Perspectives on the neural connectivity of the fornix in the human brain

The fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit.Diffusion tensor imaging enables to estimate the neural connectivity of the fornix.The anterior fornical body has high connectivity with the anterior commissure,and brain areas relevant to cholinergic nuclei(septal forebrain region and brainstem)and memory function(medial temporal lobe).In the normal subjects,by contrast,the posterior fornical body has connectivity with the cerebral cortex and brainstem through the splenium of the corpus callosum.We believe that knowledge of the neural connectivity of the fornix would be helpful in investigation of the neural network associated with memory and recovery mechanisms following injury of the fornix.     

Differential deficits in the Morris water maze following cytotoxic lesions of the anterior thalamus and fornix transection

Rats with complete fornix lesions or cytotoxic lesions placed in the anterior thalamic region were trained on an allocentric spatial memory test (the Morris water maze). While both lesions led to impairments in locating the hidden platform in this test of reference memory, the thalamic lesions led to a significantly greater deficit than that observed after fornix transection as measured by a number of performance indices. The lesions also led to different patterns of swim behaviour in the pool. The severity of the thalamic lesion deficit was associated with anterior thalamic nuclei damage but not with damage to the nucleus medialis dorsalis. Both the fornix and the thalamic lesions also severely impaired T-maze alternation. In contrast, neither set of lesions appeared to affect the recognition of small or large objects. While the study provides further evidence of a close functional relationship between the hippocampus and the anterior thalamic nuclei, it also shows that disconnection of the fornical inputs to the anterior thalamic nuclei does not provide a full explanation of the thalamic deficit.     

Altered resting-state functional connectivity and anatomical connectivity of hippocampus in schizophrenia

Hippocampus has been implicated in participating in the pathophysiology of schizophrenia. However, the functional and anatomical connectivities between hippocampus and other regions are rarely concurrently investigated in schizophrenia. In the present study, both functional magnetic resonance imaging (fMRI) during rest and diffusion tensor imaging (DTI) were performed on 17 patients with paranoid schizophrenia and 14 healthy subjects. Resting-state functional connectivities of the bilateral hippocampi were separately analyzed by selecting the anterior hippocampus as region of interest. The fornix body was reconstructed by diffusion tensor tractography, and the integrity of this tract was evaluated using fractional anisotropy (FA). In patients with schizophrenia, the bilateral hippocampi showed reduced functional connectivities to some regions which have been reported to be involved in episodic memory, such as posterior cingulate cortex, extrastriate cortex, medial prefrontal cortex, and parahippocampus gyrus. We speculated that these reduced connectivity may reflect the disconnectivity within a neural network related to the anterior hippocampus in schizophrenia. Meanwhile the mean FA of the fornix body was significantly reduced in patients, indicating the damage in the hippocampal anatomical connectivity in schizophrenia. The concurrence of the functional disconnectivity and damaged anatomical connectivity between the hippocampus and other regions in schizophrenia suggest that the functional–anatomical relationship need to be further investigated.     

Diffusion tensor tractography studies on mechanisms of recovery of injured fornix

The fornix, which connects the medial temporal lobe and the medial diencephalon, is involved in episodic memory as an important part of the Papez circuit. The mechanisms of recovery of an injured fornix revealed by diffusion tensor tractography in the five studies are summarized as follows: 1) recovery through the nerve tract from an injured fornical crus to the medial temporal lobe via the normal pathway of the fornical crus; 2) recovery through the nerve tract originating from an ipsi-lesional fornical body connected to the ipsi-lesion-al medial temporal lobe via the splenium of the corpus callosum; 3) recovery through the nerve tract from the ipsi-lesional fornical body extending to the contra-lesional medial temporal lobe via the splenium of the corpus callosum; 4) recovery through the nerve tract originating from the ipsi-lesional fornical column con-nected to the ipsi-lesional medial temporal lobe; and 5) recovery through the nerve tract originating from the contra-lesional fornical column connected to the ipsi-lesional medial temporal lobe via the contra-lesional medial temporal lobe and the splenium of the corpus callosum. These diffusion tensor tractography studies on mechanisms of recovery of injured fornical crus appeared to provide useful information for clinicians caring for patients with brain injury, however, studies on this topic are still in the beginning stages.     

