Ventral Brainstem Research Articles

Characterization of a novel transgenic rat model for imaging brain vascular dynamics in vivo using confocal endomicroscopy (686.27)

We evaluated the feasibility of imaging brain vasculature in a transgenic rat model (L7543) which expressed a construct carrying the eGFP under the control of CAG promoter (Popova et al., Transgen. Res. 2008) using fiber endomicroscopy (CellVizio, Mauna Kea Technologies). eGFP expression were first evaluated in cortical and brainstem slices from L7543 rat using confocal microscopy (Leica SP5). Expression of eGFP in the cortex and brainstem was largely restricted to endothelial cells, although astrocytes in younger rats (up to P35) were also fluorescent. Next, the brainstem and cortex were imaged, without a contrasting agent, in anaesthetized P21‐P40 rats using a fiber probe‐based confocal laser endomicroscopy. Pial microvessels of the ventral or dorsal brainstem, or cortex were imaged using S‐1500 and Mini‐Z probes (1.5 and 0.94 mm tip diameter, respectively). The vascular contractility was visualized after application of a thromboxane agonist U46619 and sodium nitroprusside. Arterioles and veins were identified based on the eGFP expression profile. In addition, beveled probes S‐300/B and S‐650/B (0.3 and 0.65 mm tip diameter, respectively) were used to visualize vascular tree in Z‐dimension. Currently we are working to adapt this method for imaging in unanaesthetized rats. This approach should be useful to investigate changes in cerebral microcirculation in hypertension and other vascular pathologies.Grant Funding Source: Supported by British Heart Foundation

Full endoscopic endonasal transclival approach: Meningioma attached to the ventral surface of the brainstem

Intracranial meningiomas without dural attachment (MWODA) are rare entities. We present the first case published, to the best of our knowledge, regarding a MWODA attached to the ventral surface of the brainstem. This location makes the patient subsidiary to treatment through an expanded endonasal transclival approach. A 16-year-old female with suspected diagnosis of recurrence of a clear cell meningioma (CCM) at a distance from the initial lesion, located on the premedullary cistern. The patient underwent a pure endoscopic low transclival approach. The attachment to the ventral surface of the brainstem was confirmed intraoperatively. Postoperative MRI confirmed gross total resection and treatment was complemented with adjuvant fractionated stereotactic radiotherapy. No complications related to the procedure were observed. MWODA may appear attached to the ventral brainstem. The expanded endonasal approach to the clivus provides a critical anatomical advantage in the treatment of medial lesions, even ventral meningiomas, to the lower cranial nerves. Reconstruction principles must be strictly respected to reduce complications.

A Comparison between the Kawase and Extended Retrosigmoid Approaches (Retrosigmoid Transtentorial and Retrosigmoid Intradural Suprameatal Approaches) for Accessing the Petroclival Tumors. A Cadaveric Study.

Background The aim of our study was to compare the area of exposure at the ventral brainstem and petroclival region offered by the Kawase, retrosigmoid transtentorial (RTT), and the retrosigmoid intradural suprameatal (RISA) approaches in cadaveric models. Methods We performed 15 approaches (five each of the Kawase, RISA, and RTT approaches) on silicone-injected adult cadaver heads. Ventral brainstem and petroclival areas of exposure were measured and compared. Results The mean ventral brainstem area exposed by the Kawase approach was 55.00 ± 24.1 mm(2), significantly less than that exposed by RTT (441 ± 63.3 mm(2)) and RISA (311 ± 61 mm(2)) (p < 0.05). The area of ventral brainstem exposure was significantly more via RTT than through RISA (p = 0.01). The mean petroclival area of exposure through the Kawase approach was significantly smaller than that obtained through the RTT and RISA approaches (101.7 ± 545.01 mm(2), 696 ± 57.7 mm(2), and 716.7 ± 51.4 mm(2), respectively). Conclusion Retrosigmoid approaches provide a greater exposure of the brainstem and petroclival areas. The Kawase approach is ideally suited for lesions around the Meckel cave with an extension into the middle fossa. These approaches can be used in conjunction with one another to access petroclival tumors.

