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Objective: The efficacy of deep brain stimulation (DBS) depends on accurate placement of electrodes. Although stereotactic frames enable co-registration of image-based surgical planning and the operative field, the accuracy of electrode placement can be degraded by intra-operative brain shift. In this study, we adapted a biomechanical model to estimate whole brain displacements from which we deformed preoperative CT (preCT) to generate an updated CT (uCT) that compensates for brain shift. Methods: We drove the deformation model using displacement data derived from deformation in the frontal cortical surface that occurred during the DBS intervention. We evaluated 15 patients, retrospectively, who underwent bilateral DBS surgery, and assessed the accuracy of uCT in terms of target registration error (TRE) relative to a CT acquired post-placement (postCT). We further divided subjects into large (Group L) and small (Group S) deformation groups based on a TRE threshold of 1.6mm. Anterior commissure (AC), posterior commissure (PC) and pineal gland (PG) were identified on preCT and postCT and used to quantify TREs in preCT and uCT. Results: In the group of large brain deformation, average TREs for uCT were 1.11 ± 0.13 and 1.07 ± 0.38 mm at AC and PC, respectively, compared to 1.85 ± 0.17 and 0.92 ± 0.52 mm for preCT. The model updating approach improved AC localization but did not alter TREs at PC. Conclusion: This preliminary study suggests that our image updating method may compensate for brain shift around surgical targets of importance during DBS surgery, although further investigation is warranted before conclusive evidence will be available. Significance: With further development and evaluation, our model-based image updating method using intraoperative sparse data may compensate for brain shift in DBS surgery efficiently, and have utility in updating targeting coordinates.

Multiple lines of evidence show that the human amygdala is part of a neural network important for perception of emotion from environmental stimuli, including for processing of intrinsic attractiveness/"goodness" or averseness/"badness," i.e., affective valence.With this in mind, we investigated the effect of electrical brain stimulation of the human amygdala on perception of affective valence of images taken from the International Affective Picture Set (IAPS).Using intracranial electrodes in patients with epilepsy, we first obtained event-related potentials (ERPs) in eight patients as they viewed IAPS images of varying affective valence. Next, in a further cohort of 10 patients (five female and five male), we measured the effect of 50 Hz electrical stimulation of the left amygdala on perception of affective valence from IAPS images.We recorded distinct ERPs from the left amygdala and found significant differences in the responses between positively and negatively valenced stimuli (These results render further evidence that the left amygdala participates in a neural network for perception of emotion from environmental stimuli. These findings support the idea that electrical stimulation disrupts this network and leads to partial disruption of perception of emotion. Harnessing this effect may have clinical implications in treatment of certain neuropsychiatric disorders using deep brain stimulation (DBS) and neuromodulation.

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide. Despite improvements in survival, treatments that improve functional outcome remain lacking. There is, therefore, a pressing need to develop novel treatments to improve functional recovery. Here, we investigated task-matched deep-brain stimulation of the nucleus accumbens (NAc) to augment reinforcement learning in a rodent model of TBI. We demonstrate that task-matched deep brain stimulation (DBS) of the NAc can enhance learning following TBI. We further demonstrate that animals receiving DBS exhibited greater behavioral improvement and enhanced neural proliferation. Treated animals recovered to an uninjured behavioral baseline and showed retention of improved performance even after stimulation was stopped. These results provide encouraging early evidence for the potential of NAc DBS to improve functional outcomes following TBI and that its effects may be broad, with alterations in neurogenesis and synaptogenesis.

