Electrochemical and electrophysiological considerations for clinical high channel count neural interfaces.

Electrophysiological recording and stimulation are the gold standard for functional mapping during surgical and therapeutic interventions as well as capturing cellular activity in the intact human brain. A critical component probing human brain activity is the interface material at the electrode contact that electrochemically transduces brain signals to and from free charge carriers in the measurement system. Here, we summarize state-of-the-art electrode array systems in the context of translation for use in recording and stimulating human brain activity. We leverage parametric studies with multiple electrode materials to shed light on the varied levels of suitability to enable high signal-to-noise electrophysiological recordings as well as safe electrophysiological stimulation delivery. We discuss the effects of electrode scaling for recording and stimulation in pursuit of high spatial resolution, channel count electrode interfaces, delineating the electrode-tissue circuit components that dictate the electrode performance. Finally, we summarize recent efforts in the connectorization and packaging for high channel count electrode arrays and provide a brief account of efforts toward wireless neuronal monitoring systems.

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development.

The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin-proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin-proteasome system but also act directly on JAKs to suppress the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor-vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.

An electroencephalogram microdisplay to visualize neuronal activity on the brain surface.

Functional mapping during brain surgery is applied to define brain areas that control critical functions and cannot be removed. Currently, these procedures rely on verbal interactions between the neurosurgeon and electrophysiologist, which can be time-consuming. In addition, the electrode grids that are used to measure brain activity and to identify the boundaries of pathological versus functional brain regions have low resolution and limited conformity to the brain surface. Here, we present the development of an intracranial electroencephalogram (iEEG)-microdisplay that consists of freestanding arrays of 2048 GaN light-emitting diodes laminated on the back of micro-electrocorticography electrode grids. With a series of proof-of-concept experiments in rats and pigs, we demonstrate that these iEEG-microdisplays allowed us to perform real-time iEEG recordings and display cortical activities by spatially corresponding light patterns on the surface of the brain in the surgical field. Furthermore, iEEG-microdisplays allowed us to identify and display cortical landmarks and pathological activities from rat and pig models. Using a dual-color iEEG-microdisplay, we demonstrated coregistration of the functional cortical boundaries with one color and displayed the evolution of electrical potentials associated with epileptiform activity with another color. The iEEG-microdisplay holds promise to facilitate monitoring of pathological brain activity in clinical settings.

The Brain Electroencephalogram Microdisplay for Precision Neurosurgery.

Brain surgeries are among the most delicate clinical procedures and must be performed with the most technologically robust and advanced tools. When such surgical procedures are performed in functionally critical regions of the brain, functional mapping is applied as a standard practice that involves direct coordinated interactions between the neurosurgeon and the clinical neurology electrophysiology team. However, information flow during these interactions is commonly verbal as well as time consuming which in turn increases the duration and cost of the surgery, possibly compromising the patient outcomes. Additionally, the grids that measure brain activity and identify the boundaries of pathological versus functional brain regions suffer from low resolution (3-10 mm contact to contact spacing) with limited conformity to the brain surface. Here, we introduce a brain intracranial electroencephalogram microdisplay (Brain-iEEG-microdisplay) which conforms to the brain to measure the brain activity and display changes in near real-time (40 Hz refresh rate) on the surface of the brain in the surgical field. We used scalable engineered gallium nitride (GaN) substrates with 6" diameter to fabricate, encapsulate, and release free-standing arrays of up to 2048 GaN light emitting diodes (µLEDs) in polyimide substrates. We then laminated the µLED arrays on the back of micro-electrocorticography (µECoG) platinum nanorod grids (PtNRGrids) and developed hardware and software to perform near real-time intracranial EEG analysis and activation of light patterns that correspond to specific cortical activities. Using the Brain-iEEG-microdisplay, we precisely ideFSntified and displayed important cortical landmarks and pharmacologically induced pathological activities. In the rat model, we identified and displayed individual cortical columns corresponding to individual whiskers and the near real-time evolution of epileptic discharges. In the pig animal model, we demonstrated near real-time mapping and display of cortical functional boundaries using somatosensory evoked potentials (SSEP) and display of responses to direct electrical stimulation (DES) from the surface or within the brain tissue. Using a dual-color Brain-iEEG-microdisplay, we demonstrated co-registration of the functional cortical boundaries with one color and displayed the evolution of electrical potentials associated with epileptiform activity with another color. The Brain-iEEG-microdisplay holds the promise of increasing the efficiency of diagnosis and possibly surgical treatment, thereby reducing the cost and improving patient outcomes which would mark a major advancement in neurosurgery. These advances can also be translated to broader applications in neuro-oncology and neurophysiology.

