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1.  Temporal association tracts and the breakdown of episodic memory in mild cognitive impairment 
Neurology  2012;79(23):2233-2240.
Objective:
To examine the pattern of association between microstructure of temporal lobe connections and the breakdown of episodic memory that is a core feature of mild cognitive impairment (MCI).
Methods:
Twenty-five individuals with MCI and 20 matched controls underwent diffusion MRI and cognitive assessment. Three temporal pathways were reconstructed by tractography: fornix, parahippocampal cingulum (PHC), and uncinate fasciculus. Tissue volume fraction—a tract-specific measure of atrophy—and microstructural measures were derived for each tract. To test specificity of associations, a comparison tract (corticospinal tract) and control cognitive domains were also examined.
Results:
In MCI, tissue volume fraction was reduced in the fornix. Axial and radial diffusivity were increased in uncinate and PHC implying more subtle microstructural change. In controls, tissue volume fraction in the fornix was the predominant correlate of free recall. In contrast, in MCI, the strongest relationship was with left PHC. Microstructure of uncinate and PHC also correlated with recognition memory, and recognition confidence, in MCI.
Conclusions:
Episodic memory in MCI is related to the structure of multiple temporal association pathways. These associations are not confined to the fornix, as they are in healthy young and older adults. In MCI, because of a compromised fornix, alternative pathways may contribute disproportionally to episodic memory performance.
doi:10.1212/WNL.0b013e31827689e8
PMCID: PMC3542350  PMID: 23175726
2.  Medial Temporal Lobe Contributions to Intra-Item Associative Recognition Memory in the Aging Brain 
Aging is associated with a decline in episodic memory function. This is accompanied by degradation of and functional changes in the medial temporal lobe (MTL) which subserves mnemonic processing. To date no study has investigated age-related functional change in MTL substructures during specific episodic memory processes such as intra-item associative memory. The aim of this study was to characterize age-related change in the neural correlates of intra-item associative memory processing. Sixteen young and 10 older subjects participated in a compound word intra-item associative memory task comprising a measure of associative recognition memory and a measure of recognition memory. There was no difference in performance between groups on the associative memory measure but each group recruited different MTL regions while performing the task. The young group recruited the left anterior hippocampus and posterior parahippocampal gyrus whereas the older participants recruited the hippocampus bilaterally. In contrast, recognition memory was significantly worse in the older subjects. The left anterior hippocampus was recruited in the young group during successful recognition memory whereas the older group recruited a more posterior region of the left hippocampus and showed a more bilateral activation of frontal brain regions than was observed in the young group. Our results suggest a reorganization of the neural correlates of intra-item associative memory in the aging brain.
doi:10.3389/fnbeh.2013.00222
PMCID: PMC3878719  PMID: 24427127
associative memory; medial temporal lobe; hippocampus; perirhinal cortex; aging
3.  Neural Correlates of Confidence during Item Recognition and Source Memory Retrieval: Evidence for Both Dual-process and Strength Memory Theories 
Journal of cognitive neuroscience  2011;23(12):3959-3971.
Although the medial-temporal lobes (MTL), PFC, and parietal cortex are considered primary nodes in the episodic memory network, there is much debate regarding the contributions of MTL, PFC, and parietal subregions to recollection versus familiarity (dual-process theory) and the feasibility of accounts on the basis of a single memory strength process (strength theory). To investigate these issues, the current fMRI study measured activity during retrieval of memories that differed quantitatively in terms of strength (high vs. low-confidence trials) and qualitatively in terms of recollection versus familiarity (source vs. item memory tasks). Support for each theory varied depending on which node of the episodic memory network was considered. Results from MTL best fit a dual-process account, as a dissociation was found between a right hippocampal region showing high-confidence activity during the source memory task and bilateral rhinal regions showing high-confidence activity during the item memory task. Within PFC, several left-lateralized regions showed greater activity for source than item memory, consistent with recollective orienting, whereas a right-lateralized ventrolateral area showed low-confidence activity in both tasks, consistent with monitoring processes. Parietal findings were generally consistent with strength theory, with dorsal areas showing low-confidence activity and ventral areas showing high-confidence activity in both tasks. This dissociation fits with an attentional account of parietal functions during episodic retrieval. The results suggest that both dual-process and strength theories are partly correct, highlighting the need for an integrated model that links to more general cognitive theories to account for observed neural activity during episodic memory retrieval.
doi:10.1162/jocn_a_00086
PMCID: PMC3521503  PMID: 21736454
4.  The medial temporal lobe and the attributes of memory 
Trends in cognitive sciences  2011;15(5):210-217.