Surgical Exposure Gained in an Extended Retrosigmoid Approach to the Cerebellopontine Angle Compared to the Traditional Retrosigmoid Approach.

Retrosigmoid approach to the posterior fossa has been a popular and dependable approach for accessing the cerebellopontine angle (CPA) and petroclival region. Although this approach is commonly used, it requires cerebellar retraction and has limitations when the lesion is located ventral to the brainstem. The aim was to quantify the angle of view provided by extended retrosigmoid approach in comparison to the traditional approach. A secondary objective was to identify a strategic initial burr hole site for craniotomy. Ten adult human cadaver heads (20 sides) were used. First, traditional retrosigmoid approach was performed and the angle of exposure was measured on cranial computerized tomography (CT). Following, extended retrosigmoid approach was performed with mastoid bone drilling and reflection of venous sinuses. Angle of exposure was measured on CT. Two measurements of both approaches were compared. Mean angle of view for the traditional retrosigmoid approach (31.4° ± 4.1°) was significantly smaller than that of the extended approach (46.0° ± 4.7°) (p < 0.001). Site of strategic burr hole was 5 mm below and 15 mm lateral to the asterion was defined. Extended retrosigmoid approach offers neurosurgeons approximately 50% larger angle of view and shorter working distance than the traditional approach provides. This modification permits better access to the CPA and ventral brain stem without cerebellar retraction.

Resection of large epidermoid tumors ventral to the brainstem: techniques to expand the operative corridor across the basilar artery

Epidermoid tumors comprise about 1% of all intracranial tumors. They are congenital lesions that arise from paramedian cisterns within the posterior fossa. These tumors present as heterogeneous hyperintense lesions on FLAIR and homogenous hyperintense lesions on DWI. Surgical resection remains the most accepted form of therapy, but epidermoid tumors may recur. These tumors are well exposed through a traditional retrosigmoid approach. The tumor can be removed relatively easily as it is avascular. However, the propensity of this tumor type to fill the small spaces within basal cisterns and attach to cranial nerves may make its complete resection challenging. Tumors resection has to preserve the surrounding arachnoid membranes encasing the cranial nerves. The author presents the case of a 42-year-old woman with a 1-year history of imbalance and nystagmus. An MRI revealed a large right-sided CP angle epidermoid tumor filling the ventral brainstem cistern and extending to the contralateral side, compressing the brainstem. The accompanying video illustrates resection of this mass through an extended (exposing the sigmoid sinus) retrosigmoid approach. The author removed the tumor piecemeal while protecting the cranial nerves. Small pieces of affected arachnoid covering the cranial nerves were not significantly manipulated. To excise the tumor along the contralateral paramedian cistern, the author used the space between the V and VII/VII cranial nerves to expose the space contralateral to the basilar artery and remove additional tumor. This maneuver allowed gross total resection of the tumor without a need to employ a more elaborate skull base approach such as petrosectomy. At 3-month follow-up visit after surgery, the patient's neurological exam returned to normal. The video can be found here: http://youtu.be/CzRb-GUvhog .

Skull Base Approaches to the Ventral and Lateral Brainstem

Skull Base Approaches to the Ventral and Lateral Brainstem

Skull Base Approaches to the Ventral and Lateral Brainstem

Skull Base Approaches to the Ventral and Lateral Brainstem

Ischemic stroke subtype and clinical characteristics of patients with locked-in syndrome

Background: Locked-in syndrome (LIS) is a state characterized by paralysis of all extremities and the facial musculature, but preserved consciousness and cognition. The most frequent cause is a bilateral ischemic lesion of ventral brainstem.

