Structural Connectivity Changes After Fornix Transection in Macaques Using Probabilistic Diffusion Tractography.

The fornix, the limbic system's white matter tract connecting the extended hippocampal system to subcortical structures of the medial diencephalon, is strongly associated with learning and memory in humans and nonhuman primates (NHPs). Here, we sought to investigate alterations in structural connectivity across key cortical and subcortical regions after fornix transection in NHPs. We collected diffusion-weighted MRI (dMRI) data from three macaque monkeys that underwent bilateral fornix transection during neurosurgery and from four age- and cohort-matched control macaques that underwent surgery to implant a head-post but remained neurologically intact. dMRI data were collected from both groups at two time points, before and after the surgeries, and scans took place at around the same time for the two groups. We used probabilistic tractography and employed the number of tracking streamlines to quantify connectivity across our regions of interest (ROIs), in all dMRI sessions. In the neurologically intact monkeys, we observed high connectivity across certain ROIs, including the CA3 hippocampal subfield with the retrosplenial cortex (RSC), the anterior thalamus with the RSC, and the RSC with the anterior cingulate cortex (ACC). However, we found that, compared to the control group, the fornix-transected monkeys showed marked, significant, connectivity changes including increases between the anterior thalamus and the ACC and between the CA3 and the ACC, as well as decreases between the CA3 and the RSC. Our results highlight cortical and subcortical network changes after fornix transection and identify candidate indirect connectivity routes that may support memory functions after damage and/or neurodegeneration.

The role of hippocampal niche exosomes in rat hippocampal neurogenesis after fimbria-fornix transection.

Exosomes transfer signaling molecules such as proteins, lipids, and RNAs to facilitate cell-cell communication and play an important role in the stem cell microenvironment. In previous work, we demonstrated that rat fimbria-fornix transection (FFT) enhances neurogenesis from neural stem cells (NSCs) in the subgranular zone (SGZ). However, how neurogenesis is modulated after denervation remains unknown. Here, we investigated whether exosomes in a denervated hippocampal niche may affect neurogenesis. Using the FFT rat model, we extracted hippocampal exosomes and identified them using western blots, transmission electron microscopy (TEM), and nanoparticle size measurement. We also used RNA sequencing and bioinformatic analysis of exosomes to identify noncoding RNA expression profiles and neurogenesis-related miRNAs, respectively. RNA sequencing analysis demonstrated 9 upregulated and 15 downregulated miRNAs. miR-3559-3P and miR-6324 increased gradually after FFT. Thus, we investigated the function of miR-3559-3P and miR-6324 with NSC proliferation and differentiation assays. Transfection of miR-3559-3p and miR-6324 mimics inhibited the proliferation of NSCs and promoted the differentiation of NSCs into neurons, while miR-3559-3p and miR-6324 inhibitors promoted NSC proliferation and inhibited neuronal differentiation. Additionally, the exosome marker molecules CD9, CD63, and Alix were expressed in exosomes extracted from the hippocampal niche. Finally, TEM showed that exosomes were ∼100 nm in diameter and had a "saucer-like" bilayer membrane structure. Taken together, these findings suggest that differentially expressed exosomes and their related miRNAs in the denervated hippocampal niche can promote differentiation of NSCs into neurons.

Flattened sheet-like fornix forming a "Cobra Hood" deformity: A previously unreported variant of fornix anatomy and its implication for surgical approaches to the third ventricle.

BACKGROUND: The fornix is the main efferent tract from the hippocampus and is an important component of the memory pathways. Variations in the anatomy of the fornix are not commonly encountered. MATERIALS AND METHODS: The anatomy of the fornix was studied in 30 cadavers of normal adult healthy males who had died in road accidents. The full extent of the hippocampus was prosected up to the tail under the magnoscope. RESULTS: In 10 of the 30 brains, the crura and the body of fornix were bilaterally broad and flat like a sheet, rather than the usual compact bundle, forming a cobra-like hood over the roof of the third ventricle. The maximum width was approximately 16 mm on the right side (mean: 11.7 mm) and 11 mm on the left (mean: 8.5mm). CONCLUSION: Knowledge of this variation will be useful during the transcallosal approach to third ventricle tumors, especially while going subchoroidal, because an unexpected lateral span of the fornix in the surgical corridor can result in inadvertent injury to it, leading to memory defects.