Neuroimaging and lesion studies have appeared to converge on the idea that the hippocampus selectively supports recollection. However, these studies usually involve a comparison between strong recollection-based memories and weak familiarity-based memories. Studies that have avoided confounding memory strength with recollection and familiarity have found that the hippocampus supports both recollection and familiarity. We argue that the functional organization of the medial temporal lobe (MTL) is unlikely to be illuminated by the psychological distinction between recollection and familiarity and will be better informed by findings from neuroanatomy and neurophysiology. These findings suggest that the different structures of the MTL process different attributes of experience. By representing the widest array of attributes, the hippocampus supports recollection-based and familiarity-based memory of multi-attribute stimuli.
doi:10.1016/j.tics.2011.03.005
PMCID: PMC3085543  PMID: 21481629
5.  A quantitative MR measure of the fornix in schizophrenia 
Schizophrenia research  2001;47(1):87-97.
Some cognitive disturbances accompanying schizophrenia may be due to abnormalities in the thalamus and components of the limbic system. The fornix is an important white-matter relay pathway connecting these structures and is likely to be affected in schizophrenia as well.
Magnetic resonance images of the fornix were analyzed in 15 schizophrenic patients and 15 matched comparison group subjects. Fornix volume was compared between the two groups and was also correlated with the volumes of other neuroanatomical structures, as well as with illness presentation, clinical status, and cognitive/psychological measures.
There was no significant difference in fornix volume between the two groups. Of note, fornix volume correlated significantly with the volumes of the hippocampus, parahippocampus, and the superior temporal gyrus in the schizophrenic subjects, but not in the controls. Moreover, the correlation between fornix and parahippocampal gyrus volumes differed significantly between the two groups. No association was found between fornix volume and illness presentation or between fornix and cognitive/clinical measures.
Results suggest that there are no marked changes in fornix volume in schizophrenia by MRI. The fornix, however, may be part of a network of structures affected in schizophrenia, as indicated by correlated volumetric changes.
PMCID: PMC2845160  PMID: 11163548
Fornix; Hippocampus; Image processing; Magnetic resonance imaging; MR; Schizophrenia; Volumetric analysis
6.  White matter correlates of cognitive domains in normal aging with diffusion tensor imaging 
The ability to perform complex as well as simple cognitive tasks engages a network of brain regions that is mediated by the white matter fiber bundles connecting them. Different cognitive tasks employ distinctive white matter fiber bundles. The temporal lobe and its projections subserve a variety of key functions known to deteriorate during aging. In a cohort of 52 healthy subjects (ages 25–82 years), we performed voxel-wise regression analysis correlating performance in higher-order cognitive domains (executive function, information processing speed, and memory) with white matter integrity, as measured by diffusion tensor imaging (DTI) fiber tracking in the temporal lobe projections [uncinate fasciculus (UF), fornix, cingulum, inferior longitudinal fasciculus (ILF), and superior longitudinal fasciculus (SLF)]. The fiber tracts were spatially registered and statistical parametric maps were produced to spatially localize the significant correlations. Results showed that performance in the executive function domain is correlated with DTI parameters in the left SLF and right UF; performance in the information processing speed domain is correlated with fractional anisotropy (FA) in the left cingulum, left fornix, right and left ILF and SLF; and the memory domain shows significant correlations with DTI parameters in the right fornix, right cingulum, left ILF, left SLF and right UF. These findings suggest that DTI tractography enables anatomical definition of region of interest (ROI) for correlation of behavioral parameters with diffusion indices, and functionality can be correlated with white matter integrity.
doi:10.3389/fnins.2013.00032
PMCID: PMC3595518  PMID: 23493587
magnetic resonance imaging; diffusion tensor imaging; executive function; information processing speed; memory; aging; white matter; temporal lobe
7.  Selective and Shared Contributions of the Hippocampus and Perirhinal Cortex to Episodic Item and Associative Encoding 
Journal of cognitive neuroscience  2008;20(8):1478-1489.