No Significant Displacement of Basal Brain Structures upon Head Movement: Kinematic MRI Morphometry Relevant to Neuroendoscopy

An appreciation of normal intracranial anatomy allows optimal planning of trajectories necessary for safe and effective neuroendoscopy. Little information exists on displacement of the caudal brain relative to the skull upon head movement; this could have important implications for planning and performance of neuroendoscopic procedures. We used kinematic magnetic resonance imaging (MRI) studies to examine the morphometric displacement and changing anatomical relationships between the clivus and basal brain structures, intracranial vessels, and subarachnoid spaces. We retrospectively analyzed 15 patients undergoing sagittal T2 kinematic MRI of the head and neck in modest flexion and extension. The angle between a horizontal axial reference plane and a line between the opisthion and the hard palate defined the degree of flexion and extension. We then measured in flexion and extension (1) the cervicomedullary angle (CMA), (2) displacement of the ventral surface of the brainstem (i.e., depth of the prepontine and premedullary cisterns), (3) total sagittal area of the combined suprasellar and ventral brainstem cisterns, and (4) the basilar tip to tuber cinereum distance. Relative to neutral head position, a mean extension angle of -15.8 degrees was achieved in all 15 patients, and a mean flexion angle of +9.9 degrees was achieved in 6 patients. The mean CMA was 146 degrees in flexion and 158 degrees in extension. The mean reduction in prepontine and premedullary cistern depth was 0.7 mm and 0.5 mm, respectively, upon flexion from extension. The combined area of suprasellar and ventral brainstem cisterns was minimally reduced from 402 mm2 in flexion to 399 mm(2) in extension. The basilar tip did not move significantly from its position in flexion to extension, 5.3 mm to 5.2 mm respectively from the tuber cinereum. Kinematic MRI shows minimal brainstem-to-clivus displacement even within minor physiological changes in head flexion. Importantly, these movements are small and there is no significant shift in the position of the basilar tip in modest flexion or extension. These results should be useful for presurgical planning of optimal patient positioning during neuroendoscopic procedures such as third ventriculostomy and the expanded endonasal transsphenoidal approach to the retroclival space.

Occipital-C2 Transarticular Fixation for Occipitocervical Instability Associated With Occipitalization of the Atlas in Patients With Klippel-Feil Syndrome, Using Intraoperative 3-Dimensional Navigation System

Retrospective case series. The aim of this study was to describe the clinical outcomes of cervical reduction and occipital-C2 transarticular (OCTA) fixation with an assistance of intraoperative 3-dimensional navigation system (ITNS) during the treatment of reducible occipitocervical instability (OCI) in patients with Klippel-Feil syndrome (KFS) with occipitalization of the atlas and fusion of C2-C3. Patients with KFS have congenital fusions of at least 2 cervical segments and may gradually develop symptoms at the hypermobile articulations adjacent to the cervical synostosis. This is particularly common in patients with KFS with occipitalization of the atlas and C2-C3 fusion. These patients may be at risk for instability and neurological complications of the occipitocervical junction that require occipitocervical reconstruction and fusion. Numerous treatment techniques are available for this pathological condition. However, there has yet to be a study of reducible OCI, showing successful treatment with intraoperative reduction and posterior OCTA fixation using ITNS. From 2006 to 2011, 9 patients with KFS with reducible OCI attributed to occipitalization of the atlas and C2-C3 fusion were surgically treated. After a limited foramen magnum decompression, reduction of the OCI was conducted by intraoperative cervical traction and extension, followed by OCTA fixation using a direct posterior approach and with the assistance of ITNS. The follow-up period ranged from 6 to 60 months (mean, 31 mo). Good decompression and bone fusion were achieved in all the patients. The clinical symptoms had improved for all patients. There were no intraoperative or postoperative complications. In patients with KFS with occipitalization of the atlas and C2-C3 fusion, manual cervical traction in tandem with cervical extension, followed by posterior OCTA fixation and fusion provides a safe, effective treatment of OCI and ventral brainstem impingement. IFTN is a feasible tool for monitoring cervical reduction and OCTA screw insertion in patients with KFS with this pathological condition.

Differential Sensitivity of Brainstem versus Cortical Astrocytes to Changes in pH Reveals Functional Regional Specialization of Astroglia