Introduction Laser interstitial thermal therapy (LITT) is a novel minimally invasive alternative to open mesial temporal resection in drug-resistant mesial temporal lobe epilepsy (MTLE). The safety and efficacy of the procedure are dependent on the pre-planned trajectory and the extent of the ablation achieved. Ablation of the mesial hippocampal head has been suggested to be an independent predictor of seizure freedom, whilst sparing of collateral structures is thought to result in improved neuropsychological outcomes. We aim to validate an automated trajectory planning platform against manually planned trajectories to objectively standardize the process. Methods Using the EpiNav™ platform we compare automated trajectory planning parameters derived from expert opinion and machine learning to undertake a multicentre validation study against manually planned and implemented trajectories in 95 patients with MTLE. We estimate ablation volumes of regions of interest and quantify the size of the avascular corridor through the use of a risk score as a marker of safety. We also undertake blinded external expert feasibility ratings and preference rankings between the trajectories. Results Automated trajectory planning employs a complex algorithm to optimize planning parameters in order to maximize ablation of the mesial hippocampal head and amygdala, whilst sparing the parahippocampal gyrus. Automated trajectories resulted in significantly lower risk scores and greater amygdala ablation percentage, whilst overall hippocampal ablation percentage did not differ significantly. Blinded external expert raters were significantly more likely to give preference to automated compared to manually planned trajectories. Conclusion Retrospective studies of automated trajectory planning show much promise in optimizing safety parameters and ablation volumes during LITT for MTLE. Multi-center validation provides evidence that the algorithm is robust and blinded external expert ratings indicate that the trajectories are clinically feasible. Prospective validation studies are now required to determine if automated trajectories result in improved seizure freedom rates and reduced neuropsychological deficits.

BACKGROUND In the coming years the number of patients with cognitive disorders, such as Alzheimer disease and traumatic brain injury, is expected to dramatically increase, leading to an ever-increasing societal cost. Unfortunately, few medical and pharmacologic treatments have shown tangible benefit in the treatment of these diseases. Deep brain stimulation (DBS) is an established surgical technique to address multiple conditions, including Parkinson disease and essential tremor. Data from patients being treated with DBS, as well as those being monitored for seizures with depth electrodes, have suggested improvement in memory with electrical neuromodulation. METHODS MEDLINE was searched from inception through March 2018 using the keywords “DBS,” “Deep Brain Stimulation,” “Memory,” “Memory Modulation,” and “Cognition.” Studies evaluating the effect of DBS on memory and learning were shortlisted and reviewed. RESULTS Efforts to stimulate various nodes within the memory circuitry suggest that the variable effects may result from different mechanisms, including alteration of neural firing patterns, increased activity across several regions, and amplification of neural plasticity. Some of these targets, such as the entorhinal cortex, hippocampus, and nucleus basalis of Meynert, have shown promising results with regards to modulation of memory. CONCLUSIONS Given the aging population and increasing numbers of patients with memory impairment from neurodegenerative diseases, interest in neuromodulation for memory enhancement will likely expand. Further work should employ more sophisticated responsive stimulation parameters and precise spatial targeting that may lead to an effective stimulation strategy for memory enhancement.

The ventromedial prefrontal cortex (vmPFC) has been thought to play an important role in processing endogenous information such as generating subjective affective meaning. Unlike sensory cortex, which processes exogenous information about the external world similarly across individuals, prior work has posited that vmPFC activity may be idiosyncratic to each individual, even when exposed to the same external stimulus. In this study, we recorded local field potentials (LFPs) from intracranial stereotactic electrodes implanted in patients with intractable epilepsy while they watched an emotionally engaging television show episode and evaluated temporal synchronization of these signals across participants in auditory cortex and vmPFC. Overall, we observed markedly lower intersubject synchronization of signals recorded from electrodes implanted in vmPFC compared to auditory cortex. A subset of patients, however, appeared to share similar vmPFC states during the more emotionally salient scenes. This work suggests that the vmPFC is involved in processing affective responses to ongoing experience in a state-like manner, but the specific states and temporal sequences are idiosyncratic to each individual, even when viewing the same television episode.

Systemic delivery of therapeutic proteins to the central nervous system (CNS) is challenging because of the blood-brain barrier restrictions. Direct intrathecal delivery is possible but does not produce stable concentrations. We are proposing an alternative approach for localized delivery into the CNS based on the Transduced Autologous Restorative Gene Therapy (TARGT) system. This system was previously developed using a gene therapy approach with dermal tissue implants. Lewis rat dermal tissue was transduced to secrete human EPO (hEPO). TARGT viability and function were retained following cryopreservation. Upon implantation into the rat cisterna magna, a mild inflammatory response was observed at the TARGT-brain interface throughout 21-day implantation. hEPO expression was verified immunohistochemically and by secreted levels in cerebrospinal fluid (CSF), serum, and in vitro post explant. Detectable CSF hEPO levels were maintained during the study. Serum hEPO levels were similar to rat and human basal serum levels. In vitro, the highest hEPO concentration was observed on day 1 post-explant culture and then remained constant for over 21 days. Prolonged incubation within the cisterna magna had no negative impact on TARGT hEPO secretion. These promising results suggest that TARGTs could be utilized for targeted delivery of therapeutic proteins to the CNS.

