The development of neural correlates for memory formation

A growing body of literature considers the development of episodic memory systems in the brain; the majority are neuroimaging studies conducted during memory encoding in order to explore developmental trajectories in memory formation. This review considers evidence from behavioral studies of memory development, neural correlates of memory formation in adults, and structural brain development, all of which form the foundation of a developmental cognitive neuroscience approach to memory development. I then aim to integrate the current evidence from developmental functional neuroimaging studies of memory formation with respect to three hypotheses. First, memory development reflects the development in the use of memory strategies, linked to prefrontal cortex. Second, developmental effects within the medial temporal lobes are more complex, and correspond to current notions about the nature in which the MTL support the formation of memory. Third, neurocognitive changes in content representation influence memory. Open issues and current directions are discussed.     

Patterns of hippocampal–neocortical interactions in the retrieval of episodic autobiographical memories across the entire life‐span of aged adults

We previously demonstrated that episodic autobiographical memories (EAMs) rely on a network of brain regions comprising the medial temporal lobe (MTL) and distributed neocortical regions regardless of their remoteness. The findings supported the model of memory consolidation, which proposes a permanent role of MTL during EAM retrieval (multiple‐trace theory or MTT) rather than a temporary role (standard model). Our present aim was to expand the results by examining the interactions between the MTL and neocortical regions (or MTL–neocortical links) during EAM retrieval with varying retention intervals. We used an experimental paradigm specially designed to engage aged participants in the recollection of EAMs, extracted from five different time‐periods, covering their whole life‐span, in order to examine correlations between activation in the MTL and neocortical regions. The nature of the memories was checked at debriefing by means of behavioral measures to control the degree of episodicity and properties of memories. Targeted correlational analyses carried out on the MTL, frontal, lateral temporal, and posterior regions revealed strong links between the MTL and neocortex during the retrieval of both recent and remote EAMs, challenging the standard model of memory consolidation and supporting MTT instead. Further confirmation was given by results showing that activation in the left and right hippocampi significantly correlated during the retrieval of both recent and remote memories. Correlations among extra‐MTL neocortical regions also emerged for all time‐periods, confirming the critical role of the prefrontal, temporal (lateral temporal cortex and temporal pole), precuneus, and posterior cingulate regions in EAM retrieval. Overall, this paper emphasizes the role of a bilateral network of MTL and neocortical areas whose activation correlate during the recollection of rich phenomenological recent and remote EAMs. © 2009 Wiley‐Liss, Inc.     

Structural and functional asymmetry of medial temporal subregions in unilateral temporal lobe epilepsy: A 7T MRI study

Mesial temporal lobe epilepsy (TLE) is a common neurological disorder affecting the hippocampus and surrounding medial temporal lobe (MTL). Although prior studies have analyzed whole‐brain network distortions in TLE patients, the functional network architecture of the MTL at the subregion level has not been examined. In this study, we utilized high‐resolution 7T T2‐weighted magnetic resonance imaging (MRI) and resting‐state BOLD‐fMRI to characterize volumetric asymmetry and functional network asymmetry of MTL subregions in unilateral medically refractory TLE patients and healthy controls. We subdivided the TLE group into mesial temporal sclerosis patients (TLE‐MTS) and MRI‐negative nonlesional patients (TLE‐NL). Using an automated multi‐atlas segmentation pipeline, we delineated 10 MTL subregions per hemisphere for each subject. We found significantly different patterns of volumetric asymmetry between the two groups, with TLE‐MTS exhibiting volumetric asymmetry corresponding to decreased volumes ipsilaterally in all hippocampal subfields, and TLE‐NL exhibiting no significant volumetric asymmetries other than a mild decrease in whole‐hippocampal volume ipsilaterally. We also found significantly different patterns of functional network asymmetry in the CA1 subfield and whole hippocampus, with TLE‐NL patients exhibiting asymmetry corresponding to increased connectivity ipsilaterally and TLE‐MTS patients exhibiting asymmetry corresponding to decreased connectivity ipsilaterally. Our findings provide initial evidence that functional neuroimaging‐based network properties within the MTL can distinguish between TLE subtypes. High‐resolution MRI has potential to improve localization of underlying brain network disruptions in TLE patients who are candidates for surgical resection.     

