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The recently developed myelin imaging method, inhomogeneous magnetization transfer (ihMT), is a surrogate measure of myelin content. The goal of the current study was to investigate alterations in myelin integrity in patients with recurrent major depressive disorder (rMDD).Fifty-two patients with rMDD (36 female and 16 male) and 42 healthy controls (HC, 29 female and 13 male) were included. Two ihMT indices, quantitative ihMT (qihMT) and quantitative MT (qMT), were estimated from the ihMT data. A 50 white matter atlas was used to extract the regional quantitative values for each subject. The differences in qihMT and qMT values between the rMDD and HC groups were compared by a general linear model. Pearson correlation analyses were conducted to investigate associations between the significantly altered ihMT indices and clinical measures (Hamilton Depression Rating Scale scores and disease duration) in rMDD group.The rMDD group showed significantly lower qihMT values in the fornix, left anterior limb of internal capsule, and left sagittal stratum, and lower qMT values in the fornix and left anterior limb of internal capsule than those of the HC group (p0.05, false discovery rate corrected). Both the qihMT and qMT values in the fornix of patients with rMDD were negatively correlated with disease duration (qihMT: r = -0.478, p0.001, Bonferroni corrected; qMT: r = -0.433, p = 0.001, Bonferroni corrected).Our findings suggested that rMDD is associated with myelin impairment in the fornix, left anterior limb of internal capsule, and left sagittal stratum. In addition, this disruption of myelin integrity in the fornix could be cumulative as the disease progresses.

Mild cognitive impairment (MCI) is an intermediate stage of cognitive decline and dementia. The absence of specific diagnostic test for identification of MCI and AD. The current study aims to find proteomics based change in plasma proteins and diffusion tensor imaging (DTI) based white matter changes in MCI for early detection of prodromal Alzheimer’s disease. Fifty cases of mild cognitive impairment and age matched control between (55–75 yrs) were screened on basis of Mini Mental State Examination (MMSE). Two dimensional gel electrophoresis and DTI imaging was performed in MCI and age matched control. The MMSE score of MCI were in the range of (28 ± 2–22.6 ± 1) as compared with healthy control (28 ± 2), DTI metrics apparent diffusion coefficient (ADC) and fractional Anisotropy (FA) has shown significant changes in fornix, corpus callosum, hippocampus, right temporal and right frontal lobe, left frontal lobe, forcep major of MCI subjects as compared with controls. The protein expression of keratin type-2 was up regulated and albumin was down regulated in MCI subjects as compared with control. The data from present study signifies that expression of Keratin type-2 and albumin along with white matter changes provides early signatures for identification of MCI at high risk of Alzheimer’s disease

Recent research dealing with the structures of the medial temporal lobe (MTL) has shifted away from exclusively investigating memory-related processes and has repeatedly incorporated the investigation of complex visual perception. Several studies have demonstrated that higher level visual tasks can recruit structures like the hippocampus and perirhinal cortex in order to successfully perform complex visual discriminations, leading to a perceptual-mnemonic or representational view of the medial temporal lobe. The current study employed a complex visual discrimination paradigm in two patients suffering from brain lesions with differing locations and origin. Both patients, one with extensive medial temporal lobe lesions (VG) and one with a small lesion of the anterior fornix (HJK), were impaired in complex discriminations while showing otherwise mostly intact cognitive functions. The current data confirmed previous results while also extending the perceptual-mnemonic theory of the MTL to the main output structure of the hippocampus, the fornix.

The cerebellum is shown to be involved in some limbic functions of the human brain such as emotion and affect. The major connection of the cerebellum with the limbic system is known to be through the cerebello-hypothalamic pathways. The consensus is that the projections from the cerebellar nuclei to the limbic system, and particularly the hypothalamus, or from the hypothalamus to the cerebellar nuclei, are through multisynaptic pathways in the bulbar reticular formation. The detailed anatomy of the pathways responsible for mediating these responses, however, is yet to be determined. Diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of the cerebello-ponto-hypothalamic (CPH) pathway. This study aimed to investigate the utility of high-spatial-resolution diffusion tensor tractography for mapping the trajectory of the CPH tract in the human brain. Fifteen healthy adults were studied. We delineated, for the first time, the detailed trajectory of the CPH tract of the human brain in fifteen normal adult subjects using high-spatial-resolution diffusion tensor tractography. We further revealed the close relationship of the CPH tract with the optic tract, temporo-pontine tract, amygdalofugal tract and the fornix in the human brain.

