were more prominent overall. These results argue for continuity in the organization of object representations in the ventral visual stream and the MTL.