Although the general role of the medial-temporal lobe (MTL) in episodic memory is well established, controversy surrounds the precise division of labor between distinct MTL subregions. The perirhinal cortex (PrC) has been hypothesized to support nonassociative item encoding that contributes to later familiarity, whereas the hippocampus supports associative encoding that selectively contributes to later recollection. However, because previous paradigms have predominantly used recollection of the item context as a measure of associative encoding, it remains unclear whether recollection of different kinds of episodic detail depends on the same or different MTL encoding operations. In our current functional magnetic resonance imaging study, we devised a subsequent memory paradigm that assessed successful item encoding in addition to the encoding of two distinct episodic details: an item–color and an item–context detail. Hippocampal encoding activation was selectively enhanced during trials leading to successful recovery of either an item–color or item–context association. Moreover, the magnitude of hippocampal activation correlated with the number, and not the kind, of associated details successfully bound, providing strong evidence for a role of the hippocampus in domain-general associative encoding. By contrast, PrC encoding activation correlated with both nonassociative item encoding as well as associative item–color binding, but not with item–context binding. This pattern suggests that the PrC contributions to memory encoding may be domain-specific and limited to the binding of items with presented item-related features. Critically, together with a separately conducted behavioral study, these data raise the possibility that PrC encoding operations—in conjunction with hippocampal mechanisms—contribute to later recollection of presented item details.
doi:10.1162/jocn.2008.20104
PMCID: PMC2789239  PMID: 18303974
8.  Fractionating Verbal Episodic Memory in Alzheimer's Disease 
NeuroImage  2010;54(2):1530-1539.
The aim of this study was to determine the neural correlates of different stages of episodic memory function and their modulation by Alzheimer's Disease (AD). Several decades of work have supported the role of the medial temporal lobes (MTL) in episodic memory function. However, more recent work, derived in part from functional neuroimaging studies, has suggested that other brain structures make up a large-scale network that appear to support successful encoding and retrieval of episodic memories. Furthermore, controversy exists as to whether dissociable MTL regions support qualitatively different aspects of memory (hippocampus: contextual memory or ‘recollection’; perirhinal/lateral entorhinal cortex: item memory or ‘familiarity’). There is limited neuropsychological support for these models and most work in AD only has examined free recall memory measures. We studied the relationship between performance on different stages of the Rey Auditory Verbal Learning Test (AVLT), a 15-item word list learning task, and structural MRI measures in mild AD patients. Structural measures included hippocampal volume and cortical thickness of several ROIs known to undergo atrophy in AD. Correlation and multiple regression analyses, controlling for age, education, and gender, were performed in 146 mild AD patients (MMSE 23.3 ± 2.0). To evaluate the robustness of these relationships, similar analyses were performed with additional standardized verbal memory measures. Early immediate recall trials (e.g. Trial 1 of the AVLT) were not associated with the size of MTL regions, but correlated most strongly with inferior parietal, middle frontal gyrus, and temporal pole ROIs. After repeated exposure (e.g. Trial 5 of the AVLT), immediate recall was correlated with both MTL and a similar distribution of isocortical structures, but most strongly the temporal pole. For delayed recall, only the hippocampus correlated with performance. In contrast, for delayed recognition discrimination, the perirhinal/entorhinal cortex correlated more strongly than hippocampus; no other isocortical regions were strongly associated with performance. Convergent results were found for immediate and delayed trials of the other memory tests. The current results suggest that a richer understanding of the memory deficits in AD can be gained by examining multiple measures, which tap different aspects of memory function. Furthermore, the present findings are consistent with models hypothesizing that different stages of verbal list learning map onto dissociable brain regions. These data have implications for understanding the anatomic basis of processes underlying episodic memory, particularly related to a division of labor within the medial temporal lobes and within the large-scale MTL-cortical memory network.
doi:10.1016/j.neuroimage.2010.09.005
PMCID: PMC2997155  PMID: 20832485
memory performance; recollection; familiarity; Alzheimer's Disease; medial temporal lobe
9.  A Medial Temporal Lobe Division of Labor: Insights from Memory in Aging and Early Alzheimer Disease 
Hippocampus  2011;21(5):461-466.
