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1.  Cholinergic Basal Forebrain Structure Influences the Reconfiguration of White Matter Connections to Support Residual Memory in Mild Cognitive Impairment 
The Journal of Neuroscience  2015;35(2):739-747.
The fornix and hippocampus are critical to recollection in the healthy human brain. Fornix degeneration is a feature of aging and Alzheimer's disease. In the presence of fornix damage in mild cognitive impairment (MCI), a recognized prodrome of Alzheimer's disease, recall shows greater dependence on other tracts, notably the parahippocampal cingulum (PHC). The current aims were to determine whether this shift is adaptive and to probe its relationship to cholinergic signaling, which is also compromised in Alzheimer's disease. Twenty-five human participants with MCI and 20 matched healthy volunteers underwent diffusion MRI, behavioral assessment, and volumetric measurement of the basal forebrain. In a regression model for recall, there was a significant group × fornix interaction, indicating that the association between recall and fornix structure was weaker in patients. The opposite trend was present for the left PHC. To further investigate this pattern, two regression models were generated to account for recall performance: one based on fornix microstructure and the other on both fornix and left PHC. The realignment to PHC was positively correlated with free recall but not non-memory measures, implying a reconfiguration that is beneficial to residual memory. There was a positive relationship between realignment to PHC and basal forebrain gray matter volume despite this region demonstrating atrophy at a group level, i.e., the cognitive realignment to left PHC was most apparent when cholinergic areas were relatively spared. Therefore, cholinergic systems appear to enable adaptation to injury even as they degenerate, which has implications for functional restoration.
doi:10.1523/JNEUROSCI.3617-14.2015
PMCID: PMC4293419  PMID: 25589767
cholinergic system; diffusion; episodic memory; fornix; mild cognitive impairment; white matter
2.  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
3.  Interindividual Variation in Fornix Microstructure and Macrostructure Is Related to Visual Discrimination Accuracy for Scenes But Not Faces 
The Journal of Neuroscience  2014;34(36):12121-12126.
Transection of the nonhuman primate fornix has been shown to impair learning of configurations of spatial features and object-in-scene memory. Although damage to the human fornix also results in memory impairment, it is not known whether there is a preferential involvement of this white-matter tract in spatial learning, as implied by animal studies. Diffusion-weighted MR images were obtained from healthy participants who had completed versions of a task in which they made rapid same/different discriminations to two categories of highly visually similar stimuli: (1) virtual reality scene pairs; and (2) face pairs. Diffusion-MRI measures of white-matter microstructure [fractional anisotropy (FA) and mean diffusivity (MD)] and macrostructure (tissue volume fraction, f) were then extracted from the fornix of each participant, which had been reconstructed using a deterministic tractography protocol. Fornix MD and f measures correlated with scene, but not face, discrimination accuracy in both discrimination tasks. A complementary voxelwise analysis using tract-based spatial statistics suggested the crus of the fornix as a focus for this relationship. These findings extend previous reports of spatial learning impairments after fornix transection in nonhuman primates, critically highlighting the fornix as a source of interindividual variation in scene discrimination in humans.
doi:10.1523/JNEUROSCI.0026-14.2014
PMCID: PMC4152609  PMID: 25186756
discrimination learning; fornix; hippocampus; scene discrimination; tractography
4.  Microstructural White Matter Changes, Not Hippocampal Atrophy, Detect Early Amnestic Mild Cognitive Impairment 
PLoS ONE  2013;8(3):e58887.
Background
Alzheimer’s disease (AD) is generally considered to be characterized by pathology in gray matter of the brain, but convergent evidence suggests that white matter degradation also plays a vital role in its pathogenesis. The evolution of white matter deterioration and its relationship with gray matter atrophy remains elusive in amnestic mild cognitive impairment (aMCI), a prodromal stage of AD.