Processing content or location: distinct brain activation in a memory task

Objects are defined by their content ("what") and by their location ("where"). In the visual system, processing of these two types of information is segregated into distinct anatomical and functional pathways. Using H2 (15)O positron emission tomography to measure cerebral blood flow, we examined the differences in processing of "what" when compared with "where" information in human memory. We found that the detection of deviations from a previously learned image sequence activates distinct brain regions depending on whether the image's content or its location has changed. When deviations of an image's content had to be detected, the left medial temporal lobe (MTL) activation increased. In contrast, detection of deviations from the learned locations of the objects induced increased activation in the right MTL and in the right parietal cortex. These data demonstrate distinct contributions of the left and right MTL to the processing of "what" vs. "where" in memory.     

Functional magnetic resonance imaging of working memory impairment after traumatic brain injury

OBJECTIVES: To examine patterns of brain activation while performing a working memory task in persons with moderate to severe traumatic brain injury (TBI) and healthy controls. It is well established that working memory is an area of cognition that is especially vulnerable to disruption after TBI. Although much has been learned about the system of cerebral representation of working memory in healthy people, little is known about how this system is disrupted by TBI. METHODS: Functional magnetic resonance imaging (fMRI) was used to assess brain activation during a working memory task (a modified version of the paced auditory serial addition test) in nine patients with TBI and seven healthy controls. RESULTS: Patients with TBI were able to perform the task, but made significantly more errors than healthy controls. Cerebral activation in both groups was found in similar regions of the frontal, parietal, and temporal lobes, and resembled patterns of activation found in previous neuroimaging studies of working memory in healthy persons. However, compared with the healthy controls, the TBI group displayed a pattern of cerebral activation that was more regionally dispersed and more lateralised to the right hemisphere. Differences in lateralisation were particularly evident in the frontal lobes. CONCLUSIONS: Impairment of working memory in TBI seems to be associated with alterations in functional cerebral activity.     

Material-specific lateralization of working memory in the medial temporal lobe

Mnemonic deficits in patients with medial temporal lobe (MTL) damage arising from temporal lobe epilepsy (TLE) are traditionally constrained to long-term episodic memory, sparing short-term and working memory (WM). This view of WM as being independent of MTL structures has recently been challenged by a small number of patient and neuroimaging studies, which have focused primarily on visual and visuospatial WM. In the present study we investigated material-specific lateralization of WM in 96 patients with unilateral damage to MTL stemming from TLE (56 left) and 30 control subjects using a pair of matched verbal and visuospatial supraspan tasks. Patients with unilateral TLE were impaired on both verbal and visuospatial WM tasks irrespective of the affected hemisphere. Patients with unilateral right TLE showed an additional deficit for visuospatial WM capacity when contrasted with patients with left TLE, whereas patients with unilateral left TLE showed increased intrusion errors on the verbal task when compared to patients with right TLE. These findings suggest a material-specific lateralization of WM in the MTL.     

Which memory system is impaired first in Alzheimer's disease?

Diagnosis of Alzheimer's disease (AD) in its earliest stages becomes increasingly important as disease modifying agents are being developed. In this area of research, many clinical and neuroimaging studies focus on markers of hippocampal dysfunction. However, during the "transentorhinal stage" of AD, neurofibrillary tangles (NFT), related to tau protein pathology, develop in the anterior subhippocampal (perirhinal/entorhinal) cortex before the hippocampus. NFT are tightly correlated with clinical symptoms. Therefore, an accurate understanding of the behavioral correlate of transentorhinal dysfunction could critically contribute to the early diagnosis of the disease. Recent findings from studies in animals and human brain-damaged patients suggest that the anterior subhippocampal region, functionally integrated into an anterior mesiotemporal network, is involved in object based context-free memory. In this article, we evaluate the hypothesis according to which tau deposition in the anterior subhippocampal region during the earliest stages of the most common form of AD, with predominant MTL dysfunction, will lead to dysfunction of neural networks implicated in context-free memory. We challenge the view that impaired episodic memory is the hallmark of early AD. Instead, a model that integrates the localization and temporal sequence of NFT within the mesial temporal lobe (MTL) is proposed. Paralleling the development of NFT in anterior subhippocampal areas, impaired context-free, object-based, memory could be the first detectable sign in AD. In a subsequent, "hippocampal" stage, context-rich, episodic and spatial memory, becomes altered as well. The question as to the "episodic" nature of "episodic memory tasks" is also addressed.     