A common human experience is noticing that emotional life events are more vividly remembered than dull ones. Studies show that the amygdala plays a central role in such emotionally driven enhancement of memory. With this in mind, we investigated the effect of electrical brain stimulation of the left human amygdala on performance on an emotional perception and emotional memory task. We randomly applied sub-threshold 50 Hz stimulation to the left amygdala in 10 patients (5 female and 5 male) with intracranial electrodes during the encoding portion of an emotional valence perception and emotional memory task. We found that amygdala stimulation did not affect reported valence for neutral stimuli (non-stimulated group average valence 5.34, stimulated 5.38, p=0.68) but it did affect positively (non-stimulated group average valence 7.31, stimulated 6.70, p=0.004) and negatively (non-stimulated group average valence 2.79, stimulated 3.55, p=0.0002) valenced stimuli in effect reporting both valence categories as more neutral. Furthermore, we found that stimulation did not significantly disrupt memory for neutral stimuli (68% vs. 61% correctly remembered p=0.48) or positive stimuli (87% vs. 70% correct, trend towards significant difference p=0.09) but did for negative stimuli (83% vs. 67% correct, p=0.03). These results suggest that electrical brain stimulation by our parameters likely reversibly inhibits amygdala function disrupting neural networks responsible for emotional perception and memory. This effect may have clinical implications in treatment of certain neuropsychiatric disorders, such as emotional dysregulation and post-traumatic stress disorder.Statement of significanceThe current study builds and expands on extensive prior research into the function of the human amygdala. It provides the first systematic description in humans of a cognitive change brought about by direct electrical stimulation of the amygdala on perception of emotional valence and emotional memory. The results provide further evidence on the importance of the amygdala in human cognition. Likewise, out method utilized to study the function of the amygdala can be extended to study the function of other brain regions in humans, such as the cingulate. While these results are preliminary and need to be duplicated, we aim to further study the effects of amygdala stimulation on emotional processing including possible therapeutic application for diverse group of neuropsychiatric conditions.

Deep brain stimulation (DBS) electrode placement is a burr-hole procedure for the treatment of patients with neuro- degenerative disease such as Parkinson’s disease, essential tremor and dystonia. Accurate placement of electrodes is the key to optimal surgical outcome. However, the accuracy of pre-operative images used for surgical planning are often degraded by intraoperative brain shift. To compensate for intraoperative target deviation, we have developed a biomechanical model, driven by partially sampled displacements between pre- and postCT, to estimate a whole brain displacement field based on which updated CT (uCT) can be generated. The results of the finite element model depend on sparse data, as the model minimizes the difference between model estimates and sparse data. Existing approaches to extract sparse data from brain surface are typically geometry or feature-based. In this paper, we explore a geometry- based iterative closest point (ICP) algorithm and a feature-based image registration algorithm, and drive the model with 1) geometry-based sparse data only, 2) feature-based sparse data only, and 3) combined data from 1) and 2). We assess the model performance in terms of model-data misfit, as well as target registration errors (TREs) at the anterior commissure (AC) and posterior commissure (PC). Results show that the model driven by the geometry-based sparse data reduced the TREs of preCT from 1.65mm to 1.26 mm and 1.88 mm to 1.58 mm at AC and PC, respectively by compensating majorly along the direction of gravity and the longitudinal axis, whereas feature-based sparse data contributed to the compensation along the lateral direction at PC.

