H. Isaac Chen

Neural substrate expansion for the restoration of brain function

Restoring neurological and cognitive function in individuals who have suffered brain damage is one of the principal objectives of modern translational neuroscience. Electrical stimulation approaches, such as deep-brain stimulation, have achieved the most clinical success, but they ultimately may be limited by the computational capacity of the residual cerebral circuitry. An alternative strategy is brain substrate expansion, in which the computational capacity of the brain is augmented through the addition of new processing units and the reconstitution of network connectivity. This latter approach has been explored to some degree using both biological and electronic means but thus far has not demonstrated the ability to reestablish the function of large-scale neuronal networks. In this review, we contend that fulfilling the potential of brain substrate expansion will require a significant shift from current methods that emphasize direct manipulations of the brain (e.g., injections of cellular suspensions and the implantation of multi-electrode arrays) to the generation of more sophisticated neural tissues and neural-electric hybrids in vitro that are subsequently transplanted into the brain. Drawing from neural tissue engineering, stem cell biology, and neural interface technologies, this strategy makes greater use of the manifold techniques available in the laboratory to create biocompatible constructs that recapitulate brain architecture and thus are more easily recognized and utilized by brain networks.

Role of monocyte chemoattractant protein-1 (MCP-1/CCL2) in migration of neural progenitor cells toward glial tumors.

Neural progenitor cells (NPCs) have been investigated as potential vehicles for brain tumor therapy because they have been shown to migrate toward central nervous system gliomas and can be genetically engineered to deliver cytotoxic agents to tumors. The mechanisms that regulate migration of NPCs to tumors are not fully understood. By means of microarray analysis, polymerase chain reaction, enzyme‐linked immunosorbent assay, and immunohistochemistry, we found that monocyte chemoattractant protein‐1 (MCP‐1/CCL‐2) was expressed in experimental brain tumor cells in vivo and in vitro. CCR2, the receptor for MCP‐1, was expressed on C17.2 NPCs. We used a modified Boyden chamber assay and found increased migration of NPCs in vitro in response to MCP‐1. By means of an in vivo model for NPC migration, we found evidence of NPC migration toward areas of MCP‐1 infusion in rat brains. An understanding of NPC migration mechanisms may be used to enhance delivery of cytotoxic agents to brain tumor cells.

Barbiturate infusion for intractable intracranial hypertension and its effect on brain oxygenation.

OBJECTIVEBarbiturate-induced coma can be used in patients to treat intractable intracranial hypertension when other therapies, such as osmotic therapy and sedation, have failed. Despite control of intracranial pressure, cerebral infarction may still occur in some patients, and the effect of barbiturates on outcome remains uncertain. In this study, we examined the relationship between barbiturate infusion and brain tissue oxygen (PbtO2). METHODSTen volume-resuscitated brain-injured patients who were treated with pentobarbital infusion for intracranial hypertension and underwent PbtO2 monitoring were studied in a neurosurgical intensive care unit at a university-based Level I trauma center. PbtO2, intracranial pressure (ICP), mean arterial pressure, cerebral perfusion pressure (CPP), and brain temperature were continuously monitored and compared in settings in which barbiturates were or were not administered. RESULTSData were available from 1595 hours of PbtO2 monitoring. When pentobarbital administration began, the mean ICP, CPP, and PbtO2 were 18 ± 10, 72 ± 18, and 28 ± 12 mm Hg, respectively. During the 3 hours before barbiturate infusion, the maximum ICP was 24 ± 13 mm Hg and the minimum CPP was 65 ± 20 mm Hg. In the majority of patients (70%), we observed an increase in PbtO2 associated with pentobarbital infusion. Within this group, logistic regression analysis demonstrated that a higher likelihood of compromised brain oxygen (PbtO2 < 20 mm Hg) was associated with a decrease in pentobarbital dose after controlling for ICP and other physiological parameters (P < 0.001). In the remaining 3 patients, pentobarbital was associated with lower PbtO2 levels. These patients had higher ICP, lower CPP, and later initiation of barbiturates compared with patients whose PbtO2 increased. CONCLUSIONOur preliminary findings suggest that pentobarbital administered for intractable intracranial hypertension is associated with a significant and independent increase in PbtO2 in the majority of patients. However, in some patients with more compromised brain physiology, pentobarbital may have a negative effect on PbtO2, particularly if administered late. Larger studies are needed to examine the relationship between barbiturates and cerebral oxygenation in brain-injured patients with refractory intracranial hypertension and to determine whether PbtO2 responses can help guide therapy.