A review and new report of medial temporal lobe dysfunction as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric family study of the parahippocampal gyrus

A central question in schizophrenia research is which brain abnormalities are independent of psychosis and which evolve before and after psychosis begins. This question can be addressed by longitudinal neuroimaging studies beginning in the prodrome, but at present there is only one published study. We reviewed the literature on structural brain imaging in persons with chronic and first episode schizophrenia, nonpsychotic persons at genetic high risk, and persons thought to be at risk for imminent psychosis ("prodromal" persons). Medial temporal lobe (MTL), especially hippocampal, volume alterations are among the most robust brain vulnerabilities for schizophrenia. Because verbal declarative memory (VDM) deficits are prominent and the parahippocampal gyrus (PHG) is considered to be centrally involved with the hippocampus in VDM processing, we analyzed PHG data from a family study of schizophrenia. Patients with schizophrenia and nonpsychotic relatives from "multiplex" families (families with multiple persons with schizophrenia) had significantly smaller right parahippocampal anterior (PHa) volumes than controls. Marginally significant findings were observed for the left PHa. Unexpectedly, relatives from "simplex" families (families with only one person with schizophrenia) had significantly larger PH posterior volumes than controls and did not differ from controls on PHa. Results provide some support for the hypothesis that the vulnerability to schizophrenia includes abnormal volumes of the PHG. These data provide additional support for the hypothesis that some MTL abnormalities in schizophrenia are independent of psychosis, at least in families with presumably high genetic loading. Implications of genetic risk studies for prodromal research are discussed.     

Intrinsic functional connectivity of the human medial temporal lobe suggests a distinction between adjacent MTL cortices and hippocampus

Functional connectivity analyses can offer insights into mechanisms of the brain that might not be revealed by traditional fMRI. These analyses compare seed voxels' activity over time to the activity of other voxels over time and identify correlations between regions. This study is the first to perform functional connectivity analyses in the human medial temporal lobe (MTL) at high enough resolution to resolve the hippocampal subfields. We calculated the average correlation coefficients between the MTL cortices, which include the entorhinal (ERC), perirhinal (PRC), and parahippocampal cortex (PHC), and the hippocampal subfields dentate gyrus/CA3, CA1, and subiculum. We found that the hippocampal subfields had relatively high correlations with each other both within and across hemispheres, but did not have exceptionally strong correlations with the MTL cortices. The opposite was also seen where there was a relatively high correlation coefficient between the ERC and PRC, but both regions had low correlation coefficients with the hippocampal subfields. We also found greater functional connectivity within a hemisphere than across hemispheres. These effects were replicated across multiple datasets which differed in task demands, participants' age, and scanner sequence/slice acquisition. Notably, all datasets were better correlated to these patterns of intrinsic functional connectivity than to a model based on anatomical constraints. This is consistent with evidence that functional connectivity is not a direct mapping of anatomical connectivity. These patterns of functional connectivity imply a distinction between the MTL cortices and the hippocampus and speak to our understanding of the organization of the MTL. © 2012 Wiley Periodicals, Inc.     