Low-frequency electrical stimulation of a fiber tract in temporal lobe epilepsy.

OBJECTIVE: Surgical resection of the temporal lobe is an effective treatment for medically intractable temporal lobe epilepsy, but can cause memory impairment. Deep brain stimulation in epilepsy has targeted gray matter structures using high frequencies, but achieved limited success. We tested the hypothesis that low-frequency stimulation of the fornix reduces interictal epileptiform discharges and seizures in patients with intractable mesial temporal lobe epilepsy, without affecting memory. METHODS: We implanted depth electrodes in 11 patients for surgical evaluation of intractable epilepsy. Low-frequency stimulation of the fornix occurred in 4-hour sessions in the video-electroencephalography unit. Mental status assessment was performed at baseline and during stimulation. We studied the effect of stimulation on hippocampal spikes and seizures. RESULTS: There were no complications, and the patients were unaware of the stimulation. Fornix stimulation elicited evoked responses in the hippocampus and the posterior cingulate gyrus. Hourly Mini-Mental Status Examination (MMSE) scores showed an increase during stimulation when compared to prestimulation MMSE, largely due to improvement in recall, possibly representing a practice effect. Hippocampal spikes were significantly reduced during and outlasting each stimulation session. Seizure odds (n = 7) were reduced by 92% in the 2 days that followed stimulation. INTERPRETATION: Low-frequency stimulation of the fornix activates the hippocampus and other areas of the declarative memory circuit. The results of this preliminary study suggest that low-frequency stimulation is tolerable and reduces epileptiform discharges and seizures in patients with intractable mesial temporal lobe epilepsy. A controlled clinical trial may be warranted.

Development of an MR-Guided Focused Ultrasound (MRgFUS) Lesioning Approach for the Fornix in the Rat Brain.

OBJECTIVE: High-intensity magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive therapy to lesion brain tissue, used clinically in patients and pre-clinically in several animal models. Challenges with focused ablation in rodent brains can include skull and near-field heating and accurately targeting small and deep brain structures. We overcame these challenges by creating a novel method consisting of a craniectomy skull preparation, a high-frequency transducer (3 MHz) with a small ultrasound focal spot, a transducer positioning system with an added manual adjustment of ∼0.1 mm targeting accuracy, and MR acoustic radiation force imaging for confirmation of focal spot placement. METHODS: The study consisted of two main parts. First, two skull preparation approaches were compared. A skull thinning approach (n = 7 lesions) was compared to a craniectomy approach (n = 22 lesions), which confirmed a craniectomy was necessary to decrease skull and near-field heating. Second, the two transducer positioning systems were compared with the fornix chosen as a subcortical ablation target. We evaluated the accuracy of targeting using histologic methods from a high-frequency transducer with a small ultrasound focal spot and MR acoustic radiation force imaging. RESULTS: Comparing a motorized adjustment system (∼1 mm precision, n = 17 lesions) to the motorized system with an added micromanipulator (∼0.1 mm precision, n = 14 lesions), we saw an increase in the accuracy of targeting the fornix by 133%. CONCLUSIONS: The described work allows for repeatable and accurate targeting of small and deep structures in the rodent brain, such as the fornix, enabling the investigation of neurological disorders in chronic disease models.

Anterior callosal section is useful for the removal of large tumors invading the dorsal part of the anterior third ventricle: operative technique and results.

Large tumors invading the dorsal part of the anterior third ventricle are difficult to manage. The anterior transcallosal approach is usually used to manage these tumors. In our clinic, anterior callosal section was combined with the anterior interhemispheric (AIH) translamina terminalis approach for these tumors with excellent results. The AIH approach is useful for removing tumors in and around the anterior part of the third ventricle. However, AIH alone is insufficient for large tumors invading the dorsal part of the anterior third ventricle. In such situations, simple anterior callosal section enables the neurosurgeon to extirpate the caudal part of the tumors deeply hidden from operative field, sparing the foramen of Monro, fornix, etc. We treated four large tumors (malignant teratoma, recurrent chordoid glioma, recurrent papillary tumor of pineal region occupying the third ventricle, and paraventricular meningioma) without major complications. The malignant teratoma case exhibited no recurrence with >10 years follow-up. The chordoid glioma and papillary tumor of pineal region were totally removed. The meningioma was subtotally removed except only a small tumor around the bilateral anterior cerebral artery. This simple technique is a new way to manage difficult large lesions in and around the third ventricle.