Astrocytes might function as brain interoceptors capable of detecting different (chemo)sensory modalities and transmitting sensory information to the relevant neural networks controlling vital functions. For example, astrocytes that reside near the ventral surface of the brainstem (central respiratory chemosensitive area) respond to physiological decreases in pH with vigorous elevations in intracellular Ca(2+) and release of ATP. ATP transmits astroglial excitation to the brainstem respiratory network and contributes to adaptive changes in lung ventilation. Here we show that in terms of pH-sensitivity, ventral brainstem astrocytes are clearly distinct from astrocytes residing in the cerebral cortex. We monitored vesicular fusion in cultured rat brainstem astrocytes using total internal reflection fluorescence microscopy and found that ∼35% of them respond to acidification with an increased rate of exocytosis of ATP-containing vesicular compartments. These fusion events require intracellular Ca(2+) signaling and are independent of autocrine ATP actions. In contrast, the rate of vesicular fusion in cultured cortical astrocytes is not affected by changes in pH. Compared to cortical astrocytes, ventral brainstem astrocytes display higher levels of expression of genes encoding proteins associated with ATP vesicular transport and fusion, including vesicle-associated membrane protein-3 and vesicular nucleotide transporter. These results suggest that astrocytes residing in different parts of the rat brain are functionally specialized. In contrast to cortical astrocytes, astrocytes of the brainstem chemosensitive area(s) possess signaling properties that are functionally relevant-they are able to sense changes in pH and respond to acidification with enhanced vesicular release of ATP.

Complex Chiari malformations in children: an analysis of preoperative risk factors for occipitocervical fusion

Chiari malformation Type I (CM-I) is a congenital anomaly often treated by decompressive surgery. Patients who fail to respond to standard surgical management often have complex anomalies of the craniovertebral junction and brainstem compression, requiring reduction and occipitocervical fusion. The authors hypothesized that a subgroup of "complex" patients defined by specific radiographic risk factors may have a higher rate of requiring occipitocervical fusion. A retrospective review was conducted of clinical and radiographic data in pediatric patients undergoing surgery for CM-I between 1995 and 2010. The following radiographic criteria were identified: scoliosis, syringomyelia, CM Type 1.5, medullary kinking, basilar invagination, tonsillar descent, craniocervical angulation (clivoaxial angle [CXA] < 125°), and ventral brainstem compression (pB-C2 ≥ 9 mm). A multivariate Cox regression analysis was used to determine the independent association between occipitocervical fusion and each variable. Of the 206 patients who underwent CM decompression with or without occipitocervical fusion during the study period, 101 had preoperative imaging available for review and formed the study population. Mean age at surgery was 9.1 years, and mean follow-up was 2.3 years. Eighty-two patients underwent suboccipital decompression alone (mean age 8.7 years). Nineteen patients underwent occipitocervical fusion (mean age 11.1 years), either as part of the initial surgical procedure or in a delayed fashion. Factors demonstrating a significantly increased risk of requiring fusion were basilar invagination (HR 9.8, 95% CI 2.2-44.2), CM 1.5 (HR 14.7, 95% CI 1.8-122.5), and CXA < 125° (HR 3.9, 95% CI 1.2-12.6). Patients presenting with basilar invagination, CM 1.5, and CXA < 125° are at increased risk of requiring an occipitocervical fusion procedure either as an adjunct to initial surgical decompression or in a delayed fashion. Patients and their families should be counseled in regard to these findings as part of a preoperative CM evaluation.

Fatal breathing dysfunction in a mouse model of Leigh syndrome

Leigh syndrome (LS) is a subacute necrotizing encephalomyelopathy with gliosis in several brain regions that usually results in infantile death. Loss of murine Ndufs4, which encodes NADH dehydrogenase (ubiquinone) iron-sulfur protein 4, results in compromised activity of mitochondrial complex I as well as progressive neurodegenerative and behavioral changes that resemble LS. Here, we report the development of breathing abnormalities in a murine model of LS. Magnetic resonance imaging revealed hyperintense bilateral lesions in the dorsal brain stem vestibular nucleus (VN) and cerebellum of severely affected mice. The mutant mice manifested a progressive increase in apnea and had aberrant responses to hypoxia. Electrophysiological recordings within the ventral brain stem pre-Bötzinger respiratory complex were also abnormal. Selective inactivation of Ndufs4 in the VN, one of the principle sites of gliosis, also led to breathing abnormalities and premature death. Conversely, Ndufs4 restoration in the VN corrected breathing deficits and prolonged the life span of knockout mice. These data demonstrate that mitochondrial dysfunction within the VN results in aberrant regulation of respiration and contributes to the lethality of Ndufs4-knockout mice.