Deep brain stimulation (DBS) of the subcallosal cingulate has emerged as a promising therapy for treatment-resistant depression (TRD). To date, all studies have employed bilateral stimulation; however, the physiology of affect and pathophysiology of depression are known to be asymmetric across hemispheres. Unilateral stimulation may provide efficacy while decreasing risk. Five patients were exposed to unilateral open-label DBS to the subcallosal cingulate for 12 weeks each to the left and then right hemispheres in a double-blind, crossover fashion. After 12 weeks of stimulation to each hemisphere, bilateral stimulation was initiated, and patients were followed for 12 additional weeks. Additionally, nine months of long-term follow up data were collected. Left, but not right, unilateral stimulation was associated with significant decrease in depression scores; with bilateral stimulation, all patients improved and one patient remitted. No serious adverse events were associated with surgery or acute or chronic stimulation. This small study suggests that unilateral DBS to the subcallosal cingulate may be an effective treatment for TRD. All patients improved with bilateral stimulation, though antidepressant effects following 12 weeks were modest. These findings contrast somewhat with prior open-label trials, though duration of bilateral stimulation was shorter in this trial. The current study continues to confirm safety of implantation and use of DBS to the subcallosal cingulate for patients with TRD and highlights the importance of personalization of therapy, for example by hemisphere, in future trials.

Spinal tumors are conventionally differentiated based on location in relation to the spinal cord. Benign spinal tumors such as schwannomas and meningiomas are typically extra-axial (intradural extramedullary) lesions, whereas more aggressive primary spinal tumors such as ependymomas are typically intramedullary masses. Rarely, ependymomas can have both intramedullary and extramedullary components (typically referred to as exophytic ependymomas). We report a case of a spinal exophytic ependymoma that radiographically masqueraded as a benign intradural extramedullary lesion causing cord compression and neurologic deficit in a 47-year-old man. The diagnosis of exophytic ependymoma was made intra-operatively, with resultant gross total resection of the extramedullary portion and subtotal resection of the intramedullary portion. Histopathological examination confirmed ependymoma with World Health Organization grade II/IV. Pre-operative suspicion of an exophytic ependymoma influences operative planning and clinical management. We review the literature and discuss clinical management strategies for these interesting spinal tumors.

BACKGROUND Implantation of depth electrodes to localize epileptogenic foci in patients with drug-resistant epilepsy can be accomplished using traditional rigid frame-based, custom frameless, and robotic stereotactic systems. OBJECTIVE To evaluate the accuracy of electrode implantation using the FHC microTargeting platform, a custom frameless platform, without a rigid insertion cannula. METHODS A total of 182 depth electrodes were implanted in 13 consecutive patients who underwent stereoelectroencephalography (SEEG) for drug-resistant epilepsy using the microTargeting platform and depth electrodes without a rigid guide cannula. MATLAB was utilized to evaluate targeting accuracy. Three manual coordinate measurements with high inter-rater reliability were averaged. RESULTS Patients were predominantly male (77%) with average age 35.62 (SD 11.0, range 21-57) and average age of epilepsy onset at 13.4 (SD 7.2, range 3-26). A mean of 14 electrodes were implanted (range 10-18). Mean operative time was 144 min (range 104-176). Implantation of 3 out of 182 electrodes resulted in nonoperative hemorrhage (2 small subdural hematomas and one small subarachnoid hemorrhage). Putative location of onset was identified in all patients. We demonstrated a median lateral target point localization error (LTPLE) of 3.95 mm (IQR 2.18-6.23), a lateral entry point localization error (LEPLE) of 1.98 mm (IQR 1.2-2.85), a target depth error of 1.71 mm (IQR 1.03-2.33), and total target point localization error (TPLE) of 4.95 mm (IQR 2.98-6.85). CONCLUSION Utilization of the FHC microTargeting platform without the use of insertion cannulae is safe, effective, and accurate. Localization of seizure foci was accomplished in all patients and accuracy of depth electrode placement was satisfactory.