Methods
We studied 155 cognitively normal (CN) and 27 ‘late’ aMCI individuals with stable diagnosis over 2 years, and 39 ‘early’ aMCI individuals who had converted from CN to aMCI at 2-year follow up. Diffusion tensor imaging (DTI) tractography was used to reconstruct six white matter tracts three limbic tracts critical for episodic memory function - the fornix, the parahippocampal cingulum, and the uncinate fasciculus; two cortico-cortical association fiber tracts - superior longitudinal fasciculus and inferior longitudinal fasciculus; and one projection fiber tract - corticospinal tract. Microstructural integrity as measured by fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) was assessed for these tracts.
Results
Compared with CN, late aMCI had lower white matter integrity in the fornix, the parahippocampal cingulum, and the uncinate fasciculus, while early aMCI showed white matter damage in the fornix. In addition, fornical measures were correlated with hippocampal atrophy in late aMCI, whereas abnormality of the fornix in early aMCI occurred in the absence of hippocampal atrophy and did not correlate with hippocampal volumes.
Conclusions
Limbic white matter tracts are preferentially affected in the early stages of cognitive dysfunction. Microstructural degradation of the fornix preceding hippocampal atrophy may serve as a novel imaging marker for aMCI at an early stage.
doi:10.1371/journal.pone.0058887
PMCID: PMC3597581  PMID: 23516569
5.  Sub-Regional Hippocampal Injury is Associated with Fornix Degeneration in Alzheimer’s Disease 
We examined in vivo evidence of axonal degeneration in association with neuronal pathology in Alzheimer’s disease (AD) through analysis of fornix microstructural integrity and measures of hippocampal subfield atrophy. Based on known anatomical topography, we hypothesized that the local thickness of subiculum and CA1 hippocampus fields would be associated with fornix integrity, reflecting an association between AD-related injury to hippocampal neurons and degeneration of associated axon fibers. To test this hypothesis, multi-modal imaging, combining measures of local hippocampal radii with diffusion tensor imaging (DTI), was applied to 44 individuals clinically diagnosed with AD, 44 individuals clinically diagnosed with mild cognitive impairment (MCI), and 96 cognitively normal individuals. Fornix microstructural degradation, as measured by reduced DTI-based fractional anisotropy (FA), was prominent in both MCI and AD, and was associated with reduced hippocampal volumes. Further, reduced fornix FA was associated with reduced anterior CA1 and antero-medial subiculum thickness. Finally, while both lesser fornix FA and lesser hippocampal volume were associated with lesser episodic memory, only the hippocampal measures were significant predictors of episodic memory in models including both hippocampal and fornix predictors. The region-specific association between fornix integrity and hippocampal neuronal death may provide in vivo evidence for degenerative white matter injury in AD: axonal pathology that is closely linked to neuronal injury.
doi:10.3389/fnagi.2012.00001
PMCID: PMC3323836  PMID: 22514534
hippocampus; fornix; fractional anisotropy; Alzheimer’s disease; mild cognitive impairment
6.  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
7.  Fractional Anisotropy of the Fornix and Hippocampal Atrophy in Alzheimer’s Disease 
Decrease in the directionality of water diffusion measured with fractional anisotropy (FA) on diffusion tensor imaging has been linked to loss of myelin and axons in the white matter. Fornix FA is consistently decreased in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Furthermore, decreased fornix FA is one of the earliest MRI abnormalities observed in cognitively normal individuals who are at an increased risk for AD, such as in pre-symptomatic carriers of familial AD mutations and in pre-clinical AD. Reductions of FA at these early stages, which predicted the decline in memory function. Fornix carries the efferent projections from the CA1 and CA3 pyramidal neurons of the hippocampus and subiculum, connecting these structures to the septal nuclei, anterior thalamic nucleus, mammillary bodies, and medial hypothalamus. Fornix also carries the afferent cholinergic and GABAergic projections from the medial septal nuclei and the adjacent diagonal band back to the medial temporal lobe, interconnecting the core limbic structures. Because fornix carries the axons projecting from the hippocampus, integrity of the fornix is in-part linked to the integrity of the hippocampus. In keeping with that, fornix FA is reduced in subjects with hippocampal atrophy, correlating with memory function. The literature on FA reductions in the fornix in the clinical spectrum of AD from pre-symptomatic carriers of familial AD mutations to pre-clinical AD, MCI, and dementia stages is reviewed.