Activity-dependent localization in spines of the F-actin capping protein CapZ screened in a rat model of dementia.

Actin reorganization in dendritic spines is hypothesized to underlie neuronal plasticity. Actin-related proteins, therefore, might serve as useful markers of plastic changes in dendritic spines. Here, we utilized memory deficits induced by fimbria-fornix transection (FFT) in rats as a dementia model to screen candidate memory-associated molecules by using a two-dimensional gel method. Comparison of protein profiles between the transected and control sides of hippocampi after unilateral FFT revealed a reduction in the F-actin capping protein (CapZ) signal on the FFT side. Subsequent immunostaining of brain sections and cultured hippocampal neurons revealed that CapZ localized in dendritic spines and the signal intensity in each spine varied widely. The CapZ content decreased after suppression of neuronal firing by tetrodotoxin treatment in cultured neurons, indicating rapid and activity-dependent regulation of CapZ accumulation in spines. To test input specificity of CapZ accumulation in vivo, we delivered high-frequency stimuli to the medial perforant path unilaterally in awake rats. This path selectively inputs to the middle molecular layer of the dentate gyrus, where CapZ immunoreactivity increased. We conclude that activity-dependent, synapse-specific regulation of CapZ redistribution might be important in both maintenance and remodeling of synaptic connections in neurons receiving specific spatial and temporal patterns of inputs.

Severe scene learning impairment, but intact recognition memory, after cholinergic depletion of inferotemporal cortex followed by fornix transection.

To examine the generality of cholinergic involvement in visual memory in primates, we trained macaque monkeys either on an object-in-place scene learning task or in delayed nonmatching-to-sample (DNMS). Each monkey received either selective cholinergic depletion of inferotemporal cortex (including the entorhinal cortex and perirhinal cortex) with injections of the immunotoxin ME20.4-saporin or saline injections as a control and was postoperatively retested. Cholinergic depletion of inferotemporal cortex was without effect on either task. Each monkey then received fornix transection because previous studies have shown that multiple disconnections of temporal cortex can produce synergistic impairments in memory. Fornix transection mildly impaired scene learning in monkeys that had received saline injections but severely impaired scene learning in monkeys that had received cholinergic lesions of inferotemporal cortex. This synergistic effect was not seen in monkeys performing DNMS. These findings confirm a synergistic interaction in a macaque monkey model of episodic memory between connections carried by the fornix and cholinergic input to the inferotemporal cortex. They support the notion that the mnemonic functions tapped by scene learning and DNMS have dissociable neural substrates. Finally, cholinergic depletion of inferotemporal cortex, in this study, appears insufficient to impair memory functions dependent on an intact inferotemporal cortex.

Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas--possible role of Cannabis inhalation.

INTRODUCTION: Spontaneous regression of pilocytic astrocytoma after incomplete resection is well recognized, especially for cerebellar and optic pathway tumors, and tumors associated with Neurofibromatosis type-1 (NF1). The purpose of this report is to document spontaneous regression of pilocytic astrocytomas of the septum pellucidum and to discuss the possible role of cannabis in promoting regression. CASE REPORT: We report two children with septum pellucidum/forniceal pilocytic astrocytoma (PA) tumors in the absence of NF-1, who underwent craniotomy and subtotal excision, leaving behind a small residual in each case. During Magnetic Resonance Imaging (MRI) surveillance in the first three years, one case was dormant and the other showed slight increase in size, followed by clear regression of both residual tumors over the following 3-year period. Neither patient received any conventional adjuvant treatment. The tumors regressed over the same period of time that cannabis was consumed via inhalation, raising the possibility that the cannabis played a role in the tumor regression. CONCLUSION: We advise caution against instituting adjuvant therapy or further aggressive surgery for small residual PAs, especially in eloquent locations, even if there appears to be slight progression, since regression may occur later. Further research may be appropriate to elucidate the increasingly recognized effect of cannabis/cannabinoids on gliomas.