Predictive, interactive multiple memory systems

Most lesion studies in animals, and neuropsychological and functional neuroimaging studies in humans, have focused on finding dissociations between the functions of different brain regions, for example in relation to different types of memory. While some of these dissociations can be questioned, particularly in the case of neuroimaging data, we start by assuming a "modal model" in which at least three different memory systems are distinguished: an episodic system (which stores associations between items and spatial/temporal contexts, and which is supported primarily by the hippocampus); a semantic system (which extracts combinations of perceptual features that define items, and which is supported primarily by anterior temporal cortex); and modality-specific perceptual systems (which represent the sensory features extracted from a stimulus, and which are supported by higher sensory cortices). In most situations however, behavior is determined by interactions between these systems. These interactions reflect the flow of information in both "forward" and "backward" directions between memory systems, where backward connections transmit predictions about the current item/features based on the current context/item. Importantly, it is the resulting "prediction error"--the difference between these predictions and the forward transmission of sensory evidence--that drives memory encoding and retrieval. We describe how this "predictive interactive multiple memory systems" (PIMMS) framework can be applied to human neuroimaging data acquired during encoding or retrieval phases of the recognition memory paradigm. Our novel emphasis is thus on associations rather than dissociations between activity measured in key brain regions; in particular, we propose that measuring the functional coupling between brain regions will help understand how these memory systems interact to guide behavior.     

Retrieval of autobiographical memory in Alzheimer's disease: relation to volumes of medial temporal lobe and other structures

The representation of autobiographical memory is distributed over a network of brain structures, with the medial temporal lobe (MTL) at its epicenter. Some believe that, over time, all memories become independent of their MTL component ("consolidation theories"). Others have suggested that this is true only of semantic memory, while episodic aspects of autobiographical memories are dependent on the MTL for as long as they exist, such as multiple trace theory (MTT). In the present study, the volumes of 28 brain regions, including the MTL, and their relation to autobiographical memory were investigated in a group of patients with Alzheimer's disease with varying degrees of retrograde memory loss as assessed by the Autobiographical Memory Interview (AMI). We used the multivariate analysis method of partial least squares (PLS) to assess patterns of atrophy that can lead to retrograde amnesia. We found that different aspects of autobiographical memory were associated with different patterns of tissue loss. Personal semantics were related to a pattern of bilateral anterior and posterior lateral temporal cortex degeneration, more pronounced on the left, as well as right frontal degeneration. Autobiographical event memory ("episodic") was associated with combined atrophy in bilateral MTL and anterior lateral temporal neocortex, more pronounced on the right. This pattern was invariant for memories from childhood, early adulthood, and recent memories, in line with the predictions of MTT, suggesting that MTL tissue is crucial for retrieval of episodic memories regardless of their age.     

Brain activity during episodic retrieval of autobiographical and laboratory events: an fMRI study using a novel photo paradigm

Functional neuroimaging studies of episodic memory retrieval generally measure brain activity while participants remember items encountered in the laboratory ("controlled laboratory condition") or events from their own life ("open autobiographical condition"). Differences in activation between these conditions may reflect differences in retrieval processes, memory remoteness, emotional content, retrieval success, self-referential processing, visual/spatial memory, and recollection. To clarify the nature of these differences, a functional MRI study was conducted using a novel "photo paradigm," which allows greater control over the autobiographical condition, including a measure of retrieval accuracy. Undergraduate students took photos in specified campus locations ("controlled autobiographical condition"), viewed in the laboratory similar photos taken by other participants (controlled laboratory condition), and were then scanned while recognizing the two kinds of photos. Both conditions activated a common episodic memory network that included medial temporal and prefrontal regions. Compared with the controlled laboratory condition, the controlled autobiographical condition elicited greater activity in regions associated with self-referential processing (medial prefrontal cortex), visual/spatial memory (visual and parahippocampal regions), and recollection (hippocampus). The photo paradigm provides a way of investigating the functional neuroanatomy of real-life episodic memory under rigorous experimental control.     

Retrograde amnesia and the volume of critical brain structures

There are many controversies concerning the structural basis of retrograde amnesia (RA). One view is that memories are held briefly within a medial temporal store ("hippocampal complex") before being "consolidated" or reorganised within temporal neocortex and/or networks more widely distributed within the cerebral cortex. An alternative view is that the medial temporal lobes are always involved in the storage and retrieval (reactivation) of autobiographical memories (multiple trace theory). The present study used quantitative magnetic resonance imaging (MRI) in 40 patients with focal pathology/volume loss in different sites, to examine the correlates of impairment on three different measures of RA. The findings supported the view that widespread neural networks are involved in the storage and retrieval of autobiographical and other remote memories. Brain volume measures in critical structures could account for 60% of variance on autobiographical memory measures (for incidents and facts) in diencephalic patients and for 60-68% of variance in patients with frontal lesions. Significant correlations with medial temporal lobe volume were found only in the diencephalic group, in whom they were thought to reflect thalamic changes, but not in patients with herpes encephalitis or hypoxia in whom the temporal lobes were particularly implicated. The latter finding fails to support one of the main predictions of multiple trace theory, as presently expounded.     