Dual process theories of recognition memory posit that recollection and familiarity represent dissociable processes. Animal studies and human functional imaging experiments support an anatomic dissociation of these processes in the medial temporal lobes (MTL). By this hypothesis, recollection may be dependent on the hippocampus; while familiarity appears to rely on extrahippocampal MTL (ehMTL) structures, particularly perirhinal and lateral entorhinal cortices. Despite these findings, the dual process model and these anatomic mappings remain controversial, in part because the study of patients with lesions to the MTL has been limited and has revealed predominantly single dissociations. We examined measures of recollection and familiarity in three groups (normal older adults, amnesic-Mild Cognitive Impairment, Alzheimer’s Disease) in which these memory measures and the relative integrity of MTL structures are variable, thus enhancing our power to detect MTL-memory relationships. Recollection and familiarity and volumes of hippocampus and ehMTL, defined as a region including entorhinal/perirhinal cortices and parahippocampus, were measured. Regression analyses revealed a stronger relationship of recollection with the hippocampus compared to ehMTL, while familiarity was more highly related to ehMTL compared to hippocampus. These results are consistent with a division of labor in the MTL and the dual process model.
doi:10.1002/hipo.20779
PMCID: PMC2918673  PMID: 20232383
10.  Content-specific source encoding in human medial temporal lobe 
While the medial temporal lobe (MTL) is known to be essential for episodic encoding, the contributions of individual MTL subregions remain unclear. Data from recognition memory studies have provided evidence that the hippocampus supports relational encoding important for later episodic recollection, while perirhinal cortex has been linked with encoding that supports later item familiarity. However, extant data also strongly implicate perirhinal cortex in object processing and encoding, suggesting that perirhinal processes may contribute to later episodic recollection of object source details. To investigate this possibility, we examined encoding activation in MTL subregions based on subsequent memory outcome while participants processed novel scenes paired with one of six repeating objects. Specifically, we analyzed BOLD encoding activation correlating with later successful scene recognition memory and source recollection for the object paired with the scene during encoding. In contrast to studies reporting a link between perirhinal cortex and item familiarity, we find that encoding activation in right perirhinal cortex correlates with successful recollection of the paired object. Furthermore, other MTL subregions also exhibit content-specific source encoding patterns of activation, suggesting that MTL subsequent memory effects are sensitive to stimulus category.
doi:10.1037/0278-7393.34.4.769
PMCID: PMC2938959  PMID: 18605867
fMRI; Perirhinal Cortex; Domain Specificity; Recollection; Medial temporal lobe
11.  Memory in the Aging Brain: Doubly Dissociating the Contribution of the Hippocampus and Entorhinal Cortex 
Hippocampus  2007;17(11):1134-1140.
Since the time of Aristotle it has been thought that memories can be divided into two basic types; conscious recollections and familiarity-based judgments. Neuropsychological studies have provided indirect support for this distinction by suggesting that different regions within the human medial temporal lobe (MTL) are involved in these two forms of memory, but none of these studies have demonstrated that these brain regions can be fully dissociated. In a group of nondemented elderly subjects, we found that performance on recall and recognition tests was predicted preferentially by hippocampal and entorhinal volumes, respectively. Structural equation modeling revealed a double dissociation, whereby age-related reductions in hippocampal volume resulted in decreases in recollection, but not familiarity, whereas entorhinal volume was preferentially related to familiarity. The results demonstrate that the forms of episodic memory supported by the human hippocampus and entorhinal cortex can be fully dissociated, and indicate that recollection and familiarity reflect neuroanatomically distinct memory processes.
doi:10.1002/hipo.20341
PMCID: PMC2194291  PMID: 17636547
recollection; familiarity; hippocampus; entorhinal cortex
12.  The Medial Temporal Lobe and Recognition Memory 
Annual review of neuroscience  2007;30:123-152.
The ability to recognize a previously experienced stimulus is supported by two processes: recollection of the stimulus in the context of other information associated with the experience, and a sense of familiarity with the features of the stimulus. Although familiarity and recollection are functionally distinct, there is considerable debate about how these kinds of memory are supported by regions in the medial temporal lobes (MTL). Here, we review evidence for the distinction between recollection and familiarity and then consider the evidence regarding the neural mechanisms of these processes. Evidence from neuropsychological, neuroimaging, and neurophysiological studies of humans, monkeys, and rats indicates that different subregions of the MTL make distinct contributions to recollection and familiarity. The data suggest that the hippocampus is critical for recollection but not familiarity. The parahippocampal cortex also contributes to recollection, possibly via the representation and retrieval of contextual (especially spatial) information, whereas perirhinal cortex contributes to and is necessary for familiarity-based recognition. The findings are consistent with an anatomically guided hypothesis about the functional organization of the MTL and suggest mechanisms by which the anatomical components of the MTL interact to support of the phenomenology of recollection and familiarity.