Perspectives on Endoscopic Transseptal Interforniceal Approach for Retroforaminal Colloid Cysts.

BACKGROUND: Although the interforniceal approach with the preservation of the fornix is useful during the endoscopic approach for retroforaminal colloid cysts, it carries a significant risk of memory and cognitive difficulties. Because most reports have reported the endoscopic approach to colloid cysts through the foramen with little emphasis on retroforaminal cysts, the aim of this study was to investigate colloid cysts as a special entity with regard to their different characteristics and surgical approaches and outcomes. METHODS: In this retrospective study, 12 patients with third ventricular colloid cysts with retroforaminal extensions were included. All patients underwent endoscopic transseptal interforniceal approach with tumor resection. The surgical technique was briefly described, and preoperative and postoperative data were evaluated. RESULTS: Among the 12 patients included in this study, most of our patients were males. Average diameter of the colloid cyst was relatively large (average 22 mm). Gross total resection was achieved in 10 cases (83.3%). The stable images showed no local recurrence in the long-term follow-up period except in 1 case at the 28-month follow-up period. CONCLUSIONS: Retroforaminal colloid cyst represents a unique entity that requires special attention to its mode of growth. The endoscopic approach for retroforaminal colloid cysts is nearly the same as that for foraminal cysts. It has a lower incidence rate of postoperative memory changes, lower chances of total resection, and lower incidence rate of hard contents. Moreover, sufficient knowledge on morbid anatomy is important to avoid fornix injury.

Long-term visuospatial retention unaffected by fornix transection.

As part of an earlier experiment (Kwok and Buckley, 2009), six macaque monkeys (three with fornix transection and three unoperated controls) were trained postoperatively to discriminate a total of 104 new concurrent visuospatial conditional problems to criterion. Our experiment measured and compared long-term retention of these problems with two separate one-trial postoperative retention tests administered 3 and 15 months, respectively, after acquisition. All animals showed some degree of forgetting of these problems but all remembered above chance levels, even after 15 months. The amount forgotten by each group did not differ significantly at either time point. These results show that long-term retention of visuospatial information is independent of the fornix. Similarities in resistance to forgetting are drawn between fornix-transected macaques and patients with amnesia and the implications for clinical rehabilitation are discussed.

Fornix transection selectively impairs fast learning of conditional visuospatial discriminations.

As the fornix has previously been implicated in the rapid learning of associations, we hypothesized that fornix transection in macaques would selectively impair the acquisition of rapidly learned conditional visuospatial discrimination problems. Macaque monkeys learned, postoperatively, three sets of concurrent problems of increasing sizes containing 8, 32, and 64 problems, respectively. Each problem consisted of four identical visual stimuli and animals had to learn which stimulus position was rewarded. The lesioned animals made significantly more errors-to-criterion on the smallest set of problems, consistent with the idea that the most rapidly acquired sets would be more vulnerable to fornical damage. Moreover, during the early stages of acquisition across all three sets, fornix transection selectively impeded monkeys' abilities to eliminate nonperseverative errors in correction trials, consistent with an inability to monitor or correct erroneous spatial responses made further back in time than the last trial. Both one-trial learning and an errorless learning (facilitation of performance) were observed in control and fornix lesioned animals but neither were fornix-dependent and overcoming the deleterious effect upon subsequent learning of having made prior errors was also unaffected by fornix transection. The data indicate that the fornix is not important for all forms of new learning; rather it is selectively concerned with the relatively rapid acquisition of spatial and temporal relationships between stimuli and responses.

Fornicotomy for the Treatment of Epilepsy: An Examination of Historical Literature in the Setting of Modern Operative Techniques.

Fornicotomy has been used to treat intractable temporal lobe epilepsy with mixed success historically; however, modern advances in stereotactic, neurosurgical, and imaging techniques offer new opportunities to target the fornix with greater precision and safety. In this review, we discuss the historical uses and quantify the outcomes of fornicotomy for the treatment of temporal lobe epilepsy, highlight the potential mechanisms of benefit, and address what is known about the side effects of the procedure. We find that fornicotomy, with or without anterior commissurotomy, resulted in 61% (83/136) of patients having some seizure control benefit. We discuss the potential operative approaches for targeting the fornix, including laser ablation and the use of focused ultrasound ablation. More work is needed to address the true efficacy of fornicotomy in the modern surgical setting. This review is intended to serve as a framework for developing this approach.