To analyze the microstructure of brain white matter according to diffusion tensor imaging (DTI) based on tract-based spatial statistics (TBSS) in early Parkinson's disease (PD).A total of 31 age- and sex-matched early PD patients and 22 healthy volunteers were recruited in the present study. DTI was performed, and the data analyzed with fsl4.0 software. The fractional anisotropy (FA) was compared between both groups with an independent t test, and the differential area was analyzed. White matter fiber tracts with significant difference in FA between the two groups were selected, and their FAs were measured. Pearson's correlation analysis was employed to analyze the unified Parkinson's disease rating scale (UPDRS) score and its association with FA of different tracts.When compared with healthy volunteers, early PD patients had reduced FA in the following areas: bilateral anterior corona radiate, upper corona radiate, fasciculus arcuatus, crus anterius capsulae internae, crus posterius capsulae internae, capsula externa, posterior thalamic radiation, optic radiation, sagittal layer (including fasciculus arcuatus and inferior fronto-occipital fasciculus), crura fornicis, stria terminalis, fornix, genu, body and pad of corpus callosum, left unciform fasciculus, right cingulate bundle, right medipeduncle, and arcuate fibers in the bilateral frontal, temporal, and occipital lobes (P 0.05). When compared with healthy volunteers, early PD patients showed abnormal FA of fasciculus in the white matter mainly in following areas: bilateral crus anterius capsulae internae, bilateral capsula externa, right anterior corona radiate, body and pad of bilateral corpus callosum, and left sagittal layer (including fasciculi longitudinalis inferior and fasciculus occipitofrontalis inferior) (P 0.05). In addition, in early PD patients, the UPDRS score and movement score had no relationship with the FA of different fasciculi in the white matter (P 0.05).There is wide alteration of white matter microstructure in early PD patients, which is characterized by disruption of projection fibers in the descending pathway, limbic system-related fasciculi, corpus callosum, thalamus after radiation, posterior thalamic radiation, Gratiolet's bundle and other fasciculi in the white matter.

Numerous studies in first-episode schizophrenia suggest the involvement of white matter (WM) abnormalities in multiple regions underlying the pathogenesis of this condition. However, there has never been a neuroimaging study in patients with first-episode, drug-naive paranoid schizophrenia by using tract-based spatial statistics (TBSS) method. Here, we used diffusion tensor imaging (DTI) with TBSS method to investigate the brain WM integrity in patients with first-episode, drug-naive paranoid schizophrenia. Twenty patients with first-episode, drug-naive paranoid schizophrenia and 26 healthy subjects matched with age, gender, and education level were scanned with DTI. An automated TBSS approach was employed to analyze the data. Voxel-wise statistics revealed that patients with paranoid schizophrenia had decreased fractional anisotropy (FA) values in the right superior longitudinal fasciculus (SLF) II, the right fornix, the right internal capsule, and the right external capsule compared to healthy subjects. Patients did not have increased FA values in any brain regions compared to healthy subjects. There was no correlation between the FA values in any brain regions and patient demographics and the severity of illness. Our findings suggest right-sided alterations of WM integrity in the WM tracts of cortical and subcortical regions may play an important role in the pathogenesis of paranoid schizophrenia.

Mash1, a member of the basic helix-loop-helix (bHLH) transcription factor family, has previously been considered essential for neuronal differentiation and specification in the nervous system. In this study, we investigated the expression of Mash1 in the hippocampus after fimbria-fornix (FF) transection. Western blot showed that protein of Mash1 increased significantly and peaked at day 7 after FF transection. Immunofluorescence indicated that after FF transection, more newborn cells differentiated into Mash1 positive cells in the deafferented side than that in the normal side, and we investigated that in the neurogenic area, subgranular zone (SGZ), a part of Mash1 positive cells were NeuN positive, and more Mash1/NeuN double positive neurons were identified in the deafferented side than that in the normal side. Additionally, the number of Mash1/NeuN double positive neurons in SGZ increased significantly and peaked at day 7 after FF transection. In vitro, immunofluorescence revealed that extracts of the deafferented hippocampus promoted neuronal differentiation to a greater extent than extracts from normal hippocampus. Deafferented extracts also enhanced Mash1 expression in MAP-2 positive neurons. This study concludes that after FF transection, Mash1 expression in the deafferented hippocampus increased and might play an important role in inducing local progenitors to differentiate into neurons.