doi:10.1146/annurev.neuro.30.051606.094328
PMCID: PMC2064941  PMID: 17417939
recollection; familiarity; hippocampus; perirhinal cortex; parahippocampal cortex; entorhinal cortex; amnesia
13.  Memory loss from a subcortical white matter infarct. 
Clinical disorders of memory are believed to occur from the dysfunction of either the mesial temporal lobe, the mesial thalamus, or the basal forebrain. Fibre tract damage at the level of the fornix has only inconsistently produced amnesia. A patient is reported who suffered a cerebrovascular accident involving the posterior limb of the left internal capsule that resulted in a persistent and severe disorder of verbal memory. The inferior extent of the lesion effectively disconnected the mesial thalamus from the amygdala and the frontal cortex by disrupting the ventral amygdalofugal and thalamic-frontal pathways as they course through the diencephalon. This case demonstrates that an isolated lesion may cause memory loss without involvement of traditional structures associated with memory and may explain memory disturbances in other white matter disease such as multiple sclerosis and lacunar state.
Images
PMCID: PMC1033163  PMID: 3404195
14.  Patterns of hippocampal-neocortical interactions in the retrieval of episodic autobiographical memories across the entire life-span of aged adults 
Hippocampus  2010;20(1):153-165.
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.
doi:10.1002/hipo.20601
PMCID: PMC3021758  PMID: 19338022
Aged; Aging; physiology; Brain; physiology; Brain Mapping; Cerebral Cortex; physiology; Female; Functional Laterality; Hippocampus; physiology; Humans; Magnetic Resonance Imaging; Mental Recall; physiology; Middle Aged; Neural Pathways; physiology; Neuropsychological Tests; Time Factors; autobiographical memory; consolidation; correlation; hippocampus; neuroimaging
15.  Diffusion tensor imaging correlates of memory and language impairments in temporal lobe epilepsy 
Neurology  2008;71(23):1869-1876.
Objective:
To investigate the relationship between white matter tract integrity and language and memory performances in patients with temporal lobe epilepsy (TLE).
Methods:
Diffusion tensor imaging (DTI) was performed in 17 patients with TLE and 17 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated for six fiber tracts (uncinate fasciculus [UF], arcuate fasciculus [AF], fornix [FORX], parahippocampal cingulum [PHC], inferior fronto-occipital fasciculus [IFOF], and corticospinal tract [CST]). Neuropsychological measures of memory and language were obtained and correlations were performed to evaluate the relationship between DTI and neuropsychological measures. Hierarchical regression was performed to determine unique contributions of each fiber tract to cognitive performances after controlling for age and hippocampal volume (HV).
Results:
Increases in MD of the left UF, PHC, and IFOF were associated with poorer verbal memory in TLE, as were bilateral increases in MD of the AF, and decreases in FA of the right AF. Increased MD of the AF and UF, and decreased FA of the AF, UF, and left IFOF were related to naming performances. No correlations were found between DTI measures and nonverbal memory or fluency in TLE. Regression analyses revealed that several fibers, including the AF, UF, and IFOF, independently predicted cognitive performances after controlling for HV.
Conclusions:
The results suggest that structural compromise to multiple fiber tracts is associated with memory and language impairments in patients with temporal lobe epilepsy. Furthermore, we provide initial evidence that diffusion tensor imaging tractography may provide clinically unique information for predicting neuropsychological status in patients with epilepsy.
GLOSSARY
= arcuate fasciculus;
= Boston Naming Test;
= corticospinal tract;
= diffusion tensor imaging;
= fractional anisotropy;
= fornix;
= hippocampal volume;
= intracranial-adjusted HV;
= inferior fronto-occipital fasciculus;
= Logical Memory;
= mean diffusivity;
= mesial temporal sclerosis;
= parahippocampal cingulum;
= temporal lobe epilepsy;
= uncinate fasciculus;
= Wechsler Memory Scale–Third Edition.
doi:10.1212/01.wnl.0000327824.05348.3b
PMCID: PMC2676974  PMID: 18946001
16.  Differential effects of experience on tuning properties of macaque MTL neurons in a passive viewing task 
Hippocampus  2012;22(10):2000-2011.