Brn-4 is upregulated in the deafferented hippocampus and promotes neuronal differentiation of neural progenitors in vitro.

Fimbria-fornix (FF), the septo-hippocampal pathway, was transected to model Alzheimer's disease (AD), which is characterized by loss of cholinergic afferent fibers in hippocampus. Various alternations may happen in the deafferented hippocampus. In this study, we determined the expression of Brn-4 in hippocampus after FF lesion. RT-PCR and Western blot showed that mRNA transcription and protein of Brn-4 increased significantly and reached to the peak at day 14 after FF lesion. Hybridization and immunohistochemistry indicated that Brn-4 signals in hippocampus and dentate gyrus (DG) of the deafferented side were significantly stronger than the normal side. More Brn-4 positive cells were identified in the DG of deafferented hippocampus. In the pyramidal and granular cells, Brn-4 positive cells were all NeuN positive neurons, whereas in the neurogenic area, subgranular zone (SGZ), only a part of Brn-4 positive cells were NeuN positive, and these Brn-4/NeuN double positive neurons in SGZ and hilus of DG increased significantly after the trauma induced by FF lesion. In vitro Brn-4 antibody attenuated the role of extract from deafferented hippocampus in promoting differentiation of hippocampal progenitors into MAP-2 positive neurons. This study demonstrated that after FF lesion, Brn-4 in the deafferented hippocampus was upregulated and might play an important role in inducing local progenitors to differentiate into neurons, which may compensate for the loss of cholinergic afferent fibers or other dysfunctions.

Interhemispheric transcallosal subchoroidal fornix-sparing craniotomy for total resection of colloid cysts of the third ventricle.

OBJECT: Endoscopic surgery has been reported to be more cost-effective and safer than open craniotomy for resection of colloid cysts, despite a 5-10% conversion rate to craniotomy, a 5% recurrence rate, a 5-10% ventricular shunting rate, a 5-10% epilepsy rate, and a 3-4 day hospital stay. In 1985, the authors developed a interhemispheric, transcallosal, subchoroidal, fornix-sparing approach that allowed safe total resection of the colloid cyst and that appeared to be superior to the endoscopic approach. The long-term results are analyzed and compared with findings in the literature. METHODS: Fifty-seven consecutive colloid cysts were totally removed via a 3 x3-in paramedian craniotomy flap and a microscopic interhemispheric, transcallosal, subchoroidal approach sparing the ipsilateral fornix. The length of the callosotomy was 1.5-2 cm in all patients. The mean follow-up duration was 12 years (range 2-22 years). A retrospective analysis comparing the authors' results with those reported in the endoscopic literature was performed. RESULTS: All patients had 1-year postoperative imaging studies (CT or MR imaging) documenting gross-total resection with no deaths, infection, hemiparesis, seizures, or disconnection syndrome. One surgery was complicated by bilateral subdural hematomas, which were successfully treated. There has been a zero recurrence rate. Three patients required a permanent ventriculoperitoneal shunt (including 2 who required emergency ventriculostomy before surgery). The mean hospital stay was 4.8 days (range 2-24 days). There was 1 patient with permanent short-term memory loss who presented with a herniation syndrome requiring emergency ventriculostomy. CONCLUSIONS: The interhemispheric, transcallosal, subchoroidal, fornix-sparing approach to gross-total resection of colloid cysts is safe and led to a zero recurrence rate with no permanent neurological sequelae including epilepsy, and these results are superior to any reported results with endoscopy.

The rs-fMRI study of effects of fornix and hippocampus-related brain function after the transcallosal interforniceal approach.