Background Electrocorticography studies are typically conducted in patients undergoing video EEG monitoring, but these studies are subject to confounds such as the effects of pain, recent anesthesia, analgesics, drug changes, antibiotics, and implant effects. New method Techniques were developed to obtain electrocorticographic (ECoG) data from freely moving subjects performing navigational tasks using the RNS® System (NeuroPace, Inc., Mountain View, CA), a brain-responsive neurostimulation medical device used to treat focal onset epilepsy, and to align data from the RNS System with cognitive task events with high precision. These subjects had not had recent surgery, and were therefore not confounded by the perioperative variables that affect video EEG studies. Results Task synchronization using the synchronization marker technique provides a quantitative measure of clock uncertainty, and can align data to task events with less than 4 ms of uncertainty. Hippocampal ECoG activity was found to change immediately before an incorrect response to a math problem compared to hippocampal activity before a correct response. In addition, subjects were found to have variable but significant changes in theta band power in the hippocampus during navigation compared to when subjects were not navigating. We found that there is theta–gamma phase-amplitude coupling in the right hippocampus while subjects stand still during a navigation task. Comparison with existing methods An alignment technique described in this study improves the upper bound on task-ECoG alignment uncertainty from approximately 30 ms to under 4 ms. The RNS System is one of the first platforms capable of providing untethered ambulatory ECoG recording in humans, allowing for the study of real world instead of virtual navigation. Compared to intracranial video EEG studies, studies using the RNS System platform are not subject to confounds caused by the drugs and recent surgery inherent to the perioperative environment. Furthermore, these subjects provide the opportunity to record from the same electrodes over the course of many years. Conclusions The RNS System enables us to study human navigation with unprecedented clarity. While RNS System patients have fewer electrodes implanted than video EEG patients, the lack of external artifact and confounds from recent surgery make this system a useful tool to further human electrophysiology research.

Patients with shunted hydrocephalus presenting with altered mental status and ventriculomegaly are generally considered to be in shunt failure requiring surgical treatment. The authors describe a case of shunted hydrocephalus secondary to a disseminated neuroectodermal tumor in a pediatric patient in whom rapid fluctuations in sodium levels due to diabetes insipidus repeatedly led to significant changes in ventricle size, with invasively confirmed normal shunt function and low intracranial pressure. This clinical picture exactly mimics shunt malfunction, requires urgent nonsurgical therapy, and underscores the importance of considering serum osmolar abnormalities in the differential diagnosis for ventriculomegaly.

Summary Objectives To determine the ability of foramen ovale electrodes (FOEs) to localize epileptogenic foci after inconclusive noninvasive investigations in patients with suspected mesial temporal lobe epilepsy (MTLE). Methods We identified patients with medically intractable epilepsy who had undergone FOE investigation for initial invasive monitoring at our institution between 2005 and 2012. Indications for initiating FOE investigation were grouped into four categories: (1) bilateral anterior temporal ictal activity on scalp electroencephalography (EEG), (2) unclear laterality of scalp EEG onset due to muscle artifact or significant delay following clinical manifestation, (3) discordance between ictal and interictal discharges, and (4) investigation of a specific anatomic abnormality or competing putative focus. The FOE investigation was classified as informative if it provided sufficient evidence to make a treatment decision. Results Forty-two consecutive patients underwent FOE investigation, which was informative in 38 patients (90.5%). Of these 38 patients, 24 were determined to be appropriate candidates for resective surgery. Five were localized sufficiently for surgery, but were considered high risk for verbal memory deficit, and nine were deemed poor surgical candidates because of bilateral ictal origins. The remaining 4 of 42 patients had inconclusive FOE studies and were referred for further invasive investigation. Of the 18 patients who underwent resective surgery, 13 (72%) were seizure-free (Engel class I) at last follow-up (mean 22.5 months). Significance More than 90% of our 42 FOE studies provided sufficient evidence to render treatment decisions. When undertaken with an appropriate hypothesis, FOE investigations are a minimally invasive and efficacious means for evaluating patients with suspected MTLE after an inconclusive noninvasive investigation. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Object Surgical treatment of moyamoya disease in the adult population commonly uses direct revascularization, the superficial temporal artery (STA) to middle cerebral artery (MCA) bypass (STA-MCA). Pial synangiosis, a method of indirect revascularization, has been used in adult patients with moyamoya when STA-MCA bypass was not technically feasible. Although the effectiveness of pial synangiosis has been well described in children, only limited reports have examined its role in adult patients with moyamoya disease. In this study the authors report on their experience with pial synangiosis revascularization for this population. Methods The authors reviewed the clinical and radiographic records of all adult patients (≥ 18 years of age) with moyamoya disease who underwent cerebral revascularization surgery using pial synangiosis at a single institution. Results From 1985 to 2010, 66 procedures (6 unilateral, 30 bilateral) were performed on 36 adult patients with moyamoya disease. The mean age at surgery was 28.3 years, and 30 patients were female. Twenty-eight patients (77.8%) presented with transient ischemic attacks (TIAs), 24 (66.7%) with stroke, and 3 (8.3%) with hemorrhage. Preoperative Suzuki stage was III or higher in 50 hemispheres (75.8%) and 3 patients had undergone prior treatments to the affected hemisphere before pial synangiosis surgery. Clinical follow-up was available for an average of 5.8 years (range 0.6–14.1 years), with 26 patients (72.2%) followed for longer than 2 years. Postoperative angiography was available for 24 patients and 46 revascularized hemispheres, and 39 (84.8%) of the 46 hemispheres demonstrated good collateral formation (Matsushima Grade A or B). Postoperative complications included 3 strokes, 5 TIAs, and 2 seizures, and there was no hemorrhage during the follow-up period. One patient required additional revascularization surgery 8 months after pial synangiosis. Conclusions Pial synangiosis is a safe and durable method of cerebral revascularization in adult patients with moyamoya and can be considered as a potential treatment option for moyamoya disease in adults.