A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease.

Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

Adult H3K27M-mutant diffuse midline glioma with gliomatosis cerebri growth pattern: Case report and review of the literature.

INTRODUCTION: H3K27M-mutant diffuse midline glioma is a recently classified unique entity predominantly affecting pediatric patients and rarely adults. The clinicopathologic features in adults remain poorly characterized. PRESENTATION OF CASE: A 36-year-old man presented with subacute progressive cognitive and visual deterioration, and hydrocephalus requiring ventricular shunting. MRI revealed a diffusely infiltrating lesion with a gliomatosis cerebri growth pattern, multiple foci of contrast enhancement, and diffuse leptomeningeal involvement. Suboccipital craniotomy with exploration of the posterior fossa revealed a subtle capsular lesion infiltrating into the choroid plexus. Although histologically low-grade, the tumor was found to have an H3K27 M mutation establishing the diagnosis. DISCUSSION: In spite of diverse clinicopathologic characteristics, H3K27M-mutant diffuse midline gliomas are incurable, WHO grade IV lesions with poor prognosis. We discuss our case in the context of a review of published reports of H3K27-mutant diffuse midline gliomas in adults. Findings late in the disease course may mimic inflammatory or infectious pathologies radiographically, and low-grade infiltrative neoplasms histologically. CONCLUSION: The diverse clinical, radiographic and molecular features of H3K27M-mutant diffuse midline gliomas in adults remain to be completely characterized. A high index of suspicion is required to avoid missing the diagnosis. Early biopsy and detailed molecular characterization are critical for accurate diagnosis and patient counseling.

Transient Aphasia Following Resection of a Thalamic Cavernous Malformation.

BACKGROUND: The thalamus has a demonstrated role in language, particularly through its connectivity to frontal language cortices. CASE DESCRIPTION: A 59-year-old man with transient mixed aphasia following resection of a left-sided thalamic cavernous malformation is reported. No operative complications were encountered, and there was no surgical contact with cortical language areas. The patient recovered full language function within a week postoperatively. CONCLUSIONS: The role of thalamic nuclei in language processes and other reports of transient thalamic aphasia are reviewed.

Inguinal Extrusion of a Ventriculoperitoneal Shunt.

BACKGROUND: Complications of ventriculoperitoneal (VP) shunts include migration into various anatomic compartments and even extrusion through tissue layers. CASE DESCRIPTION: A 31-year-old female patient with a VP shunt presented with distal shunt tubing extruding through the skin at the level of the inguinal ligament. Shunt hardware was removed, and cultures grew Dermacoccus. The patient was treated with broad-spectrum antibiotics and underwent placement of a lumboperitoneal shunt. CONCLUSIONS: Dermacoccus is a gram-positive skin organism with rare human pathogenicity and not previously known to cause shunt infections.

Transdifferentiation of rat fetal brain stem cells into penile smooth muscle cells.

OBJECTIVES: To evaluate whether rat fetal brain stem cells can be induced to acquire cell fates outside the nervous system, hypothesising that cell-based replacement therapy with stem cells can aid in the regeneration of penile smooth musculature and might help to attenuate organic erectile dysfunction (ED), as the degeneration of penile smooth muscle cells leading to subsequent impairment of function is important in organic ED. MATERIALS AND METHODS: Fetal brain stem cells (FBSCs) from embryonal 12-day Fisher 344 rats were isolated and characterized. For in vitro studies, undifferentiated FBSCs were cultured for 21 days in either N2 media (control) or N2 media conditioned in rat penile smooth muscle cell culture. These were then subjected to immunocytochemistry for specific markers of neural stem cells (nestin) and penile smooth muscle cells, i.e. alpha-smooth muscle actin (alphaSMA), penis-specific myosin light chain (MLC) desmin, calponin, vimentin, phosphodiesterase-5 (PDE5) and connexin. For in vivo studies, male adult Fisher 344 rats had an intracavernous injection with saline (five rats, control) or FBSCs that were labelled genetically by an expression construct for green fluorescent protein (GFP, nine rats, experimental) and maintained for 6 weeks. The rats were then killed and penile tissue was harvested and subjected to immunocytochemistry for markers of neural stem cells, smooth muscle cells, and sinusoidal endothelium (vascular endothelial growth factor, VEGF). RESULTS: Undifferentiated cells exposed to N2 media continued to maintain the characteristic morphological and protein marker features of FBSCs, while the cells exposed to the conditioned media acquired the morphological features of smooth muscle cells. In addition, the differentiated cells (30-40%) expressed smooth muscle markers. Rats implanted with FBSCs had cells that showed double-labelling for GFP/alphaSMA, GFP/calponin and GFP/VEGF. The control group had no evidence of such double-labelling. CONCLUSIONS: These results suggest the transdifferentiation of FBSCs into penile smooth muscle cells. Such transdifferentiated cells showed long-term survival when injected into the cavernous tissue, thus raising the possibility of a novel therapeutic option for organic ED.