doi:10.3389/fnagi.2014.00316
PMCID: PMC4230048  PMID: 25431558
fornix; DTI; Alzheimer’s disease; hippocampus; MRI imaging
8.  Fornix as an imaging marker for episodic memory deficits in healthy aging and in various neurological disorders 
The fornix is a part of the limbic system and constitutes the major efferent and afferent white matter tracts from the hippocampi. The underdevelopment of or injuries to the fornix are strongly associated with memory deficits. Its role in memory impairments was suggested long ago with cases of surgical forniceal transections. However, recent advances in brain imaging techniques, such as diffusion tensor imaging, have revealed that macrostructural and microstructural abnormalities of the fornix correlated highly with declarative and episodic memory performance. This structure appears to provide a robust and early imaging predictor for memory deficits not only in neurodegenerative and neuroinflammatory diseases, such as Alzheimer's disease and multiple sclerosis, but also in schizophrenia and psychiatric disorders, and during neurodevelopment and “typical” aging. The objective of the manuscript is to present a systematic review regarding published brain imaging research on the fornix, including the development of its tracts, its role in various neurological diseases, and its relationship to neurocognitive performance in human studies.
doi:10.3389/fnagi.2014.00343
PMCID: PMC4294158  PMID: 25642186
fornix; development; aging; episodic memory; neuropsychiatric disorders; DTI
9.  Diffusion tensor imaging in Alzheimer's disease: insights into the limbic-diencephalic network and methodological considerations 
Glucose hypometabolism and gray matter atrophy are well known consequences of Alzheimer's disease (AD). Studies using these measures have shown that the earliest clinical stages, in which memory impairment is a relatively isolated feature, are associated with degeneration in an apparently remote group of areas—mesial temporal lobe (MTL), diencephalic structures such as anterior thalamus and mammillary bodies, and posterior cingulate. These sites are thought to be strongly anatomically inter-connected via a limbic-diencephalic network. Diffusion tensor imaging or DTI—an imaging technique capable of probing white matter tissue microstructure—has recently confirmed degeneration of the white matter connections of the limbic-diencephalic network in AD by way of an unbiased analysis strategy known as tract-based spatial statistics (TBSS). The present review contextualizes the relevance of these findings, in which the fornix is likely to play a fundamental role in linking MTL and diencephalon. An interesting by-product of this work has been in showing that alterations in diffusion behavior are complex in AD—while early studies tended to focus on fractional anisotropy, recent work has highlighted that this measure is not the most sensitive to early changes. Finally, this review will discuss in detail several technical aspects of DTI both in terms of image acquisition and TBSS analysis as both of these factors have important implications to ensure reliable observations are made that inform understanding of neurodegenerative diseases.
doi:10.3389/fnagi.2014.00266
PMCID: PMC4183111  PMID: 25324775
neurodegenerative diseases; Alzheimer's disease neurobiology; axonal loss; circuit of Papez; long association tracts; splenium; DTI criteria; Alzheimer's disease biomarkers
10.  Diffusion Tractography of the Fornix in Schizophrenia 
Schizophrenia research  2008;107(1):39-46.
Background
White matter fiber tracts, especially those interconnecting the frontal and temporal lobes, are likely implicated in pathophysiology of schizophrenia. Very few studies, however, have focused on the fornix, a compact bundle of white matter fibers, projecting from the hippocampus to the septum, anterior nucleus of the thalamus and the mamillary bodies. Diffusion Tensor Imaging (DTI), and a new post-processing method, fiber tractography, provides a unique opportunity to visualize and to quantify entire trajectories of fiber bundles, such as the fornix, in vivo. We applied these techniques to quantify fornix diffusion anisotropy in schizophrenia.