The object of this work was to determine whether the changes in field activity and neuronal excitability recorded in the hippocampus during eyeblink classical conditioning are induced by the cholinergic input, and their relationships with the conditioned response performance. The pyramidal layer field activity, its response to fornix stimulation and eyelid responses were recorded during paired tone-air puff presentations, under scopolamine (25, 50 and 100 microg/kg) or saline administration, following well-established eyeblink conditioning in a trace paradigm in cats. Scopolamine impaired behavioral performance, and, in the hippocampus, disrupted conditioned stimulus-evoked field potential, high frequency shift in field activity, and paired presentation-induced hyperexcitability. These findings indicate that the cholinergic input participates in hippocampal information processing in a way that allows precise conditioned response performance and memory trace formation.

mRNA, Western analysis and immunohistochemistry were used to study the expression of the small heat shock protein (HSP) 27 in the rat septum and hippocampus following fimbria-fornix lesions, a model of neurodegeneration and regeneration. (HSP) 27 mRNA level was increased 2.5-fold in the medial septum 3 days after lesion and this increase persisted for 10 days. In the hippocampus, after an initial 15-fold increase at 3 days post-injury, HSP27 mRNA returned to basal levels 10 days after the lesion. Three and 10 days after lesion, HSP27 protein levels were increased in the septum (4.5 and 5-fold, respectively) and hippocampus (65 and 10-fold, respectively). The morphology of the HSP27 positive cells was indistinguishable from that of GFAP-immunoreactive cells. In addition, in the septum of injured rats, occasional neurons were heavily labelled with anti-HSP27 antibodies. Thus, up-regulation of HSP27, particularly in glial cells, may be a component of glial input in the processes on degeneration/regeneration which occur in this model.

Interleukin-1 β (Il-1 β ) is a cytokine known to have somnogenic properties. We have previously shown that Il-1 β decreases food intake when injected into the lateral part of the paraventricular nucleus of the hypothalamus (PVH), and, because food intake and sleep are closely related behaviors, we tested the hypothesis that Il-1 β could alter sleep when injected into the lateral PVH area. We compared the effects of Il-1 β with those of two other peptides involved in feeding behavior and known to act in the PVH area, the corticotropin-releasing factor (CRF) and salmon calcitonin (sCT). The EEG of rats was recorded for 48 h after the injection. The results showed that CRF had no effects, Il-1 β reduced significantly sleep duration during the first 5 h following the injection, and sCT profoundly affected sleep cycles, producing an almost 30-h long insomnia, with a major reduction of slow wave sleep and a long period of alternation of REM sleep and wakening. It is concluded that (i) the area between the lateral part of the PVH and the fornix is a brain site involved in sleep regulation, (ii) Il-1 β , a peptide generally considered as somnogenic, decreases sleep when administered in this area, and (iii) sCT is an extremely potent suppressor of slow wave sleep.

A few studies have reported on the neural connectivity of the fornix in the human brain, however, little is known about the neural connectivity of the anterior body of the fornix. In this study, we used diffusion tensor imaging in investigation of the neural connectivity of the anterior body of the fornix in normal subjects. Forty healthy subjects were recruited for this study. A seed region of interest was placed on the anterior body of the fornix using the FMRIB Software Library. Connectivity was defined as the incidence of connection between the anterior body of the fornix and any neural structure of the brain at the threshold of 5, 25, and 50 streamlines. In all subjects, the anterior body of the fornix showed 100% connectivity to the anterior commissure and hypothalamus at thresholds of 5, 25, and 50. On the other hand, regarding the thresholds of 5, 25, and 50, the anterior body of the fornix showed connectivity to the septal forebrain region (53.8, 23.8, and 15.0%), frontal lobe via anterior commissure (41.3,12.5, and 10.0%), medial temporal lobe (85.0,66.3, and 62.5%), lateral temporal lobe (75.0, 56.3, and 35.0%), occipital lobe (21.3, 5.0, and 1.3%), frontal lobe via septum pellucidum (28.8, 13.8, and 8.8%), tegmentum of midbrain (7.5, 5.0, and 0%), tectum of midbrain (2.5,0, and 0%), and tegmentum of pons (5.0,0, and 0%). The anterior body of the fornix showed high connectivity with the anterior commissure and hypothalamus, and brain areas relevant to cholinergic nuclei (the septal forebrain region and brainstem) and memory function (the medial temporal lobe).

