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.

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.

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.

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.

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.

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.

Anatomy of the Limbic White Matter Tracts as Revealed by Fiber Dissection and Tractography.

BACKGROUND: The limbic tracts are involved in crucial cerebral functions such as memory, emotion, and behavior. The complex architecture of the limbic circuit makes it harder to approach compared with other white matter networks. Our study aims to describe the 3-dimensional anatomy of the limbic white matter by the use of 2 complementary study methods, namely ex vivo fiber dissection and in vivo magnetic resonance imaging-based tractography. METHODS: Three fiber dissection protocols were performed using blunt wooden instruments and a surgical microscope on formalin-fixed brains prepared according to the Klingler method. Diffusion tensor imaging acquisitions were done with a 3-Tesla magnetic resonance scanner on patients with head and neck pathology that did not involve the brain. Fiber tracking was performed with manually selected regions of interest. RESULTS: Cingulum, fornix, the anterior thalamic peduncle, the accumbofrontal bundle, medial forebrain bundle, the uncinate fasciculus, the mammillothalamic tract, ansa peduncularis, and stria terminalis were dissected and fiber tracked. For each tract, location, configuration, segmentation, dimensions, dissection and tractography particularities, anatomical relations, and terminations are described. The limbic white matter tracts were systematized as 2 concentric rings around the thalamus. The inner ring is formed by fornix, mammillothalamic tract, ansa peduncularis, stria terminalis, accumbofrontal fasciculus, and medial forebrain bundle and anterior thalamic peduncle, and the outer ring is formed by the cingulum and uncinate fasciculus. CONCLUSIONS: This paper proposes a fiber-tracking protocol for the limbic tracts inspired and validated by fiber dissection findings that can be used routinely in the clinical practice.

The Surgical White Matter Chassis: A Practical 3-Dimensional Atlas for Planning Subcortical Surgical Trajectories.

BACKGROUND: The imperative role of white matter preservation in improving surgical functional outcomes is now recognized. Understanding the fundamental white matter framework is essential for translating the anatomic and functional literature into practical strategies for surgical planning and neuronavigation. OBJECTIVE: To present a 3-dimensional (3-D) atlas of the structural and functional scaffolding of human white matter-ie, a "Surgical White Matter Chassis (SWMC)"-that can be used as an organizational tool in designing precise and individualized trajectory-based neurosurgical corridors. METHODS: Preoperative diffusion tensor imaging magnetic resonance images were obtained prior to each of our last 100 awake subcortical resections, using a clinically available 3.0 Tesla system. Tractography was generated using a semiautomated deterministic global seeding algorithm. Tract data were conceptualized as a 3-D modular chassis based on the 3 major fiber types, organized along median and paramedian planes, with special attention to limbic and neocortical association tracts and their interconnections. RESULTS: We discuss practical implementation of the SWMC concept, and highlight its use in planning select illustrative cases. Emphasis has been given to developing practical understanding of the arcuate fasciculus, uncinate fasciculus, and vertical rami of the superior longitudinal fasciculus, which are often-neglected fibers in surgical planning. CONCLUSION: A working knowledge of white matter anatomy, as embodied in the SWMC, is of paramount importance to the planning of parafascicular surgical trajectories, and can serve as a basis for developing reliable safe corridors, or modules, toward the goal of "zero-footprint" transsulcal access to the subcortical space.

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.

Implementation of a Functional Observation Battery for the Assessment of Postoperative Well-being in Rats Subjected to Fimbria-Fornix Transection.

The postoperative well-being of Wistar rats subjected to fimbria-fornix transections was assessed using a functional observational battery (FOB), including observations of relative body weight change, general condition, fur quality, body posture and movement, appetite, and pica behavior. Fimbria-fornix transected animals (FF), sham-operated animals (Sham), and two non-operated control groups with and without administration of buprenorphine (+BUP and -BUP, respectively) were observed twice daily for seven days after surgery. Buprenorphine (0.4 mg/kg) mixed in a nut paste for voluntary ingestion was supplied twice daily for 84 h to all groups except the -BUP control group starting on the day of surgery. Body weight was slightly decreased postoperatively in both surgical groups (FF and Sham) compared to control groups. The +BUP control group lost weight starting at day four after discontinuation of buprenorphine. Furthermore, the FF group exhibited significantly reduced general condition one day after surgery, with significantly affected body posture and movement for two days after surgery. In addition, mild pica behavior was observed in the FF group during the first postsurgical day. In conclusion, the FOB implemented in the present study appears to be a sensitive and accurate protocol for assessing animal well-being in the experimental setup applied. It is apparent that the FF transection is an invasive procedure that causes mildly adverse postoperative effects on the rats' well-being. We therefore recommend that this FOB is applied as a routine welfare monitoring protocol in experiments using mechanical central nervous system injury models, such as FF transection.

Delayed restraint procedure enhances cognitive recovery of spatial function after fimbria-fornix transection.