Methods
DTI images were used to evaluate the left and the right fornix in 36 male patients diagnosed with chronic schizophrenia and 35 male healthy individuals, group matched on age, parental socioeconomic status, and handedness. Regions of interest were drawn manually, blind to group membership, to guide tractography, and Fractional Anisotropy (FA), a measure of fiber integrity, was calculated and averaged over the entire tract for each subject. The Doors and People test (DPT) was used to evaluate visual and verbal memory, combined recall and combined recognition.
Results
Analysis of variance was performed and findings demonstrated a difference between patients with schizophrenia and controls for fornix FA (P=0.006). Protected post-hoc independent sample t-tests demonstrated a bilateral FA decrease in schizophrenia, compared with control subjects (left side: P=0.048; right side P=0.006). Higher fornix FA was statistically significantly correlated with DPT and measures of combined visual memory (r=.554, p=.026), combined verbal memory (r=.647, p=.007), combined recall (r=.516, p=.041), and combined recognition (r=.710, p=.002) for the control group. No such statistically significant correlations were found in the patient group.
Conclusions
Our findings show the utility of applying DTI and tractography to study white matter fiber tracts in vivo in schizophrenia. Specifically, we observed a bilateral disruption in fornix integrity in schizophrenia, thus broadening our understanding of the pathophysiology of this disease.
doi:10.1016/j.schres.2008.10.022
PMCID: PMC2646850  PMID: 19046624
11.  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
12.  The Fornix in Mild Cognitive Impairment and Alzheimer’s Disease 
The fornix is an integral white matter bundle located in the medial diencephalon and is part of the limbic structures. It serves a vital role in memory functions and as such has become the subject of recent research emphasis in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). As the characteristic pathological processes of AD progress, structural and functional changes to the medial temporal lobes and other regions become evident years before clinical symptoms are present. Though gray matter atrophy has been the most studied, degradation of white matter structures especially the fornix may precede these and has become detectable with use of diffusion tensor imaging (DTI) and other complimentary imaging techniques. Recent research utilizing DTI measurement of the fornix has shown good discriminability of diagnostic groups, particularly early and preclinical, as well as predictive power for incident MCI and AD. Stimulating and modulating fornix function by the way of DBS has been an exciting new area as pharmacological therapeutics has been slow to develop.
doi:10.3389/fnagi.2015.00001
PMCID: PMC4301006  PMID: 25653617
Alzheimer’s; MCI; fornix; DTI; DBS
13.  Individual Differences in Fornix Microstructure and Body Mass Index 
PLoS ONE  2013;8(3):e59849.
The prevalence of obesity and associated health conditions is increasing in the developed world. Obesity is related to atrophy and dysfunction of the hippocampus and hippocampal lesions may lead to increased appetite and weight gain. The hippocampus is connected via the fornix tract to the hypothalamus, orbitofrontal cortex, and the nucleus accumbens, all key structures for homeostatic and reward related control of food intake. The present study employed diffusion MRI tractography to investigate the relationship between microstructural properties of the fornix and variation in Body Mass Index (BMI), within normal and overweight ranges, in a group of community-dwelling older adults (53–93 years old). Larger BMI was associated with larger axial and mean diffusivity in the fornix (r = 0.64 and r = 0.55 respectively), relationships that were most pronounced in overweight individuals. Moreover, controlling for age, education, cognitive performance, blood pressure and global brain volume increased these correlations. Similar associations were not found in the parahippocampal cingulum, a comparison temporal association pathway. Thus, microstructural changes in fornix white matter were observed in older adults with increasing BMI levels from within normal to overweight ranges, so are not exclusively related to obesity. We propose that hippocampal-hypothalamic-prefrontal interactions, mediated by the fornix, contribute to the healthy functioning of networks involved in food intake control. The fornix, in turn, may display alterations in microstructure that reflect weight gain.
doi:10.1371/journal.pone.0059849
PMCID: PMC3610894  PMID: 23555805
14.  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
15.  The impact of fornix lesions in rats on spatial learning tasks sensitive to anterior thalamic and hippocampal damage 
Behavioural Brain Research  2015;278:360-374.