Quantitative electron microscopy confirmed that the neuropil of the ventrolateral part of the ventromedial hypothalamic nucleus (VL-VMHN) of the rat is sexually dimorphic with respect to the density of shaft and axo-spinous synapses, both of which are more numerous in the male. In addition, adult rats with complete interruption of the fornix displayed a sexually dimorphic input in the density of fornical synapses in the neuropil of the VL-VMHN, in which degenerating terminals were more numerous in the male. Perinatal exposure of the female to exogenous testosterone or castration of the newborn male ‘inverted’ these sex differences, demonstrating their hormonal dependence. It is concluded that (1) the fornix provides synaptic input to the VL-VMHN as proven by orthograde degeneration; (2) the number of fornical endings synapsing in the VL-VMHN is greater in the male than in the female; (3) this dimorphism depends of the organizational effect of gonadal sex steroids.

Many studies have reported on vulnerable areas of the brain in hypoxic ischemic brain injury (HI-BI). However, little is known about the involvement of neural tracts following HI-BI. We investigated neural tract injuries in adult patients with HI-BI, using diffusion tensor tractography (DTT). Twelve consecutive patients with HI-BI and 12 control subjects were recruited for this study. We classified the patients into two subgroups according to the preservation of alertness: subgroup A-5 patients who had intact alertness and subgroup B-7 patients who had impaired alertness. DTI-Studio software was used for evaluation of seven neural tracts: corticospinal, cingulum, fornix, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and optic radiation. We measured the DTT parameters (fractional anisotropy, apparent diffusion coefficient and voxel number) of each neural tract. In the individual analysis, all 12 patients showed injuries in all 24 neural tracts in terms of both DTT parameters and integrity, except for the corticospinal tract (75.0% injury). In the group analysis, the patient group showed neural injuries in all 24 neural tracts. In comparison of subgroups A and B, subgroup B showed more severe injuries: subgroup B showed a higher rate of disruption (39.8%) than subgroup A (12.9%) on individual DTTs and subgroup B had more severe injuries in both the cingulum and superior longitudinal fasciculus. In conclusion, we found that extensive injuries in the neural tracts were accompanied by HI-BI. Patients with impaired alertness appeared to show more severe injuries of neural tracts.

Nerve growth factor (NGF) receptor-like immunoreactivity has been demonstrated in the normal adult human hippocampus, using minimally fixed cryostat sections obtained from snap-frozen tissue and incubated with the mouse monoclonal antibody, ME 20.4. The majority of the reactivity was associated with nerve fibre processes and their terminals. Numerous fibres were apparent in the alveus, originating from the fornix, and extending into the stratum oriens and pyramidal layer of the hippocampal formation. A more diffuse particulate reactivity, presumed to be nerve terminal, was observed around the pyramidal neurons and in the stratum radiatum, stratum lacunosum moleculare and also in the dentate fascia. The pattern of hippocampal NGF receptor immunoreactivity was broadly similar to acetylcholinesterase histochemical localization, indicating a principal localization on cholinergic axons innervating this area. Preliminary observations indicate an overall reduction in NGF receptor-immunoreactive axons and terminals in old age and Alzheimer's disease.