Abnormalities of the fornix in mild cognitive impairment are related to episodic memory loss

The fornix is a major efferent tract of the hippocampus, a structure critical for normal memory function. However, the role of structural degradation of the fornix in memory dysfunction in mild cognitive impairment (MCI) has remained unclear. We used diffusion tensor tractography to measure microstructural properties of the fornix and the corticospinal tract (CST), as a control tract, in 206 cognitively normal subjects, 76 amnestic MCI (aMCI) and 51 non-amnestic MCI (naMCI) subjects. Hippocampal volumes were measured using deformation-based morphometry. We found significant fractional anisotropy reductions in the left fornix and radial diffusivity (RD) increases in bilateral fornices in aMCI, but not in naMCI, compared with controls. No significant changes in the CST were found in aMCI subjects, but naMCI subjects showed significantly increased RD and axial diffusivity of the right CST, compared with controls. Increased left fornical RD measure was correlated with poor verbal memory performance in aMCI subjects. In addition, reduced microstructural integrity of the fornix was associated with hippocampal atrophy in aMCI. This study suggests that microstructural alteration of the fornix is a contributor to early episodic memory dysfunction in non-demented individuals.     

Anterograde amnesia with fornix damage following removal of IIIrd ventricle colloid cyst.

Two patients developed anterograde amnesia following the apparently uncomplicated transcallosal-transventricular removal of a colloid cyst. Damage to the fornical columns was demonstrated on CT and MRI scans, whilst other memory related structures were entirely normal. Longitudinal neuropsychological evaluation, over 12-24 months, has revealed a very similar pattern of deficit in the two cases: verbal memory has remained persistently impaired whilst nonverbal anterograde memory has improved to some degree. Formal tests of remote public (famous faces and events) and personal autobiographical memory have supported the clinical impression that neither patient has a temporally extensive retrograde amnesia. These findings address the role of the fornix, and the dissociation of memory processes in humans.     

Recollection is impaired,but familiarity remains intact in rats with lesions of the fornix

It has been argued that a neural system including the hippocampus, fornix, mamillary bodies, and anterior thalamus is specifically involved in recollection, but not in familiarity based memory processes. Here we test this hypothesis using a task of episodic‐like memory within an E‐shaped maze. Animals seek out a preferred object (what) in a particular location (where) that is unique to a particular context (which occasion). As objects are hidden from view at the point of decision making, the animals can only base their decision on recall of their previous episode in the E‐shaped maze. In contrast, once a decision has been made animals are free to explore both objects and display an object preference when objects are visible to the animal and decisions can be made on the basis of familiarity. Animals with fornix lesions are impaired at recalling a past event. However, the same animals on the same trials show no such impairment in a judgement of familiarity. We therefore demonstrate that recall is dependent upon the fornix, while familiarity based memory is not. © 2009 Wiley‐Liss, Inc.     

The role of hippocampal subfield volume and fornix microstructure in episodic memory across the lifespan

Advancing age is associated with both declines in episodic memory and degradation of medial temporal lobe (MTL) structure. The contribution of MTL to episodic memory is complex and depends upon the interplay among hippocampal subfields and surrounding structures that participate in anatomical connectivity to the cortex through inputs (parahippocampal and entorhinal cortices) and outputs (fornix). However, the differential contributions of MTL system components in mediating age effects on memory remain unclear. In a sample of 177 healthy individuals aged 20–94 we collected high‐resolution T1‐weighted, ultrahigh‐resolution T2/PD, and diffusion tensor imaging (DTI) MRI sequences on a 3T Phillips Achieva scanner. Hippocampal subfield and entorhinal cortex (ERC) volumes were measured from T2/PD scans using a combination of manual tracings and training of a semiautomated pipeline. Parahippocampal gyrus volume was estimated using Freesurfer and DTI scans were used to obtain diffusion metrics from tractography of the fornix. Item and associative episodic memory constructs were formed from multiple tests. Competing structural equation models estimating differential association among these structural variables were specified and tested to investigate whether and how fornix diffusion and volume of parahippocampal gyrus, ERC, and hippocampal subfields mediate age effects on associative and/or item memory. The most parsimonious, best‐fitting model included an anatomically based path through the MTL as well as a single hippocampal construct which combined all subfields. Results indicated that fornix microstructure independently mediated the effect of age on associative memory, but not item memory. Additionally, all regions and estimated paths (including fornix) combined to significantly mediate the age‐associative memory relationship. These findings suggest that preservation of fornix connectivity and MTL structure with aging is important for maintenance of associative memory performance across the lifespan.     

