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 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.

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.

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.

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.

BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype.

BACKGROUND: Cholinergic projection from the septum to the hippocampus is crucial for normal cognitive function and degeneration of cells and nerve fibers within the septohippocampal pathway contributes to the pathophysiology of Alzheimer's disease. Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether BMP9 could protect the adult cholinergic septohippocampal pathway from axotomy-evoked loss of the cholinergic phenotype, we performed unilateral fimbria-fornix transection in mice and treated them with a continuous intracerebroventricular infusion of BMP9 for six days. The number of choline acetyltransferase (CHAT)-positive cells was reduced by 50% in the medial septal nucleus ipsilateral to the lesion as compared to the intact, contralateral side, and BMP9 infusion prevented this loss in a dose-dependent manner. Moreover, BMP9 prevented most of the decline of hippocampal acetylcholine levels ipsilateral to the lesion, and markedly increased CHAT, choline transporter CHT, NGF receptors p75 (NGFR-p75) and TrkA (NTRK1), and NGF protein content in both the lesioned and unlesioned hippocampi. In addition, BMP9 infusion reduced bilaterally hippocampal levels of basic FGF (FGF2) protein. CONCLUSIONS/SIGNIFICANCE: These data indicate that BMP9 administration can prevent lesion-evoked impairment of the cholinergic septohippocampal neurons in adult mice and, by inducing NGF, establishes a trophic environment for these cells.

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.

Transcallosal interforniceal approach to pineal region tumors in 150 children.

OBJECT: Pediatric pineal region tumors are very difficult to cure surgically. The authors used the transcallosal interforniceal approach in patients with these lesions. METHODS: One hundred fifty children, 98 boys and 52 girls, with pineal region tumors underwent tumor resection via the transcallosal interforniceal approach in the pediatric neurosurgery ward of TianTan Hospital. The patients ranged in age from 1 to 15 years. Fifty-eight patients had mature teratomas; 57, immature teratomas; 14, astrocytomas; 3, glioblastomas; 4, pineoblastomas; 2, pineocytomas; 4, choriocarcinomas; 4, cavernous hemangiomas; 2, germ cell tumors; and 2, epidermoid cysts. RESULTS: One hundred twenty-nine tumors were totally removed, 15 were subtotally removed, and 6 were partly removed. There were no deaths and no subsequent instances of disconnection syndrome. Short-term memory deficits appeared in 94 patients but resolved within 6 months in most; only a few patients retained persistent deficits. There were 2 patients with mutism that resolved within 10 days. Parinaud syndrome was observed in 45 patients after surgery; 21 of these cases had appeared preoperatively. The syndrome resolved within 6 months in 31 patients, while it remained in the other 14. CONCLUSIONS: The transcallosal interforniceal approach appears to be a safe route for pineal region tumors in children, and complete resection can be achieved in the majority of patients.

Cornel iridoid glycoside improves memory ability and promotes neuronal survival in fimbria-fornix transected rats.

Cornel iridoid glycoside (CIG) is a main component extracted from a traditional Chinese herb Cornus officinalis. Our previous study found that CIG improved neurological function in cerebral ischemic rats. The aim of this study was to investigate the therapeutic benefit of CIG in rats with fimbria-fornix transection (FFT) and explore the underlying molecular mechanisms. CIG (20, 60 and 180 mg/kg) or vehicle was intragastrically administered once daily to rats, starting immediately after the surgery and lasting for 4 weeks. Morris water maze and step-through tests showed that the memory deficits seen in FFT rats were significantly improved by CIG treatment. Immunohistochemical analysis showed that CIG treatment attenuated the loss of neurons in hippocampus. To elucidate the memory-improving mechanism of CIG, the neurotrophic factors, synaptic proteins and Bcl-2 family proteins in hippocampus were measured by Western blot analysis. FFT reduced hippocampal protein levels of nerve growth factor (NGF), tyrosine receptor kinase A (Trk A), brain-derived neurotrophic factor (BDNF), synaptophysin (SYP) and B-cell lymphoma-2 (Bcl-2), but not levels of tyrosine receptor kinase B (Trk B) and growth-associated protein 43 (GAP-43). FFT also elevated cytochorome C (Cyt c) and bcl-2-associated X protein (Bax). Administration of CIG to FFT rats significantly elevated the expression of NGF, TrkA, BDNF, SYP, GAP-43 and Bcl-2, and decreased the expression of Cyt c and Bax. These results indicated that CIG effectively counteracted cognitive impairments caused by fimbria-fornix lesions, and the mechanisms might be related to promoting neuronal survival and providing a beneficial environment for brain repair.

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.

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.

The denervated hippocampus provides proper microenvironment for the survival and differentiation of neural progenitors.

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<0.05). We concluded that the deafferented hippocampus provided proper microenvironment for the survival and neuronal differentiation of neural progenitors.

Endoscopic approach to colloid cysts.

OBJECTIVE: The aim of this study is to discuss the variations in the morbid anatomy of colloid cysts with its impact on the choice of endoscopic approach through a standard Kocher's burr hole. METHODS: This study was conducted on 18 patients between 1996 and 2006. All patients were operated through a single burr hole at Kocher's point using a rigid endoscope with a single working channel. The anatomical variations of the cyst and the foramen of Monro dictated the use of the transforaminal approach, the transseptal interforniceal approach or both. RESULTS: There were no mortalities or significant morbidities. The operative time ranged between 90 to 240 minutes (with a mean of 133 minutes). Five patients (27.7%) developed remediable postoperative chemical meningitis successfully controlled with steroids. Postoperative transient memory disturbance was observed in 3 patients (16.7%). One patient had a postoperative CSF leak that stopped spontaneously. Aspiration of the cyst's contents showed variable degrees of resistance to aspiration. The period of follow-up ranged between 5 months to 8 years and 3 months (mean: 4 years and 2 months). None of our patients showed radiological evidence of cyst recurrence during the follow-up period. CONCLUSION: Through a single right pre-coronal burr hole at Kocher's point, several endoscopic manoeuvres can be done. These include aspiration of the contents or its piecemeal removal, combined balloon squeeze and aspiration, foraminoplasty, pellucidotomy, coagulation of cyst capsule and ETV. The choice of the appropriate approach is largely dependent on the location of the cyst and the shape of the foramen of Monro. Coronal MRI may aid in preoperative evaluation of the tucked up retroforaminal growth of the cyst. We had no recurrence in our series with a follow-up reaching more than 8 years. This could be attributed to both the marsupialization and coagulation done for the remaining cyst capsule.