In order to observe acetylcholinesterase (AChE) and its distribution into soluble and membrane-bound molecular forms in cholinergically denervated hippocampus, AChE was analyzed in the hippocampus of adult mice with and without bilateral fornix lesions made by stereotactically positioned knife cuts. Homogenates from lesioned mice contained an average of 3% of choline acetyltransferase-specific activity, 12% of AChE-specific activity and 98% of protein compared to homogenates from controls. After lesioning, the relative proportion of membrane-bound G4 decreased from 77% to 56% of total AChE while soluble G4, membrane-bound G1–G2, and soluble G1–G2 each increased in relative abundance.

The fate of neural stem/progenitor cells (NSCs/NPCs) in vivo lies on the local microenvironment. Whether the denervated hippocampus provides a stimulative role on the survival and differentiation of the anterior subventricular zone (SVZa) progenitors was investigated in the present study. In vivo the SVZa progenitors were transplanted into the denervated hippocampus and the contralateral side, and were found migrating along the subgranular layer. More implanted cells were found survived and differentiated into the Neurofilament 200 (NF-200) or beta-Tubulin-III positive neurons in the denervated than in the normal hippocampus at all points studied. In vitro the extracts from the denervated and normal hippocampus were used to induce differentiation of the SVZa progenitors. More progenitors incubated with the denervated hippocampal extract differentiated significantly into the MAP-2 or AChE positive neurons than those incubated with the normal hippocampal extract (P

Abnormalities of temporal lobe structure and frontal lobe function occur in schizophrenia. There have been few studies of young people with schizophrenia and little is known about temporo-frontal connectivity in the disease. Therefore, the cross-sectional area of the body of the fornix was measured on MR images from 17 young people with schizophrenia, nine with other serious psychiatric illnesses and eight without illness. The mean age of each group was 16-17 years. The mean cross-sectional fornix area in subjects with schizophrenia was significantly larger than that in subjects without illness ( approximately 40%) and psychiatric controls ( approximately 26%). There was no such significant difference between subjects without illness and psychiatric controls. The nature of the larger fornix in early-onset schizophrenia, whether it persists and whether it occurs in schizophrenia presenting in adulthood, remain to be elucidated.

A direct projection from the entorhinal cortex to the mammillary nuclei was found in the rat, by using retrograde and anterograde transport of wheat germ agglutinin-horseradish peroxidase. The projection originates from cells in layer III of the medial entorhinal area and terminates almost ipsilaterally within the ventrolateral region of the pars lateralis of the medial mammillary nucleus. The terminal fields consist of two distinct spots; one is located ventral to the fornix fibers entering the mammillary nuclei and the other situated more caudoventrally in the most ventrolateral region of the pars lateralis. The results suggest that cells in the medial entorhinal area are directly connected with cells in the two restricted regions of the medial mammillary nucleus.

Bilateral complete transection of the fimbria-fornix causes a significant increase in nerve growth factor (NGF) content both in the septum and hippocampus of the adult rat as measured by a sensitive immunoassay 7 days after lesioning. The finding, that elevation of NGF in septum (250%) was much more pronounced than that in the hippocampus (30–50%), cannot be explained by retrograde axonal transport. Degeneration of central cholinergic neurons might be a potential trigger for NGF production in the CNS.

The axons of the septohippocampal pathway reach the hippocampal formation via the fimbria, dorsal fornix and supracallosal striae. Complete lesions of these pathways denervate most of the hippocampal formation but a small, residual innervation occurs via a different ventral route. The cells of origin for this additional route for cholinergic innervation of the hippocampal formation have been identified in the present study with a combined technique using a fluorescent retrograde tracer and acetylcholinesterase histochemistry. These cells were localized to the diagonal band of Broca. In a subsequent experiment it was demonstrated, by destroying these cells unilaterally, that they were responsible to a large extent for the cholinergic compensatory collateral sprouting in the hippocampus that has previously been shown to develop following complete fimbria-fornix transection.