BACKGROUND: The tumors in third ventricle are common intracranial tumors in children, characterized by various pathological types and difficult to be removed. The transcallosal interforniceal approach is often used for these tumors. The separation of bilateral fornix causes multiple surgical complications. In the past, complications could only be assessed by clinical feature and traditional imaging, lack of quantitative data to support. Resting-state functional magnetic resonance imaging (rs-fMRI) can assess brain functional connectivity between local regions and different regions in quiet state. The changes of ReHo, ALFF, fALFF and brain function connections (DMN and Hippocampus as ROI) can be used to evaluate the effects caused by operation. OBJECTIVE: To evaluate the effects of brain function caused by operation. METHODS: 9 children patients with tumors in third ventricle were randomly selected in Yuquan hospital, and scanned by rs-fMRI before and after operation. ReHo, ALFF, fALFF and function connections (DMN and Hippocampus as ROI) were chosen to analyze rs-fMRI data. RESULTS: The results of ReHo, ALFF, fALFF and brain function connections (DMN and Hippocampus as ROI) showed that: (1) Compared with preoperative state, ReHo decreased in left superior frontal gyrus in 1 month after operation, while increased in right middle occipital gyrus, right middle temporal gyrus, and left posterior central gyrus. In 2 months after operation, ReHo decreased in left superior temporal gyrus and right precentral gyrus compared with that in 1 month after operation. (2) Compared with preoperative state, ALFF decreased in left middle frontal gyrus and increased in left superior temporal gyrus in 1 month after operation; ALFF decreased in right fusiform gyrus and right supramarginal gyrus, while increased in left parahippocampal gyrus and left caudate nucleus in 2 months after operation. When compared with these in 1 month after operation, ALFF decreased in right fusiform gyrus and left precentral gyrus in 2 months after operation. (3) Compared with preoperative state, fALFF decreased in left superior frontal gyrus in 1 month after operation, and decreased in left middle frontal gyrus in 2 months after surgery. (4) The connections of DMN showed that enhanced connections of bilateral middle frontal gyrus and other regions in 1 month after operation, which restored to preoperative state in 3 months after operation. (5) There were changes of connections between bilateral hippocampus and related brain regions without any interruption occurred. The effects of approach can disappear in 3 months after operation. CONCLUSIONS: The short-term effects of ReHo, ALFF and fALFF in brain regions of children patients can recover to preoperative state with time. The operation did not interrupt the connections between DMN and hippocampus related brain areas. The effects of surgery can restore to the preoperative state in 3 months after operation.

Therapeutic effects of a restraint procedure on posttraumatic place learning in fimbria-fornix transected rats.

Restraint procedures have been shown to influence the neural processes in the brain (dendritic changes or changes in the expression of neurotrophines, etc.) as well as to alter the behavioural performance. While many report deleterious effects of this procedure in normal animals, there are also indications of positive effects in the context of brain injury. In order to address the issue from the perspective of functional posttraumatic recovery, we studied 6 experimental groups of rats--3 groups undergoing a fimbria-fornix transection, and 3 groups remaining neurally intact. Within the lesioned and intact groups, respectively, one group of animals was subjected to an 8-day long restraint procedure (2 h daily) that ended immediately prior to the infliction of trauma; another group was subjected to the same procedure starting immediately after the infliction of trauma; and one group was not subjected to the restraint procedure at all. After a brief period of postoperative pause, the animals were tested on their acquisition of an 8-arm radial maze based place learning task and the effects of the restraint procedure on the task acquisition were evaluated. The results show that within the neurally intact groups, the administration of this procedure had no effect at all. However, the lesioned groups that were subjected to the restraint procedure showed significantly improved acquisition of the studied task compared to the lesioned animals that did not undergo the restraint procedure. The improved task performance suggests a therapeutic effect of this manipulation on the functional recovery after a mechanical trauma.

Memory loss resulting from fornix and septal damage: impaired supra-span recall but preserved recognition over a 24-hour delay.

Despite increasing evidence that the fornix is important for memory, uncertainty remains about the exact nature of subsequent impairments arising from damage to this tract. This uncertainty is often created by pathology in additional brain structures. The present study involved a young man, DN, who had almost complete bilateral loss of the rostral columns of the fornix and much of the surrounding septum in the left hemisphere following the surgical removal of a cavernous angioma. Quantitative MRI analyses of structure size, normalized to intracranial volume, showed no difference in any of the additional brain regions measured, apart from those areas removed to expose the tumor. DN showed a marked, stable anterograde memory impairment that was still present 4 years postsurgery. In contrast, DN performed within normal levels on most tests of recognition memory. This sparing was most striking when given a 24-hr delay between study and test of the Warrington Recognition Memory Test. This recall/recognition dissociation provides further evidence for neuroanatomical divisions within recognition memory processes.