The structures of the medial temporal lobe (MTL) have been shown to be causally involved in episodic and recognition memory. However, recent work in a number of species has demonstrated that impairments in recognition memory seen following lesions of the perirhinal cortex can be accounted for by deficits in perceptual discrimination. These findings suggest that object representation, rather than explicit recognition memory signals, may be crucial to the mnemonic process. Given the large amount of visual information encountered by primates, there must be a reconsideration of the mechanisms by which the brain efficiently stores visually presented information. Previous neurophysiological recordings from MTL structures in primates have largely focused on tasks that implicitly define object familiarity (i.e., novel vs. familiar) or contain significant mnemonic demands (e.g., conditional associations between two stimuli), limiting their utility in understanding the mechanisms underlying visual object recognition and information storage. To clarify how different regions in the MTL may contribute to visual recognition we recorded from three rhesus macaques performing a passive viewing task. The task design systematically varies the relative familiarity of different stimuli enabling an examination of how neural activity changes as a function of experience. The data collected during this passive viewing task revealed that neurons in the MTL are generally not sensitive to the relative familiarity of a stimulus. In addition, when the specificity (i.e., which images a neuron was selective for) of individual neurons was analyzed, there was a significant dissociation between different medial temporal regions, with only neurons in TF, but not CA3 or the perirhinal cortex, altering their activity as stimuli became familiar. The implications of these findings are discussed in the context of how MTL structures process information during a passive viewing paradigm.
doi:10.1002/hipo.22070
PMCID: PMC3537226  PMID: 22987678
macaque; sparse; medial temporal lobe; passive viewing; tuning
17.  Human medial temporal lobe damage can disrupt the perception of single objects 
The idea that the medial temporal lobe (MTL), traditionally viewed as an exclusive memory system, may also subserve higher-order perception has been debated fiercely. To support this suggestion, monkey and human lesion studies have demonstrated that perirhinal cortex damage impairs complex object discrimination. The interpretation of these findings has, however, been disputed since these impairments may reflect a primary deficit in MTL-mediated working memory processes or, in the case of human patients, undetected damage to visual processing regions beyond the MTL. To address these issues, this study investigated object perception in two human amnesic patients who were chosen on the basis of their lesion locations and suitability for detailed neuroimaging investigation. A neuropsychological task with minimal working memory demands was administered in which participants assessed the structural coherency of single novel objects. Critically, only the patient with perirhinal atrophy was impaired. Moreover, volumetric and functional neuroimaging data demonstrated that this deficit cannot be attributed to the dysfunction of visual cortical areas. Additional analyses of eye-movement patterns during the perceptual task revealed an inability of this patient to detect structural incoherency consistently. This study uses a combination of techniques to provide strong evidence that the perirhinal cortex subserves perception and suggests that the MTL perceptual-mnemonic debate cannot be dismissed on the basis of anatomy or a working memory impairment.
doi:10.1523/JNEUROSCI.0116-10.2010
PMCID: PMC3079896  PMID: 20463221
Memory; Amnesia; Hippocampus; Parahippocampal; Imaging; Eye movement
18.  Ecphory of Autobiographical Memories: an fMRI Study on Recent and Remote Memory Retrieval 
NeuroImage  2005;30(1):285-298.
Ecphory occurs when one recollects a past event cued by a trigger, such as a picture, odor, or name. It is a central component of autobiographical memory, which allows us to “travel mentally back in time” and re-experience specific events from our personal past. Using fMRI and focusing on the role of medial temporal lobe (MTL) structures, we investigated the brain bases of autobiographical memory and whether they change with the age of memories. Importantly, we used an ecphory task in which the remote character of the memories was ensured. The results showed that a large bilateral network supports autobiographical memory: temporal lobe, temporo-occipito-parietal junction, dorsal prefrontal cortex, medial frontal cortex, retrosplenial cortex and surrounding areas, and MTL structures. This network, including MTL structures, changed little with the age of the memories.
doi:10.1016/j.neuroimage.2005.09.025
PMCID: PMC1513614  PMID: 16257547
remote memory; episodic memory; semantic memory; consolidation
19.  Medial temporal lobe activity during source retrieval reflects information type, not memory strength 
Journal of cognitive neuroscience  2010;22(8):1808-1818.