Dense amnesia in the monkey after transection of fornix, amygdala and anterior temporal stem

The traditional explanation of dense amnesia after medial temporal lesions is that the amnesia is caused by damage to the hippocampus and related structures. An alternative view is that dense amnesia after medial temporal lesions is caused by the interruption of afferents to the temporal cortex from the basal forebrain. These afferents travel to the temporal cortex through three pathways, namely the anterior temporal stem, the amygdala and the fornix-fimbria, and all these three pathways are damaged in dense medial temporal amnesia. In four experiments using different memory tasks, we tested the effects on memory of sectioning some or all of these three pathways in macaque monkeys. In a test of scene-specific memory for objects, which is analogous in some ways to human episodic memory, section of fornix alone, or section of amygdala and anterior temporal stem sparing the fornix, each produced a significant but mild impairment. When fornix section was added to the section of anterior temporal stem and amygdala in this task, however, a very severe impairment resulted. In an object recognition memory task (delayed matching-to-sample) a severe impairment was seen after section of anterior temporal stem and amygdala alone, with or without the addition of fornix section; this impairment was significantly more severe than that which was seen in the same task after amygdalectomy leaving the temporal stem intact, with or without fornix section. Animals with combined section of anterior temporal stem, amygdala and fornix were also impaired in object-reward association learning. However, the retention of pre-operatively acquired object-reward associations was at a high level. These results show that the pattern of impairments after section of anterior temporal stem, amygdala and fornix in the monkey, leaving hippocampus intact, resembles human dense amnesia and is different from the effects of hippocampal lesions in the monkey.     

Selective disconnection of the hippocampal formation projections to the mammillary bodies produces only mild deficits on spatial memory tasks: Implications for fornix function

It is now clear that the integrity of the fornix is important for normal mnemonic function. The fornix, however, is a major white matter tract, carrying numerous hippocampal formation afferents and efferents, and it is not known which specific components support memory processes. Established theories of extended hippocampal function emphasize the sequential pathway from the hippocampal formation (i.e., subicular complex) to the mammillary bodies and, thence, to the anterior thalamus, as pathology in each of these structures is implicated in anterograde amnesia in humans and spatial memory deficits in rats. The specific importance of the hippocampal formation projections that just innervate the mammillary bodies has, however, never been tested. This study isolated these specific projections in the rat by selectively cutting the descending component of the postcommissural fornix. Two successive, cohorts of rats with these tract lesions were tested on working memory tasks in the water‐maze, T‐maze, and radial‐arm maze. Disconnecting the descending postcommissural fornix had only a mild effect or sometimes no apparent effect on the performance of these spatial memory tasks, even though tracing experiments confirmed the loss of hippocampal formation‐mammillary projections. One implication is that the spatial deficits found in rats following standard fornix lesions are only partly attributable to the loss of projections from the hippocampal formation to the mammillary bodies. Perhaps more surprising, the behavioral impact of cutting the descending postcommissural fornix in rats appeared appreciably less than the effect of either mammillary body or mammillothalamic tract lesions. The present experiments show that the mammillary bodies can still effectively support spatial memory in the absence of their dense subicular complex inputs, so revealing the importance of the other afferents for sustaining mammillary body function. This new evidence for independent functions shows that the mammillary bodies are more than just a hippocampal relay. © 2010 Wiley‐Liss, Inc.     

Injury of fornix in patients with intracerebral hemorrhage

ABSTRACT Objectives: Many diffusion tensor tractography (DTT) studies have reported on fornix injury in various diseases. However, there has been no DTT study on fornix injury by intracerebral hemorrhage (ICH). We attempted to investigate fornix body injury in patients with ICH, using DTT. Methods: We identified 58 consecutive stroke patients using the following criteria: (1) first-ever stroke, (2) age: 45-65 years, (3) hemorrhage confined within the corona radiata and basal ganglion level, (4) an available DTT scan performed during the early stage of ICH (1-5 weeks after onset). Among 58 consecutive patients, we identified six patients who showed disruption at the fornix body.Results: Following ICH, 10.7% of patients revealed complete disruption of the fornix body on DTT. Results from DTT of the fornix showed disruption in anterior and posterior portions of the fornix body in three patients, in the anterior portion of the fornix body in two patient, and in the posterior portion of the fornix body in one patient. Conclusions: We report on six patients who showed complete disruption of the fornix body following ICH. It is our belief that the fornix of patients with ICH could be evaluated using DTT.     

Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia

Schizophrenia and Attention-Deficit/Hyperactivity Disorder (ADHD) are associated with similar deficits in working memory, attention, and inhibition. Both disorders also involve abnormalities of white matter integrity, possibly reflecting neural communication disruptions. There are likely some regional white matter abnormalities that underlie the common cognitive impairment, though also some regional abnormalities unique to each disorder. We used diffusion tensor imaging (DTI) to compare white matter integrity, as indicated by fractional anisotropy (FA), in adolescents with schizophrenia (n = 15) or ADHD (n = 14) and healthy controls (n = 26). Schizophrenia patients had uniquely low FA, relative to the other two groups, in bilateral cerebral peduncles, anterior and posterior corpus callosum, right anterior corona radiata, and right superior longitudinal fasciculus. ADHD patients had uniquely high FA in left inferior and right superior frontal regions. Both clinical groups had lower FA than controls in left posterior fornix. The two disorders generally demonstrated distinct patterns of abnormal connectivity suggesting that common cognitive and behavioral deficits derive from distinct sources, though the posterior fornix may be involved in both disorders. Schizophrenia was associated with abnormally low FA in widespread circuitry indicative of general connectivity disruptions, whereas ADHD was associated with abnormally high FA in frontal networks that may indicate impaired branching of fibers.     

Memory consolidation of fear conditioning: Bi-stable amygdala connectivity with dorsal anterior cingulate and medial prefrontal cortex

Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms of fear acquisition and extinction. However, the neural mechanism of memory consolidation of fear conditioning is not well understood. To address this question, we measured brain activity and the changes in functional connectivity following fear acquisition using resting-state functional magnetic resonance imaging. The amygdala–dorsal anterior cingulate cortex (dACC) and hippocampus–insula functional connectivity were enhanced, whereas the amygdala–medial prefrontal cortex (mPFC) functional coupling was decreased during fear memory consolidation. Furthermore, the amygdala–mPFC functional connectivity was negatively correlated with the subjective fear ratings. These findings suggest the amygdala functional connectivity with dACC and mPFC may play an important role in memory consolidation of fear conditioning. The change of amygdala-mPFC functional connectivity could predict the subjective fear. Accordingly, this study provides a new perspective for understanding fear memory consolidation.     

Structural and functional papez circuit integrity in amyotrophic lateral sclerosis

Cognitive impairment in amyotrophic lateral sclerosis (ALS) is heterogeneous but now recognized as a feature in non-demented patients and no longer exclusively attributed to executive dysfunction. However, despite common reports of temporal lobe changes and memory deficits in ALS, episodic memory has been less explored. In the current study, we examined how the Papez circuit—a circuit known to participate in memory processes—is structurally and functionally affected in ALS patients (n?=?20) compared with healthy controls (n?=?15), and whether these changes correlated with a commonly used clinical measure of episodic memory. Our multimodal MRI approach (cortical volume, voxel-based morphometry, diffusion tensor imaging and resting state functional magnetic resonance) showed reduced gray matter in left hippocampus, left entorhinal cortex and right posterior cingulate as well as increased white matter fractional anisotropy and decreased mean diffusivity in the left cingulum bundle (hippocampal part) of ALS patients compared with controls. Interestingly, thalamus, mammillary bodies and fornix were preserved. Finally, we report a decreased functional connectivity in ALS patients in bilateral hippocampus, bilateral anterior and posterior parahippocampal gyrus and posterior cingulate. The results revealed that ALS patients showed statistically significant structural changes, but more important, widespread prominent functional connectivity abnormalities across the regions comprising the Papez circuit. The decreased functional connectivity found in the Papez network may suggest these changes could be used to assess risk or assist early detection or development of memory symptoms in ALS patients even before structural changes are established.     

Neurophysiology of the caudally directed hippocampal efferent system in the rat: Projections to the subicular complex

We performed experiments studying the responses of rat subicular and entorhinal neurons to electrical stimulation of the fornix and hippocampus. Four main results were obtained: (1) extracellular recordings from principal neurons showed prolonged inhibition in response to stimulation, and intracellular recordings showed prominent IPSPs; (2) neither fornical nor commissural afferents were necessary for the inhibitory responses; they were present even in animals that had received prior surgical sections of the fornix and hippocampal commissures; (3) antidromic responses to fornix or hippocampal stimulation were recorded in neurons of the subicular complex; and (4) 3 cells in the subicular and entorhinal cortex were encountered that showed some of the properties associated with interneurons. The results suggest that principal neurons of the subicular complex share a number of properties with hippocampal pyramidal cells, including intrinsic recurrent inhibitory circuitry. Further study is required to determine the pathway for entorhinal inhibitory responses.     