Intercorrelations of glucose metabolic rates between brain regions: application to healthy males in a state of reduced sensory input

We use a correlational analysis of regional metabolic rates to characterize relations among different brain regions. Starting with rates of local glucose metabolism (rCMRglc) obtained by positron emission tomography using [18F]fluorodeoxyglucose, we propose that the strength of the association is proportional to the magnitude of the correlation coefficient. Partial correlation coefficients, controlling for whole brain glucose metabolism, are used in the analysis. We also introduce a graphical technique to display simultaneously all the correlations, allowing us to examine patterns of relations among them. The method was applied to 40 very healthy males under conditions of reduced auditory and visual inputs (the "resting state"). Dividing the brain into 59 regions, and keeping only those partial correlation coefficients significant to p less than 0.01, we found the following: (a) All regions were significantly correlated with their contralateral homologues. For the most part, the largest partial correlation coefficients were between homologous brain regions. (b) Generally, the pattern of significant correlations between any two lobes in the left hemisphere did not differ statistically from the corresponding pattern in the right hemisphere. (c) Strong correlations were observed between primary somatosensory areas and premotor association areas. Correlations between these association areas and primary visual and auditory regions were not statistically significant. (d) Significant correlations between inferior occipital and temporal areas were found. Metabolic rates in the superior part of the occipital lobe were not correlated significantly with metabolic rates in regions of the temporal lobe, nor with metabolism in the parietal lobe. (e) As a whole, there were numerous correlations among frontal and parietal lobe regions, on the one hand, and among temporal and occipital lobe regions, on the other, but few statistically significant correlations between these two domains. We relate our results to various aspects of known brain anatomy, physiology, and cognitive functioning.     

Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: insights from functional MRI studies

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have begun to reveal abnormalities in memory circuit function in humans suffering from memory disorders. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies, reviewed here, have focused on this region of the brain. By the time individuals are diagnosed clinically with AD dementia, the substantial memory impairments appear to be associated with not only MTL atrophy but also hypoactivation during memory task performance. Prior to dementia, when individuals are beginning to manifest signs and symptoms of memory impairment, the hippocampal formation and other components of the MTL memory system exhibit substantial functional abnormalities during memory task performance. It appears that, early in the course of MCI when memory deficits and hippocampal atrophy are less prominent, there may be hyperactivation of MTL circuits, possibly representing inefficient compensatory activity. Later in the course of MCI, when considerable memory deficits are present, MTL regions are no longer able to activate during attempted learning, as is the case in AD dementia. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, such as for use in clinical trials.     

Similar 1H magnetic resonance spectroscopic metabolic pattern in the medial temporal lobes of patients with mild cognitive impairment and Alzheimer disease

Structures of the medial temporal lobes are recognized to play a central role in memory processing and to be the primary sites of deterioration in Alzheimer disease (AD). Mild cognitive impairment (MCI) represents potentially an intermediate state between normal aging and AD. Proton magnetic resonance spectroscopy (MRS) was used to examine brain metabolic changes in patients with AD and MCI in the medial temporal lobes (MTLs), parietotemporal cortices (PTCs) and prefrontal cortices (PFCs). Fourteen patients with MCI, 14 patients with mild AD and 14 age- and sex-matched control subjects were studied. Patients with AD and MCI demonstrated significant reductions of NAA/H(2)O and Cho/H(2)O in the left MTL relative to control subjects. Patients with AD showed mI/H(2)O increases relative to patients with MCI and control subjects in all six regions investigated, and a statistically significant mI/H(2)O increase was measured in the right PTC. Patients with AD and MCI demonstrated the same metabolic pattern in the left MTL, suggesting a similar pathological process underlying memory impairment. Increased mI signal appears to be a neurochemical abnormality associated mostly with AD and the dementia process. Some interhemispheric metabolite asymmetries were increased in AD patients.     