Critical Appraisal of Extent of Resection of Clival Lesions Using the Expanded Endoscopic Endonasal Approach

Background: The expanded endoscopic endonasal approach has become a well-accepted technique for accessing clival lesions. Cadaveric anatomical studies have demonstrated the unobstructed view of the clivus and ventral brainstem that may be achieved with this approach. Critical neurovascular structures, primarily the paraclival internal carotid artery (ICA) segments, are generally considered to represent the lateral limits of safe exposure. To determine what true anatomic limitations exist using an endoscopic endonasal approach in patients with actual clival lesions, a detailed analysis of the postoperative imaging following resection of these lesions was performed.

Activation of the brainstem precedes and outlasts the K-complex in humans

A K-complex (KC) in the electroencephalographs (EEGs) indicates a moderate depth of slow-wave sleep (SWS) in humans and animals. The cortical activities are upregulated during the periods between the KCs (“up state”), and it is proposed that temporarily stored memories during wakeful periods will be consolidated during these periods. Although the underlying mechanism for KCs is proposed to be in the cortex itself, the involvement of the brainstem has not been explored. Here we investigate the excitability changes of the brainstem preceding, during, and after KCs in humans. We simultaneously recorded brainstem auditory evoked potentials (BAEPs) with EEGs, and sequentially analyzed BAEPs around the KCs. The results showed a transient activation of the ventral brainstem preceding the KC and a sustained activation of the dorsal brainstem outlasting the KC. Thus, it is suggested that KCs are triggered by the activation of the brainstem and that the “up state” is maintained by the sustained activation of the brainstem.

Cavernous Malformations: A Paradigm for Progress

Cavernous Malformations: A Paradigm for Progress

Far lateral -combined presigmoid approach in microsurgical treatment for giant petroclival and ventral brain stem lesions

Objective To study the outcome of the far lateral -combined presigmoid approach in microsurgical treatment for patients with giant petroclival tumors and vertebral - basilar artery aneurysms.Methods The clinical features,imaging data,surgical approach,outcome of operation and postoperative complications of two cases of giant vertebral - basilar artery aneurysms and one giant intra - and extracranial petroelival glomus jugulare tumor resected via the far lateral - combined presigmoid approach were analyzed retrospectively.Results Subtotal resection of the tumor was achieved in one patient.Postoperatively,this patient had drinking irritating,phonal hoarseness and peripheral facial paralysis.The first two complications of this patient were fully recovered 10 days later,and his facial paralysis was transiently getting worse,and recovered to basic level three months after surgery.Drinking irritating of two cases of giant vertebral - basilar artery aneurysms was fully recovered without limb paralysis.Conclusions The far lateral - combined presigmoid approach is a safe and effective minimal invasive surgical treatment for patient with giant petroclival tumors and vertebral- basilar artery aneurysms. Key words: Far lateral approach presigmoid approach ; Giant petroclival tumors ; Giant vertebral-basilar artery aneurysms ;

Population calcium imaging of spontaneous respiratory and novel motor activity in the facial nucleus and ventral brainstem in newborn mice

The brainstem contains rhythm and pattern forming circuits, which drive cranial and spinal motor pools to produce respiratory and other motor patterns. Here we used calcium imaging combined with nerve recordings in newborn mice to reveal spontaneous population activity in the ventral brainstem and in the facial nucleus. In Fluo-8AM loaded brainstem-spinal cord preparations, respiratory activity on cervical nerves was synchronized with calcium signals at the ventrolateral brainstem surface. Individual ventrolateral neurons at the level of the parafacial respiratory group showed perfect or partial synchrony with respiratory nerve bursts. In brainstem-spinal cord preparations, cut at the level of the mid-facial nucleus, calcium signals were recorded in the dorsal, lateral and medial facial subnuclei during respiratory activity. Strong activity initiated in the dorsal subnucleus, followed by activity in lateral and medial subnuclei. Whole-cell recordings from facial motoneurons showed weak respiratory drives, and electrical field potential recordings confirmed respiratory drive to particularly the dorsal and lateral subnuclei. Putative facial premotoneurons showed respiratory-related calcium signals, and were predominantly located dorsomedial to the facial nucleus. A novel motor activity on facial, cervical and thoracic nerves was synchronized with calcium signals at the ventromedial brainstem extending from the level of the facial nucleus to the medulla–spinal cord border. Cervical dorsal root stimulation induced similar ventromedial activity. The medial facial subnucleus showed calcium signals synchronized with this novel motor activity on cervical nerves, and cervical dorsal root stimulation induced similar medial facial subnucleus activity. In conclusion, the dorsal and lateral facial subnuclei are strongly respiratory-modulated, and the brainstem contains a novel pattern forming circuit that drives the medial facial subnucleus and cervical motor pools.