PURPOSE: To i) evaluate the effect of a restraint procedure (7 days, 2 h/day) on place learning after fimbria-fornix transection (FF), ii) investigate effects of early vs. late administration of restraint, and iii) establish effects of the restraint procedure on expression of brain derived neurotrophic factor (BDNF) in prefrontal cortex and hippocampus. METHODS: Fifty rats subjected to FF or sham surgery and divided into groups exposed to restraint immediately (early restraint) or 21 days (late restraint) after surgery were trained to acquire an allocentric place learning task. In parallel, 29 animals were subjected to FF or sham surgery and an identical restraint procedure in order to measure concentrations of BDNF and corticosterone. RESULTS: The performance of the sham operated rats was positively affected by the late restraint. In FF-lesioned animals, the late restraint significantly improved task performance compared to the lesioned group with no restraint, while the early restraint was associated with a negative impact on task acquisition. Biochemical analysis after restraint procedure revealed a lesion-induced upregulation of BDNF in FF animals. CONCLUSIONS: The improved task performance of lesioned animals suggests a therapeutic effect of this manipulation, independent of BDNF. This effect is sensitive to the temporal administration of treatment.

A 3D endoscopic transtubular transcallosal approach to the third ventricle.

OBJECT: Surgical approaches to deep-seated brain pathologies, specifically lesions of the third ventricle, have always been a challenge for neurosurgeons. In certain cases, the transcallosal approach remains the most suitable option for targeting lesions of the third ventricle, although retraction of the fornices and wall of the third ventricle have been associated with neuropsychological and hypothalamic deficits. The authors investigated the feasibility of an interhemispheric 3D endoscopic transcallosal approach through a minimally invasive tubular retractor system for the management of third ventricular lesions. METHODS: Three-dimensional endoscopic transtubular transcallosal approaches were performed on 5 preserved cadaveric heads (10 sides). A parasagittal bur hole was placed using neuronavigation, and a tubular retractor was inserted under direct endoscopic visualization. Following observation of the vascular structures, fenestration of the corpus callosum was performed and the retractor was advanced through the opening. Transforaminal, interforniceal, and transchoroidal modifications were all performed and evaluated by 3 surgeons. RESULTS: This approach provided enhanced visualization of the third ventricle and more stable retraction of corpus callosum and fornices. Bayonetted instruments were used through the retractor without difficulty, and the retractor applied rigid, constant, and equally distributed pressure on the corpus callosum. CONCLUSIONS: A transtubular approach to the third ventricle is feasible and facilitates blunt dissection of the corpus callosum that may minimize retraction injury. This technique also provides an added degree of safety by limiting the free range of instrumental movement. The combination of 3D endoscopic visualization with a clear plastic retractor facilitates safe and direct monitoring of the surgical corridor.

Only repeated administration of the serotonergic agonist 8-OH-DPAT improves place learning of rats subjected to fimbria-fornix transection.

Serotonergic agonists may act neuroprotectively against brain injury. This study addressed the therapeutic potential of 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT), a selective 5-HT1A/7 receptor agonist, after mechanical brain injury, and evaluated its effects in terms of acquisition of an allocentric place learning task in a water maze. Rats were divided into 6 experimental groups, three of which were subjected to bilateral transection of fimbria-fornix (FF), while three groups were given control surgery (Sham). After surgery, within both the lesioned, and sham-operated animals, respectively, one group was administered a single dose of saline, one group was given a single dose (0.5 mg/kg/b.w.) of 8-OH-DPAT, and one group was treated with daily administration of 8-OH-DPAT (0.5 mg/kg/b.w.) for eight days. The acquisition of the water maze based place learning task started on the 8th day post-surgery and continued for 20 days. The results show that the lesioned group subjected to repeated administration of 8-OH-DPAT demonstrated a significantly improved acquisition of the place learning task compared to the vehicle injected lesion group. In contrast, the lesioned group treated with a single administration displayed impaired performance compared to the baseline lesion group. There were no significant effects of the 8-OH-DPAT administration in the sham control groups. We conclude that only the repeated stimulation of the 5-HT1A/7 system was associated with beneficial, recovery enhancing effects.

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.

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.

Deep brain stimulation for the treatment of Alzheimer disease and dementias.

OBJECTIVE: To review the use of deep brain stimulation (DBS) for treatment of dementia. METHODS: A PubMed literature search was conducted to identify all studies that have investigated the use of DBS for treatment of dementia. RESULTS: Three studies examined the use of DBS for dementia. One study involved fornix DBS for Alzheimer disease (AD), and two studies involved DBS of the nucleus basalis of Meynert, one to treat AD and one to treat Parkinson disease dementia. CONCLUSIONS: Evidence for the use of DBS to treat dementia is preliminary and limited. Fornix and nucleus basalis of Meynert DBS can influence activity in the pathologic neural circuits that underlie AD and Parkinson disease dementia. Further investigation into the potential clinical effects of DBS for dementia is warranted.