The medial temporal lobes (MTL) are critical for episodic memory but the functions of MTL subregions are controversial. According to memory strength theory, MTL subregions collectively support declarative memory in a graded manner. In contrast, other theories assert that MTL subregions support functionally distinct processes. For instance, one view is that perirhinal cortex (PRc) processes item information, parahippocampal cortex (PHc) processes context information, and the hippocampus binds item and context. Here, we report two experiments that tested competing predictions from these models. In these studies, subjects encoded color-word associations by imagining color either as a contextual association (context detail condition) or as a feature of the item to be encoded (item detail condition). Results showed that encoding color information as an item detail improved source recognition in amnesic patients with recollection deficits. Furthermore, event-related fMRI data from healthy subjects revealed PRc activation associated with successful retrieval of item details, whereas activation in the hippocampus and PHc was associated with recollection-based source retrieval. The qualitatively different patterns of results observed in PRc and hippocampus/PHc are inconsistent with a memory strength account and are consistent with the idea that different MTL regions process different types of episodic information.
doi:10.1162/jocn.2009.21335
PMCID: PMC2862119  PMID: 19702458
memory; hippocampus; parahippocampal; memory formation; medial; temporal
20.  Fornix integrity and hippocampal volume predict memory decline and progression to AD 
Background
The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer’s disease (AD). The aims of the present study were to: 1) examine the cross-sectional relationship between fornix DTI measurements (fractional anisotropy (FA), and mean (MD), axial (DA) and radial (DR) diffusivities), hippocampal volume, and memory performance, and 2) compare fornix DTI measures to hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment (MCI) to AD dementia.
Methods
23 MCI participants with baseline hippocampal volumetry and diffusion tensor imaging received detailed evaluations at baseline, 3, 6, 12 months, and 2.5 years. Six participants converted to AD over the follow-up. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the MMSE, CDR-Sum of boxes and Memory z-scores; ROC analyses examined the predictive value for conversion to AD.
Results
There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, DR, DA) were cross-sectionally correlated with memory z-scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression with likelihood ratios>83, and better than 90% accuracy.
Conclusion
Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually-drawn fornix ROI shows comparable promise to hippocampal volume as a predictive biomarker of progression and warrants replication in a larger study.
doi:10.1016/j.jalz.2011.05.2416
PMCID: PMC3305232  PMID: 22404852
Fornix; Hippocampus; Mild Cognitive Impairment; Biomarker; Diffusion tensor imaging
21.  Why is there a special issue on perirhinal cortex in a journal called Hippocampus?: The perirhinal cortex in historical perspective 
Hippocampus  2012;22(10):1941-1951.
Despite its small size, the perirhinal cortex (PRh) plays a central role in understanding the cerebral cortex, vision and memory; it figures in discussions of cognitive capacities as diverse as object perception, semantic knowledge, feelings of familiarity and conscious recollection. Two conceptual constructs have encompassed PRh. The current orthodoxy incorporates PRh within the medial temporal lobe (MTL) as a memory area; an alternative considers PRh to be a sensory area with a role in both perception and memory. A historical perspective provides insight into both of these ideas. PRh came to be included in the MTL because of two accidents of history. In evolutionary history, the hippocampus migrated from its ancestral situation, as medial cortex, into the temporal lobe; in the history of neuropsychology, a “memory system” that originally consisted of the amygdala and hippocampus came to include PRh. These two histories explain why a part of the sensory neocortex, PRh, entered into the conceptual construct called the MTL. They also explain why some experimental results seem to exclude a perceptual function for this sensory area, while others embrace perception. The exclusion of perceptual functions results from a history of categorizing tasks as perceptual or mnemonic, often on inadequate grounds. By instead exploring the role of PRh in encoding, representing and retrieving stimulus information, it can be understood as a part of the sensory neocortex, one that has much the same relationship with the hippocampus as do other parts of the neocortex that evolved at about the same time.
doi:10.1002/hipo.22055
PMCID: PMC3951742  PMID: 22987673
medial temporal lobe; memory systems; prefrontal cortex; ventral stream
22.  Can Complex Visual Discrimination Deficits in Amnesia Be Attributed to the Medial Temporal Lobe? An Investigation Into the Effects of Medial Temporal Lobe Damage on Brain Connectivity 
Hippocampus  2012;23(1):7-13.