Highlights
•Fornix damage mildly impair spatial biconditional and passive place learning tasks.•Fornix lesions impair spatial go/no-go and alternation problems.•Fornix lesions impair tests making flexible demands on spatial memory.•Fornix connections are not always required for learning fixed spatial responses.
The present study sought to understand how the hippocampus and anterior thalamic nuclei are conjointly required for spatial learning by examining the impact of cutting a major tract (the fornix) that interconnects these two sites. The initial experiments examined the consequences of fornix lesions in rats on spatial biconditional discrimination learning. The rationale arose from previous findings showing that fornix lesions spare the learning of spatial biconditional tasks, despite the same task being highly sensitive to both hippocampal and anterior thalamic nuclei lesions. In the present study, fornix lesions only delayed acquisition of the spatial biconditional task, pointing to additional contributions from non-fornical routes linking the hippocampus with the anterior thalamic nuclei. The same fornix lesions spared the learning of an analogous nonspatial biconditional task that used local contextual cues. Subsequent tests, including T-maze place alternation, place learning in a cross-maze, and a go/no-go place discrimination, highlighted the impact of fornix lesions when distal spatial information is used flexibly to guide behaviour. The final experiment examined the ability to learn incidentally the spatial features of a square water-maze that had differently patterned walls. Fornix lesions disrupted performance but did not stop the rats from distinguishing the various corners of the maze. Overall, the results indicate that interconnections between the hippocampus and anterior thalamus, via the fornix, help to resolve problems with flexible spatial and temporal cues, but the results also signal the importance of additional, non-fornical contributions to hippocampal-anterior thalamic spatial processing, particularly for problems with more stable spatial solutions.
doi:10.1016/j.bbr.2014.10.016
PMCID: PMC4274319  PMID: 25453745
Biconditional learning; Cognitive map; Configural learning; Hippocampus; Incidental learning; Thalamus
16.  Fornix Integrity and Hippocampal Volume in Male Schizophrenic Patients 
Biological psychiatry  2006;60(1):22-31.
Background
The hippocampus has been shown to be abnormal in schizophrenia. The fornix is one of the main fiber tracts connecting the hippocampus with other brain regions. Few studies have evaluated the fornix in schizophrenia, however. A focus on fornix abnormalities and their association with hippocampal abnormalities might figure importantly in our understanding of the pathophysiology of schizophrenia.
Methods
Line-scan diffusion tensor imaging (DTI) was used to evaluate diffusion in the fornix in 24 male patients with chronic schizophrenia and 31 male control subjects. Maps of fractional anisotropy (FA) and mean diffusivity (Dm), which are indices sensitive to white-matter integrity, were generated to quantify diffusion within the fornix. We used high spatial resolution magnetic resonance imaging (MRI) to measure hippocampal volume.
Results
FA and cross-sectional area of the fornix were significantly reduced in patients compared with control subjects. Dm was significantly increased, whereas hippocampal volume was bilaterally reduced in patients. Reduced hippocampal volume was correlated with increased mean Dm and reduced cross-sectional area of the fornix for patients. Patients also showed a significant correlation between reduced scores on neuropsychologic measures of declarative-episodic memory and reduced hippocampal volumes.
Conclusions
These findings demonstrate a disruption in fornix integrity in patients with schizophrenia.
doi:10.1016/j.biopsych.2005.09.021
PMCID: PMC2768597  PMID: 16406249
Anisotropy; diffusion tensor imaging; fornix; hippocampus; MRI; white matter
17.  Stimulus content and the neural correlates of source memory 
Brain Research  2011;1373(2):110-123.