The distribution of thyrotropin-releasing hormone (TRH) in the hippocampal formation was determined using a radioimmunoassay (RIA) specific for TRH. RIA of hippocampal subregions revealed that the CA3 region of the hippocampal formation contained the highest amount of TRH, followed by intermediate levels in region CA1 and the dentate gyrus. The hilus and subiculum contained the lowest levels. The issue of whether hippocampal TRH is derived from extrinsic and/or intrinsic sources was evaluated by making lesions of the major subcortical afferent to the hippocampus, the fornix pathway. Analysis of the hippocampal formation by RIA revealed that the ventral hippocampus contains higher levels of TRH than the dorsal hippocampus (6.01 ± 0.62 pg/mg tissue weight vs 1.11 ± 0.19 pg/mg tissue weight). Lesions of the fornix produced significant decreases in ventral TRH to 52.9% of its control level and in dorsal TRH to 28.8% of its control level. The results from these studies suggest that (1) there is a differential distribution of TRH in the hippocampal formation, (2) the hippocampal formation might be composed of extrinsic and intrinsic sources of TRH, and (3) extrinsic sources of TRH might enter the hippocampus via the fornix pathway. In addition (4) the greater post-lesion decrement in ventral vs dorsal hippocampal TRH suggests that TRH fibers traversing the fornix innervate the ventral hippocampal formation in preference to its dorsal counterpart.

Using the remarkable capability of tetramethylbenzidine (TMB) neurohistochemistry to delinate anterogradely transported horseradish peroxidase (HRP) following HRP gel implants in the prearcuate prefrontal cortex of macaque and cebus monkeys, this study revealed bilateral projections to the caudate nucleus and inferior parietal lobule that followed the median subcallosal fasciculus, a rostrocaudally running, midline trajectory located between the body of the corpus callosum and the fornix. This seemingly aberrant fascicle runs through the septum pellucidum from the genu to the splenium of the corpus callosum, and gives off fibers bilaterally to the body of the caudate nucleus and inferior parietal lobule. The description of this unique pathway re-emphasizes the close relationship that exists between the granular frontal and inferior parietal cortices, and the striatum, and explains earlier observations based upon silver degeneration and autoradiographic studies, of prefrontal corticofugal projections to the septum and fornix.

The spread of ventral hippocampal afterdischarge activity to nuclei of the basal diencephalon was studied in rats with fornix lesions and combined lesions of the fornix and stria terminalis. The results indicate that a major hippocampal influence on specific hypothalamic, preoptic and basal forebrain structures is conveyed by way of the amygdala's stria terminalis. An additional hippocampal influence on certain basal forebrain nuclei is consistent with projections via the ventral amygdalofugal pathway.

The area lateral to the stria medullaris and the fornix at the level of the interventricular foramen, an area known to be occupied by the medial dorsal accessory group and the anterior fornical nucleus of the magnocellular neurosecretory system, was found to be studded with serotonin (5-HT)-like immunoreactive (LI) varicosities. Double immunostaining with antisera against 5-HT and oxytocin (OXY) proved that the 5-HT-LI varicosities were in close proximity to the OXY-LI neurons in the medial dorsal accessory group and the anterior fornical nucleus. These nuclei were distributed more densely with 5-HT-LI varicosities than other cell groups in the magnocellular neurosecretory system.

The loss and recovery of hippocampal acetylcholinesterase (AChE) molecular forms was studied following fornix lesions. Two weeks after lesioning, the G4 form, which constituted the majority (91%) of AChE activity in the unlesioned hippocampus, was significantly reduced (P less than 0.01) to levels 21% of those in the unlesioned hippocampus, suggesting that this form is probably presynaptic. Thirteen weeks after lesioning total hippocampal AChE activity had increased 3-fold relative to 2-week animals, with the majority of the recovery in total AChE activity being due to a significant (P less than 0.05) increase in the abundance of the G4 form to levels 340% of those at 2 weeks. The increase in the abundance of the G4 form, which appears to be a functionally important molecular form of AChE within the CNS, serves as a marker of the integrity of the newly formed hippocampal cholinergic synapses.

Transection of the non-glutamatergic septohippocampal fibers 3-5 days prior to intrahippocampal microinjection of 1 microgram kainic acid (KA) or 3 micrograms ibotenic acid (IBO) protect dentate granule cells against KA but not IBO. In the transected animals, a significant reduction of KA-induced behavioral seizures can be observed. Neither transection of the hippocampal commissural system nor the fornix contralateral to the intrahippocampal injections protected against KA or IBO neurotoxicity. These findings are discussed in the light of the current hypothesis of KA- and IBO-induced neuronal degeneration.