Associations between cortical β-amyloid burden,fornix microstructure and cognitive processing of faces,places, bodies and other visual objects in early Alzheimer's disease

Using two imaging modalities, that is, Pittsburgh compound B (PiB) positron emission tomography (PET) and diffusion tensor imaging (DTI) the present study tested associations between cortical amyloid-beta (Aβ) burden and fornix microstructural changes with cognitive deficits in early Alzheimer's disease (AD), namely deficits in working memory (1-back) processing of visual object categories (faces, places, objects, bodies and verbal material). Second, we examined cortical Aβ associations with fornix microstructure. Seventeen early AD patients and 17 healthy-matched controls were included. Constrained spherical deconvolution-based tractography was used to segment the fornix and a control tract the central branch of the superior longitudinal fasciculus (CB-SLF) previously implicated in working memory processes. Standard uptake value ratios (SUVR) of Aβ were extracted from 45 cortical/subcortical regions from the AAL atlas and subject to principal component analysis for data reduction. Patients exhibited (i) impairments in cognitive performance (ii) reductions in fornix fractional anisotropy (FA) and (iii) increases in a component that loaded highly on cortical Aβ. There were no group differences in CB-SLF FA and in a component loading highly on subcortical Aβ. Partial correlation analysis in the patient group showed (i) positive associations between fornix FA and performance for all the visual object categories and (ii) a negative association between the cortical Aβ component and performance for the object categories but not for the remaining classes of visual stimuli. A subsequent analysis showed a positive association between overall cognition (performance across distinct 1-back task conditions) with fornix FA but no association with cortical Aβ burden, in keeping with influential accounts on early onset AD. This indicates that the fornix degenerates early in AD and contributes to deficits in working memory processing of visual object categories; though it is also important to acknowledge the importance of prospective longitudinal studies with larger samples. Overall, the effect sizes of fornical degeneration on visual working memory appeared stronger than the ones related to amyloid burden.     

Lesions of the fornix but not the amygdala impair the acquisition of concurrent discriminations by rats.

Rats with lesions in either the fornix, the amygdala, or both were compared with control animals on the acquisition of three different concurrent object discrimination tasks. In the first task the animals received one trial per day on each of six pairs of stimulus objects ('spaced' condition). In the second task the animals received four trials per day on each of six stimulus pairs ('standard' condition), and in the last task the animals received 36 trials on each of two stimulus pairs in just a single day ('massed' condition). Animals with fornical lesions were impaired on all three conditions. In contrast, the amygdala lesions only affected the 'massed' condition and then only when the animals had to select the 'non-preferred' stimulus. Although animals with combined amygdala and fornical lesions were impaired on all three conditions there was no evidence that their deficit was greater than that in the animals with lesions restricted to just the fornix. In view of the evidence that concurrent discrimination learning offers an appropriate test for anterograde amnesia these findings are seen as consistent with the notion that the hippocampus, but not the amygdala, is critically involved in the mnemonic processes disrupted by amnesia.     

White matter changes in patients with hypoxic amnesia

A deficit of declarative memory is a common sequela after a hypoxic episode. While the role of gray matter changes (i.e., atrophy of hippocampal formation) as mainly responsible for memory loss has been emphasized, the role of the white matter damage has so far been neglected. The present study was aimed at evaluating whether white matter damage, within the neural circuitry responsible for declarative memory functioning, is present in anoxic patients. We assessed, by means of voxel-based morphometry, the integrity of white matter regions in five patients with hypoxic amnesia. When anoxic patients were compared to healthy controls, significantly less white matter density was detected in the fornix, anterior portion of the cingulum bundle and uncinate fasciculus bilaterally. We conclude that cerebral hypoxia may alter, together with the hippocampi, the integrity of white matter fibers throughout the memory-limbic system.     

White matter changes in patients with hypoxic amnesia

A deficit of declarative memory is a common sequela after a hypoxic episode. While the role of gray matter changes (i.e., atrophy of hippocampal formation) as mainly responsible for memory loss has been emphasized, the role of the white matter damage has so far been neglected. The present study was aimed at evaluating whether white matter damage, within the neural circuitry responsible for declarative memory functioning, is present in anoxic patients. We assessed, by means of voxel-based morphometry, the integrity of white matter regions in five patients with hypoxic amnesia. When anoxic patients were compared to healthy controls, significantly less white matter density was detected in the fornix, anterior portion of the cingulum bundle and uncinate fasciculus bilaterally. We conclude that cerebral hypoxia may alter, together with the hippocampi, the integrity of white matter fibers throughout the memory-limbic system.