It has been suggested that several regions of the brain, including subregions of the medial temporal lobe (MTL) and the posterior parietal cortex, contribute to source memory success in a material-general manner, with most models highlighting the importance of memory process rather than material type. For the MTL in particular, however, increasing evidence suggests that MTL subregions may be specialized for processing different materials, raising the possibility that source memory-related activity may be material-sensitive. Previous fMRI studies have not directly compared source memory activity for different categories of stimuli, and it remains unclear whether source memory effects, in the MTL or elsewhere, are influenced by material. To investigate this issue, young participants were scanned during study while they made semantic judgments about words, pictures of objects and scenes, and during test when they retrieved the context (source) in which these items were studied. Several regions, including the hippocampi, medial and lateral parietal cortex, exhibited source memory effects common to words, objects and scenes, at both study and test. Material-dependent source memory effects were also identified in the left posterior inferior frontal and left perirhinal cortex for words and objects, respectively, at study but not test. These results offer direct support for the hypothesis that the MTL and posterior parietal cortex make material-general contributions to recollection. These results also point to a dissociation between encoding and retrieval with regard to the influence of material on the neural correlates of source memory accuracy, supporting the idea that a relatively small proportion of the activity elicited by a stimulus during encoding is incorporated into an episodic memory representation of the stimulus.
Research highlights
► Direct support for material-general role of MTL and parietal cortex in recollection. ► Source memory activity varies according to the nature of the stimulus materials. ► Material type influences source memory-related activity at study but not test.
doi:10.1016/j.brainres.2010.11.086
PMCID: PMC3098368  PMID: 21145314
Source memory; fMRI; Hippocampus; Perirhinal; Recollection; MTL
18.  Amnesia and neglect: beyond the Delay-Brion system and the Hebb synapse. 
Hippocampal damage in people causes impairments of episodic memory, but in rats it causes impairments of spatial learning. Experiments in macaque monkeys show that these two kinds of impairment are functionally similar to each other. After any lesion that interrupts the Delay-Brion system (hippocampus, fornix, mamillary bodies and anterior thalamus) monkeys are impaired in scene-specific memory, where an event takes place against a background that is specific to that event. Scene-specific memory in the monkey corresponds to human episodic memory, which is the memory of a unique event set in a particular scene, as opposed to scene-independent human knowledge, which is abstracted from many different scenes. However, interruption of the Delay-Brion system is not sufficient to explain all of the memory impairments that are seen in amnesic patients. To explain amnesia the specialized function of the hippocampus in scene memory needs to be considered alongside the other, qualitatively different functional specializations of other memory systems of the temporal lobe, including the perirhinal cortex and the amygdala. In all these specialized areas, however, including the hippocampus, there is no fundamental distinction between memory systems and perceptual systems. In explaining memory disorders in amnesia it is also important to consider them alongside the memory disorders of neglect patients. Neglect patients fail to represent in memory the side of the world that is contralateral to the current fixation point, in both short- and long-term memory retrieval. Neglect was produced experimentally by unilateral visual disconnection in the monkey, confirming the idea that visual memory retrieval is retinotopically organized; patients with unilateral medial temporal-lobe removals showed lateralized memory impairments for half-scenes in the visual hemifield contralateral to the removal. Thus, in scene-memory retrieval the Delay-Brion system contributes to the retrieval of visual memories into the retinotopically organized visual cortex. This scene memory interpretation of hippocampal function needs to be contrasted with the cognitive-map hypothesis. The cognitive-map model of hippocampal function shares some common assumptions with the Hebb-synapse model of association formation, and the Hebb-synapse model can be rejected on the basis of recent evidence that monkeys can form direct associations in memory between temporally discontiguous events. Our general conclusion is that the primate brain encompasses widespread and powerful memory mechanisms which will continue to be poorly understood if theory and experimentation continue to concentrate too much, as they have in the past, on the hippocampus and the Hebb synapse.