Development of and psychometric testing for the Brief Pain Inventory-Facial in patients with facial pain syndromes

OBJECT Outcomes in clinical trials on trigeminal pain therapies require instruments with demonstrated reliability and validity. The authors evaluated the Brief Pain Inventory (BPI) in its existing form plus an additional 7 facial-specific items in patients referred to a single neurosurgeon for a diagnosis of facial pain. The complete 18-item instrument is referred to as the BPI-Facial. METHODS This study was a cross-sectional analysis of patients who completed the BPI-Facial. The diagnosis of classic versus atypical trigeminal neuralgia (TN) was made before analyzing the questionnaire results. A hypothesis-driven factor analysis was used to determine the principal components of the questionnaire. Item reliability and questionnaire validity were tested for these specific constructs. RESULTS Data from 156 patients were analyzed, including 114 patients (73%) with classic and 42 (27%) with atypical TN. Using orthomax rotation factor analysis, 3 factors with an eigenvalue > 1.0 were identified-pain intensity, interference with general activities, and facial-specific pain interference-accounting for 97.6% of the observed item variance. Retention of the 3 factors was confirmed via a Cattell scree plot. Internal reliability was demonstrated by calculating Cronbachs alpha: 0.86 for pain intensity, 0.89 for interference with general activities, 0.95 for facial-specific pain interference, and 0.94 for the entire instrument. Initial validity of the BPI-Facial instrument was supported by the detection of statistically significant differences between patients with classic versus atypical pain. Patients with atypical TN rated their facial pain as more intense (atypical 6.24 vs classic 5.03, p = 0.013) and as having greater interference in general activities (atypical 6.94 vs classic 5.43, p = 0.0033). Both groups expressed high levels of facial-specific pain interference (atypical 6.34 vs classic 5.95, p = 0.527). CONCLUSIONS The BPI-Facial is a rigorous measure of facial pain in patients with TN and appears to have sound psychometric properties and is responsive to differences between classic and atypical TN. Future studies must assess the instruments test-retest reliability, validity in additional populations, and responsiveness with respect to changes in patient outcomes following neurosurgical interventions and medical therapies.

Lumbar vertebral hemangioma presenting with the acute onset of neurological symptoms : Case report

Vertebral hemangiomas are common entities that rarely present with neurological deficits. The authors report the unusual case of a large L-3 vertebral hemangioma with epidural extension in a 27-year-old woman who presented with hip flexor and quadriceps weakness, foot drop, and leg pain. The characteristics of the mass on magnetic resonance imaging suggested an aggressive, hypervascular lesion. The patient underwent embolization of the lesion followed by direct intralesional injection of ethanol. Significant resolution of clinical symptoms was observed immediately after the procedure and at her follow-up visits. Follow-up imaging studies obtained 9 months after the procedure also documented a considerable reduction in the size of the hemangioma with minimal loss of vertebral height and a mild kyphosis at the affected level. On repeated imaging studies obtained 21 months postoperatively, the size of the hemangioma and the degree of vertebral body compression were stable. As demonstrated in this case, patients with vertebral hemangiomas can present with acute nerve root compression and signs and symptoms similar to those of disc herniation. Vertebral hemangiomas can be treated effectively with interventional techniques such as embolization and ethanol injection.

Association of a younger age with an increased risk of angiographic and symptomatic vasospasms following subarachnoid hemorrhage

OBJECT Vasospasm is a leading cause of morbidity and death following aneurysmal subarachnoid hemorrhage (SAH). It is important to predict which patients are at risk for vasospasm so that interventions can be made. There are several potential risk factors for vasospasm, one of which is age. However, the effect of age on vasospasm, particularly symptomatic vasospasm, remains controversial. METHODS Three hundred ninety-one patients were retrospectively identified from a prospective observational database of patients with SAH who had been admitted to a single center. Demographic and clinical data were recorded, and cerebral angiograms obtained at admission and between 5 and 10 days later were compared. The relationship between age and angiographic and symptomatic vasospasms was examined using logistic regression techniques. RESULTS Mild (86 patients), moderate (69 patients), severe (56 patients), and no angiographic vasospasms (180 patients) were documented by comparing admission and follow-up angiograms in each patient. Symptomatic vasospasm was identified in 69 patients (17.6%). Angiographic vasospasm was more frequent as age decreased. Except in patients < 30 years old, the frequency of symptomatic vasospasm also increased with decreasing age (p = 0.0001). After adjusting for variables known to be associated with vasospasm, an advanced age was associated with a reduced incidence of any angiographic vasospasm (OR 0.96, 95% CI 0.94-0.97), severe angiographic vasospasm (OR 0.96, 95% CI 0.95-0.98), and symptomatic vasospasm (OR 0.98, 95% CI 0.96-0.99). CONCLUSIONS Results in this study show that a younger age is associated with an increased incidence of angiographic and symptomatic vasospasm.

Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function

Traumatic brain injury (TBI) causes selective hippocampal cell death which is believed to be associated with the cognitive impairment observed in both clinical and experimental settings. The endogenous neurotrophin-4/5 (NT-4/5), a TrkB ligand, has been shown to be neuroprotective for vulnerable CA3 pyramidal neurons after experimental brain injury. In this study, infusion of recombinant NT-4/5 increased survival of CA2/3 pyramidal neurons to 71% after lateral fluid percussion brain injury in rats, compared with 55% in vehicle-treated controls. The functional outcome of this NT-4/5-mediated neuroprotection was examined using three hippocampal-dependent behavioral tests. Injury-induced impairment was evident in all three tests, but interestingly, there was no treatment-related improvement in any of these measures. Similarly, injury-induced decreased excitability in the Schaffer collaterals was not affected by NT-4/5 treatment. We propose that a deeper understanding of the factors that link neuronal survival to recovery of function will be important for future studies of potentially therapeutic agents.

Transorbital endoscopic amygdalohippocampectomy: a feasibility investigation.

OBJECT Resection of the hippocampus is the standard of care for medically intractable epilepsy in patients with mesial temporal sclerosis. Although temporal craniotomy in this setting is highly successful, the procedure carries certain immutable risks and may be associated with cognitive deficits related to cortical and white matter disruption. Alternative surgical approaches may reduce some of these risks by preserving the lateral temporal lobe. This study examined the feasibility of transorbital endoscopic amygdalohippocampectomy (TEA) as an alternative to open craniotomy in cadaveric specimens. METHODS TEA dissections were performed in 4 hemispheres from 2 injected cadaveric specimens fixed in alcohol. Quantitative predictions of the limits of exposure based on predissection imaging were compared with intradissection measurements. The extent of resection and angles of exposure during the dissection and on postdissection imaging were recorded. These measurements were validated with MRI studies from 10 epilepsy patients undergoing standard surgical evaluations. RESULTS The transorbital approach permitted direct access to the mesial temporal structures through the lateral orbital wall. Up to 97% of the hippocampal formation was resected with no brain retraction and minimal (mean 6.0 ± 1.4 mm) globe displacement. Lateral temporal lobe white matter tracts were preserved. CONCLUSIONS TEA permits hippocampectomy comparable to standard surgical approaches without disrupting the lateral temporal cortex or white matter. This novel approach is feasible in cadaveric specimens and warrants clinical investigation in carefully selected cases.

Dislocation of the mandible into the middle cranial fossa

Dislocation of the mandibular condyle into the middle cranial fossa is a rare event due to anatomical and biomechanical factors. The authors report the case of a 12-year-old girl who presented with this condition after colliding with a classmate. One day after her injury, the patient demonstrated an inability to close her mouth completely, and she had minor tenderness to palpation anterior to the tragus, without neurological deficits. Imaging studies demonstrated a fractured glenoid fossa with intrusion of the mandible into the cranial cavity. Open reduction of the mandibular condyle was performed, and the glenoid fossa was reconstructed with a split-thickness bone graft and titanium screws. Several dural tears noted at the time of surgery were repaired primarily. Mandibular condyle dislocation into the middle cranial fossa is often misdiagnosed initially because of its low incidence and nonspecific symptoms. Computed tomography scanning is the most sensitive diagnostic study for detecting this injury. Closed reduction after induction of general anesthesia has been recommended in recently suffered injuries without neurological deficits, but this approach may overlook damage to intracranial structures. Surgical repair is recommended if neurological injury is suspected. Treatment options should be tailored to the individual factors of each case.

Endoscopic Microvascular Decompression: A Stepwise Operative Technique.

Background/Aims: Microvascular decompression (MVD) of the trigeminal nerve is a widely accepted treatment for patients with trigeminal neuralgia caused by vascular compression. The neuroendoscope is rapidly becoming a complementary tool in minimally invasive neurosurgery of the ventral anterior skull base. Its adoption in the lateral approach to the posterior fossa has been slower and has been used primarily as an adjunct to conventional microscopic surgical techniques, e.g. endoscope-assisted microsurgery. Methods: In this paper, we describe a stepwise, technical commentary on a purely endoscopic MVD of the trigeminal nerve via the retrosigmoid route. Results: From our experience, the endoscope provides excellent visualization of the neurovascular relationship. By allowing full visualization of the trigeminal nerve, endoscopy may likely lead to an increase in the number of successful MVDs and a decrease in the number of complications. Conclusion: We believe endoscopic MVD is a safe and effective method of accessing the trigeminal nerve in the cerebellopontine angle and of performing MVD. This endoscopic technique can be implemented in other neurosurgical and neuro-otological procedures such as resection of cerebellopontine angle masses.