It has been suggested that complex visual discrimination deficits in patients with medial temporal lobe (MTL) damage may be explained by damage or dysfunction beyond the MTL. We examined the resting functional networks and white matter connectivity of two amnesic patients who have consistently demonstrated discrimination impairments for complex object and/or spatial stimuli across a number of studies. Although exploratory analyses revealed some significant differences in comparison with neurologically healthy controls (more specifically in the patient with a larger MTL lesion), there were no obvious findings involving posterior occipital or posterior temporal regions, which can account entirely for their discrimination deficits. These findings converge with previous work to support the suggestion that the MTL does not subserve long-term declarative memory exclusively. © 2012 Wiley Periodicals, Inc.
doi:10.1002/hipo.22056
PMCID: PMC3555392  PMID: 23233411
resting state networks; diffusion tensor imaging; MRI; hippocampus; perirhinal cortex
23.  IMPAIRED CATEGORY FLUENCY IN MEDIAL TEMPORAL LOBE AMNESIA: THE ROLE OF EPISODIC MEMORY 
Memory tasks are often classified as semantic or episodic, but recent research shows that these types of memory are highly interactive. Category fluency, for example, is generally considered to reflect retrieval from semantic memory, but behavioral evidence suggests that episodic memory is also involved: Participants frequently draw on autobiographical experiences while generating exemplars of certain categories. Neuroimaging studies accordingly have reported increased medial temporal lobe (MTL) activation during exemplar generation. Studies of fluency in MTL amnesics have yielded mixed results but were not designed to determine the precise contributions of episodic memory. We addressed this issue by asking MTL amnesics and controls to generate exemplars of three types of categories. One type tended to elicit autobiographical and spatial retrieval strategies (AS). Another type elicited strategies that were autobiographical but nonspatial (AN). The third type elicited neither autobiographical nor spatial strategies (N). Amnesic patients and control participants generated exemplars for 8 categories of each type. Patients were impaired on all category types but were more impaired on AS and AN categories. After covarying for phonemic fluency (total FAS score), the N category impairment was not significant, but the impairment on AS and AN categories remained. The same results were obtained for patients with lesions restricted to the MTL and those with more extensive lesions. We conclude that patients’ episodic memory impairment hindered their performance on this putatively semantic task. This interaction between episodic and semantic memory might partially account for fluency deficits seen in aging, mild cognitive impairment, and Alzheimer’s disease.
doi:10.1523/JNEUROSCI.1202-09.2009
PMCID: PMC2761020  PMID: 19726648
AMNESIA; EPISODIC; SEMANTIC; MEDIAL TEMPORAL; FLUENCY; MEMORY
24.  Amygdala lesions selectively impair familiarity in recognition memory 
Nature neuroscience  2011;14(11):1416-1417.
A major controversy in the study of memory concerns whether there are distinct medial temporal lobe (MTL) substrates of recollection and familiarity. Studies using Received Operating Characteristics (ROC) analyses of recognition memory indicate that the hippocampus is essential to recollection but not familiarity. We report the converse pattern wherein amygdala damage impairs familiarity while sparing recollection. Combined with previous findings, these results dissociate recollection and familiarity by selective MTL damage.
doi:10.1038/nn.2919
PMCID: PMC3203336  PMID: 21946327
25.  An fMRI investigation of posttraumatic flashbacks 
Brain and Cognition  2013;81(1):151-159.
Highlights
► Flashbacks in PTSD are associated with decreased rather than increased MTL activation. ► Flashbacks in PTSD are associated with activation in the insula and in motor and sensory areas. ► Flashbacks in PTSD may correspond to familiarity rather than recollection responses.
Flashbacks are a defining feature of posttraumatic stress disorder (PTSD), but there have been few studies of their neural basis. We tested predictions from a dual representation model of PTSD that, compared with ordinary episodic memories of the same traumatic event, flashbacks would be associated with activity in dorsal visual stream and related areas rather than in the medial temporal lobe. Participants with PTSD, with depression but not PTSD, and healthy controls were scanned during a recognition task with personally relevant stimuli. The contrast of flashbacks versus ordinary episodic trauma memories in PTSD was associated with increased activation in sensory and motor areas including the insula, precentral gyrus, supplementary motor area, and mid-occipital cortex. The same contrast was associated with decreased activation in the midbrain, parahippocampal gyrus, and precuneus/posterior cingulate cortex. The results were discussed in terms of theories of PTSD and dual-process models of recognition.
doi:10.1016/j.bandc.2012.10.002
PMCID: PMC3549493  PMID: 23207576
PTSD; Flashbacks; Memory; Dual-process; Familiarity

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