Impairment of verbal recollection following ischemic damage to the right anterior hippocampus

Damage to the left medial temporal lobe (MTL) leads to an impairment of verbal recognition memory, affecting both the process of conscious recollection and familiarity-based recognition. Neuroimaging evidence, on the other hand, suggests a bilateral MTL contribution to verbal recollection. We investigated verbal recognition memory in three patients with focal ischemic lesions to the right MTL. The dual-process signal detection model and the process-dissociation procedure were applied to assess the contributions of recollection and familiarity to recognition memory. Compared to a group of 27 healthy age-matched controls, patients were impaired at recollection while familiarity was intact, and this effect was found for both estimation procedures. Detailed single-case analyses confirmed this pattern in two of the three right MTL patients. The findings suggest that, when task demands are high, as during recollective recognition, the right anterior hippocampus may also contribute to verbal recollection, thereby confirming neuroimaging evidence of a joint involvement of the left and the right MTL in verbal recollection.     

Medial temporal lobe structure and cognition in individuals with schizophrenia and in their non-psychotic siblings

Medial temporal lobe (MTL) structures play a central role in episodic memory. Prior studies suggest that individuals with schizophrenia have deficits in episodic memory as well as structural abnormalities of the medial temporal lobe (MTL). While correlations have been reported between MTL volume loss and episodic memory deficits in such individuals, it is not clear whether such correlations reflect the influence of the disease state or of underlying genetic influences that might contribute to risk. We used high resolution magnetic resonance imaging and probabilistic algorithms for image analysis to determine whether MTL structure, episodic memory performance and the relationship between the two differed among groups of 47 healthy control subjects, 50 control siblings, 39 schizophrenia subjects, and 33 siblings of schizophrenia subjects. High-dimensional large deformation brain mapping was used to obtain volume measures of the hippocampus. Cortical distance mapping was used to obtain volume and thickness measures of the parahippocampal gyrus (PHG) and its substructures: the entorhinal cortex (ERC), the perirhinal cortex (PRC), and the parahippocampal cortex (PHC). Neuropsychological data was used to establish an episodic memory domain score for each subject. Both schizophrenia subjects and their siblings displayed abnormalities in episodic memory performance. Siblings of individuals with schizophrenia, and to a lesser extent, individuals with schizophrenia themselves, displayed abnormalities in measures of MTL structure (volume loss or cortical thinning) as compared to control groups. Further, we observed correlations between structural measures and memory performance in both schizophrenia subjects and their siblings, but not in their respective control groups. These findings suggest that disease-specific genetic factors present in both patients and their relatives may be responsible for correlated abnormalities of MTL structure and memory impairment. The observed attenuated effect of such factors on MTL structure in individuals with schizophrenia may be due to non-genetic influences related to the development and progression of the disease on global brain structure and cognitive processing.     

Encoding activity in the medial temporal lobe examined with anatomically constrained fMRI analysis

Functional neuroimaging studies have produced a sizable number of observations of increased activity in the human medial temporal lobe (MTL) during encoding of novel memories. The studies have suggested possible functional specialization within the anatomical components of the MTL (hippocampus and the entorhinal, perirhinal, and parahippocampal cortical areas). Neuroimaging studies have just begun to link anatomical regions to specific functions. To address functional specialization hypothesis, a method is described for using high-resolution structural information from magnetic resonance imaging MRI to constrain the analysis of functional magnetic resonance imaging (fMRI) data, for independent assessment of functional activity change in each component of the MTL. With this method, increased activity was detected throughout the MTL in a group of participants (n = 5) who encoded novel pictures. A separate group (n = 5) who encoded words exhibited lower-levels of evoked activity. Laterality effects were found reflecting increased right hemisphere activity during picture encoding (parahippocampal cortex) and increased left hemisphere activity during word encoding (posterior hippocampus and parahippocampal cortex). Neither condition provided evidence for greater activity in the posterior hippocampus than in the anterior hippocampus during encoding, although the greatest increases in activity were observed in the parahippocampal cortex. The anatomically driven methodology is shown to provide detailed comparison of levels of activity change across specific brain areas and to provide increased sensitivity to functional change in each region of the MTL.