Brain stem cells adopt a pituitary fate after implantation into the adult rodent pituitary gland.

Fetal brain stem cells (RSCs) have been induced to express pituitary phenotypes in vitro in co-cultures with GH(3) cells and by exposure to GH(3)-conditioned media. In the current studies, we graft RSCs into the pituitary glands of adult rat to investigate whether grafted RSCs can be induced by the native gland to acquire pituitary properties. Grafted cells survive for 4 weeks and express Pit-1, GH, FSH, LH, ACTH, TSH and to a lesser extent PRL indicating that inductive influences are operative in vivo as well. This demonstrates that pluripotential cells can be induced to acquire properties of tissues different from their organ of origin likely through the action of cell-cell contact and local tissue factors.

Selective differentiation of central nervous system-derived stem cells in response to cues from specific regions of the developing brain.

OBJECT: Each region of the brain is distinguished by specific and distinct markers and functions. The authors hypothesized that each region possesses unique trophic properties that dictate and maintain its development. To test this hypothesis, they isolated central nervous system (CNS) stem cells from fetal rodents, and these rat CNS-derived stem cells (RSCs) were placed in coculture with primary cultures of the developing neonatal hippocampus and hypothalamus to determine whether region-specific primary cells would direct the differentiation of stem cells in a region-specific manner. METHODS: Primary cultures were first established from the neonatal (3-7 days postnatal) hippocampus and hypothalamus. Rodent CNS stem cells, which had been genetically engineered to express green fluorescent protein, were then placed in coculture with the primary CNS cells. The expression of region-specific markers in the RSCs was then evaluated after 2 weeks using immunocytochemistry. Data from previous studies have indicated that primary adult cells lack a differentiation-inducing capacity. RESULTS: When placed in coculture with primary CNS cells, RSCs began to express both neuronal (MAP2) and glial (glial fibrillary acidic protein) markers. Those that were placed in coculture with hippocampal cells expressed region-specific markers such as gamma-aminobutyric acid, whereas those placed in coculture with hypothalamic cells expressed growth hormone-releasing hormone primarily in the hypothalamus. Conclusions. Pluripotential RSCs were induced to express region-specific phenotypes on coculture with primary cells derived from the developing hippocampus and hypothalamus. The differentiation of RSCs into specific lineages on exposure to specific cell types is likely modulated through direct cell-cell contact. Secreted factors from the primary neural cells may also play a role in this induction. Such a differentiation influence is also likely age dependent.

Intraoperative brain ultrasound: a new approach to study flow dynamics in intracranial aneurysms.

The aim was to evaluate the potential of contrast-enhanced ultrasound to visualize the hemodynamics in intracranial aneurysms during neurosurgical intervention and to quantify the ultrasound data using digital particle image velocimetry (DPIV) technique. Aneurysms were scanned through the intact dura mater, preclipping and again postclipping after closure of the dura. After intravenous injection of Optison, angio-like views of the vascular tree surrounding the aneurysm, including the aneurysm sac, were obtained. Single ultrasound contrast agent microbubbles could be visualized in the aneurysm sac and the flow dynamics could be assessed in vivo. Spatial and temporal distributions of the velocity in the aneurysm and in the parent vessels were measured with DPIV using the backscattered signals from the microbubbles. Subsequently, the fluid stresses, vorticity, circulation, etc., were calculated from the velocity fields. We demonstrate in this paper that intraoperative contrast-enhanced ultrasound can be used to quantify the flow dynamics within an aneurysm.

Intracranial Rhabdomyoma: Case Report and Review of the Literature.

A 24-year-old male presented with eight months of increasingly severe frontal headaches, decreased right facial sensation, and periodic vertigo. Magnetic resonance imaging demonstrated a heterogeneously contrast-enhancing mass involving and expanding the right foramen ovale.  A biopsy of the lesion was performed, and the final pathologic diagnosis revealed a neoplastic rhabdomyoma. To date, only five cases of intracranial rhabdomyoma have been reported, and a rhabdomyoma involving the trigeminal nerve has never been described in an adult. This manuscript reviews the available literature and highlights the clinical, imaging, pathologic characteristics, and surgical management of these exceedingly rare lesions.