Contribution of the mouse calyx of Held synapse to tone adaptation

The calyx of Held synapse is a giant synapse in the medial nucleus of the trapezoid body (MNTB) of the ventral brainstem, which is involved in sound localization. Although it has many release sites, it can show transmission failures and display an increase in synaptic delay during high-frequency signalling. Its apparent lack of reliability and precision raises the question whether this synapse makes a sizeable contribution to tone adaptation, the decline in response to sustained or repetitive auditory stimuli. We observed evidence for the presence of both ipsilateral and contralateral inhibition, but these effects were already present in the inputs to the MNTB, suggesting that synaptic inhibition within the MNTB does not contribute to tone adaptation. During trains of brief tones at variable intervals, there were no clear changes in reliability or precision at tone intervals of 20 ms or longer. A progressive decrease in the number of spikes measured in the MNTB was observed at shorter tone intervals, but this decrease largely originated upstream from the MNTB. In addition, for tones with short intervals, during the train a progressive increase in first-spike latencies was observed, but much smaller changes were observed in the delay between excitatory postsynaptic potentials and postsynaptic action potentials within the MNTB. We conclude that despite the failures and variability in synaptic delay that are present at the calyx of Held synapse, their contribution to tone adaptation is relatively small compared with upstream factors.

Pressor Effect of Apelin-13 in the Rostral Ventrolateral Medulla: Role of NAD(P)H Oxidase-Derived Superoxide

Microinjection of apelin-13 into the rostral ventrolateral medulla (RVLM) in the brainstem increases blood pressure in rats. In the present study, we tested the hypotheses that apelin-13 directly stimulates neuronal activity in neurons cultured from the brainstem and that NAD(P)H oxidase-derived reactive oxygen species are involved in this action of apelin-13. Microinjection of apelin-13 into the RVLM resulted in increases in arterial pressure and in renal sympathetic nerve activity in Sprague-Dawley rats. The pressor effect of apelin-13 was attenuated by the specific NAD(P)H-oxidase inhibitor gp91ds-tat. In neurons cultured from the ventral brainstem, spontaneous action potentials were recorded using current-clamp recording. Superfusion of neurons with apelin-13 (100 nM) increased the neuronal firing rate from 0.79 ± 0.14 to 1.45 ± 0.26 Hz (n = 7, P < 0.01) in angiotensin II receptor-like 1-positive neurons, identified with single-cell reverse transcriptase-polymerase chain reaction. Neither the angiotensin II type 1 receptor antagonist losartan nor the angiotensin II type 2 receptor antagonist 1-[[4-(dimethylamino)-3-methylphenyl[methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate (PD123319) altered the positive chronotropic effect of apelin-13. Pretreatment of cells with either the reactive oxygen species scavenger superoxide dismutase [polyethylene glycol-superoxide dismutase (PEG-SOD), 25 U/ml] or with gp91ds-tat significantly attenuated the chronotropic action of apelin-13. PEG-SOD and gp91ds-tat alone had no effect on basal neuronal firing. In addition, apelin-13 significantly increased NAD(P)H oxidase activity and elevated intracellular superoxide levels in neuronal cultures. The superoxide generator xanthine-xanthine oxidase also increased neuronal activity in neurons, mimicking the neuronal response to apelin-13. These observations provide the first evidence that apelin-13 directly increases neuronal activity via stimulation of NAD(P)H oxidase-derived superoxide, a cellular signaling mechanism that may be involved in the pressor effect of apelin-13 in the RVLM.