PMCID: PMC1692054  PMID: 9368937
19.  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
20.  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
21.  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
22.  White matter disruption at the prodromal stage of Alzheimer's disease: Relationships with hippocampal atrophy and episodic memory performance 
NeuroImage : Clinical  2015;7:482-492.
White matter tract alterations have been consistently described in Alzheimer's disease (AD). In particular, limbic fronto-temporal connections, which are critical to episodic memory function, may degenerate early in the course of the disease. However the relation between white matter tract degeneration, hippocampal atrophy and episodic memory impairment at the earliest stages of AD is still unclear. In this magnetic resonance imaging study, white matter integrity and hippocampal volumes were evaluated in patients with amnestic mild cognitive impairment due to AD (Albert et al., 2011) (n = 22) and healthy controls (n = 15). Performance in various episodic memory tasks was also evaluated in each participant. Relative to controls, patients showed a significant reduction of white matter fractional anisotropy (FA) and increase of radial diffusivity (RD) in the bilateral uncinate fasciculus, parahippocampal cingulum and fornix. Within the patient group, significant intra-hemispheric correlations were notably found between hippocampal grey matter volume and FA in the uncinate fasciculus, suggesting a relationship between atrophy and disconnection of the hippocampus. Moreover, episodic recognition scores were related with uncinate fasciculus FA across patients. These results indicate that fronto-hippocampal connectivity is reduced from the earliest pre-demential stages of AD. Disruption of fronto-hippocampal connections may occur progressively, in parallel with hippocampal atrophy, and may specifically contribute to early initial impairment in episodic memory.
Highlights
•Limbic fronto-temporal connections (cingulum, uncinate fasciculus and fornix) are altered from the prodromal stage of AD.•In prodromal AD patients, intra-hemispheric correlations were found between uncinate fasciculus FA and hippocampal atrophy.•In prodromal AD patients, uncinate fasciculus FA was correlated with scores on episodic recognition.
doi:10.1016/j.nicl.2015.01.014
PMCID: PMC4326466
Alzheimer's disease; Prodromal AD; Diffusion tensor imaging; Uncinate fasciculus; Cingulum; Episodic memory
23.  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
24.  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
25.  Faces are special but not too special: Spared face recognition in amnesia is based on familiarity 
Neuropsychologia  2010;48(13):3941-3948.
Most current theories of human memory are material-general in the sense that they assume that the medial temporal lobe (MTL) is important for retrieving the details of prior events, regardless of the specific type of materials. Recent studies of amnesia have challenged the material-general assumption by suggesting that the MTL may be necessary for remembering words, but is not involved in remembering faces. We examined recognition memory for faces and words in a group of amnesic patients, which included hypoxic patients and patients with extensive left or right MTL lesions. Recognition confidence judgments were used to plot receiver operating characteristics (ROCs) in order to more fully quantify recognition performance and to estimate the contributions of recollection and familiarity. Consistent with the extant literature, an analysis of overall recognition accuracy showed that the patients were impaired at word memory but had spared face memory. However, the ROC analysis indicated that the patients were generally impaired at high confidence recognition responses for faces and words, and they exhibited significant recollection impairments for both types of materials. Familiarity for faces was preserved in all patients, but extensive left MTL damage impaired familiarity for words. These results suggest that face recognition may appear to be spared because performance tends to rely heavily on familiarity, a process that is relatively well preserved in amnesia. The findings challenge material-general theories of memory, and suggest that both material and process are important determinants of memory performance in amnesia, and different types of materials may depend more or less on recollection and familiarity.
doi:10.1016/j.neuropsychologia.2010.09.005
PMCID: PMC4084520  PMID: 20833190
episodic memory; recollection; familiarity; amnesia; face recognition; word recognition

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