Fetal brain progenitor cells transdifferentiate to fates outside the nervous system.

Central nervous system stem cells give rise to neurons and glia when exposed to specific trophic factors. In our studies with rat fetal brain-derived stem cells (RSCs), we showed that they could be induced to express the developmentally regulated transcription factors and cell markers characteristic of cells derived from another germ layer, e.g. pituitary cells. Therefore, rat fetal brain-derived stem cells do not seem to be restricted to a defined developmental fate. They may retain pluripotentiality and can be redirected to develop into other cell types not found in the brain provided the correct set of stimuli is present. This multipotent developmental behavior also suggests that instructive signals are operative.

Inflammatory Myofibroblastic Tumor of the Left Sphenoid and Cavernous Sinus Successfully Treated with Partial Resection and High Dose Radiotherapy: Case Report and Review of the Literature.

Inflammatory myofibroblastic tumors, also known as plasma cell granulomas or inflammatory pseudotumors, are uncommon lesions that are known to arise in many areas of the body. They are uncommonly found in the skull base region where effective treatment can be difficult. Steroids and radiation therapy with gross total excision when possible remain the treatments of choice. However, the dosing of radiation remains controversial and many patients develop relapse despite medical management. We present the case of a patient who had an inflammatory myofibroblastic tumor of the sphenoid bone and cavernous sinus. He underwent partial surgical resection and transient steroid therapy. This was followed by high-dose fractionated radiotherapy. The patient demonstrated significant resolution in symptomatology and evidence of disease-free progression on repeat imaging.

Strongyloides stercoralis Hyperinfection Syndrome Presenting as Severe, Recurrent Gastrointestinal Bleeding, Leading to a Diagnosis of Cushing Disease.

A 50-year-old male immigrant from Ethiopia presented for consultation after 3 years of hematochezia/melena requiring > 25 units of blood transfusions. Physical examination revealed severe proximal muscle wasting and weakness, central obesity, proptosis, and abdominal striae, accompanied by eosinophilia, elevated hemoglobin A1c, elevated 24-hour urinary cortisol, lack of suppression of 8 am cortisol levels by 1 mg dexamethasone, and inappropriately elevated random adrenocorticotropic hormone (ACTH) level. Histopathological examination of gastrointestinal biopsies showed large numbers of Strongyloides stercoralis, indicating Strongyloides hyperinfection. Treatment with 2 days of ivermectin led to resolution of gastrointestinal bleeding. This syndrome was due to chronic immunosuppression from a pituitary ACTH (corticotroph) microadenoma, of which resection led to gradual normalization of urine cortisol, improved glycemic control, resolution of eosinophilia, and no recurrence of infection.

Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease.

IMPORTANCE: Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment. OBJECTIVE: To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. DESIGN, SETTING, AND PARTICIPANTS: Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined. MAIN OUTCOMES AND MEASURES: Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay. RESULTS: Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P < .05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed. CONCLUSIONS AND RELEVANCE: These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.

Growth factor gene therapy for Alzheimer disease.

The capacity to prevent neuronal degeneration and death during the course of progressive neurological disorders such as Alzheimer disease (AD) would represent a significant advance in therapy. Nervous system growth factors are families of naturally produced proteins that, in animal models, exhibit extensive potency in preventing neuronal death due to a variety of causes, reversing age-related atrophy of neurons, and ameliorating functional deficits. The main challenge in translating growth factor therapy to the clinic has been delivery of growth factors to the brain in sufficient concentrations to influence neuronal function. One means of achieving growth factor delivery to the central nervous system in a highly targeted, effective manner may be gene therapy. In this article the authors summarize the development and implementation of nerve growth factor gene delivery as a potential means of reducing cell loss in AD.

An early venous abnormality: a potential cause of arteriovenous malformation recurrence.

In adults, complete surgical resection of arteriovenous malformations (AVMs) is generally curative. Recurrence of AVMs is extremely rare and most often delayed over many years. The authors report the case of a man in his 20s with rapid AVM recurrence and dual blood supply from the dura and intracerebral vessels. Early recurrence of the AVM allowed documentation of the early events associated with this recurrence. This was evidenced by the first appearance of an early vein without any signs of abnormal vasculature, suggesting that abnormality of the venous drainage system might be an inciting event in the recurrence and perhaps genesis of AVMs.