Object Recurrence after endovascular coiling of intracranial aneurysms is reported in up to 42% of cases and is attributed to the lack of endothelialization across the neck. In this study the authors used a novel tissue engineering approach to promote endothelialization by seeding endothelial progenitor cells (EPCs) within a fibrin polymer injected endovascularly into the aneurysm. Methods Experimental aneurysms were created in New Zealand White rabbits and were left untreated, surgically clipped, or embolized with platinum coils, fibrin biopolymer alone, or fibrin combined with autologous cultured EPCs. Results In aneurysms treated with EPCs, a confluent monolayer of endothelial cells with underlying neointima was demonstrated across the neck at 16 weeks posttreatment, which was not observed with aneurysms treated using the other methods. Conclusions This novel technique may address reasons for the limited durability of standard coil embolization and provides further avenues for the development of improved devices for the care of patients with aneurysms.

Surgical treatment of moyamoya disease in the adult population commonly uses direct revascularization, the superficial temporal artery (STA) to middle cerebral artery (MCA) bypass (STA-MCA). Pial synangiosis, a method of indirect revascularization, has been used in adult patients with moyamoya when STA-MCA bypass was not technically feasible. Although the effectiveness of pial synangiosis has been well described in children, only limited reports have examined its role in adult patients with moyamoya disease. In this study the authors report on their experience with pial synangiosis revascularization for this population.The authors reviewed the clinical and radiographic records of all adult patients (≥ 18 years of age) with moyamoya disease who underwent cerebral revascularization surgery using pial synangiosis at a single institution.From 1985 to 2010, 66 procedures (6 unilateral, 30 bilateral) were performed on 36 adult patients with moyamoya disease. The mean age at surgery was 28.3 years, and 30 patients were female. Twenty-eight patients (77.8%) presented with transient ischemic attacks (TIAs), 24 (66.7%) with stroke, and 3 (8.3%) with hemorrhage. Preoperative Suzuki stage was III or higher in 50 hemispheres (75.8%) and 3 patients had undergone prior treatments to the affected hemisphere before pial synangiosis surgery. Clinical follow-up was available for an average of 5.8 years (range 0.6-14.1 years), with 26 patients (72.2%) followed for longer than 2 years. Postoperative angiography was available for 24 patients and 46 revascularized hemispheres, and 39 (84.8%) of the 46 hemispheres demonstrated good collateral formation (Matsushima Grade A or B). Postoperative complications included 3 strokes, 5 TIAs, and 2 seizures, and there was no hemorrhage during the follow-up period. One patient required additional revascularization surgery 8 months after pial synangiosis.Pial synangiosis is a safe and durable method of cerebral revascularization in adult patients with moyamoya and can be considered as a potential treatment option for moyamoya disease in adults.

This article describes the basis for neuromodulation procedures for obsessive-compulsive disorder (OCD) and summarizes the literature on the efficacy of these interventions. Discussion includes neural circuitry underlying OCD pathology, the history and types of ablative procedures, the targets and modalities used for neuromodulation, and future therapeutic directions.

Focal cortical dysplasia (FCD) causes medically intractable seizures in 5–10% of adult epilepsy patients, but patients can become seizure free through surgical resection. The authors present the utility of three-dimensional surface visualization (3DSV) that expands on existing imaging datasets to highlight surface vasculature as a tool for achieving more successful resections in patients with FCD. In this prospective series of six patients, preoperative 3DSV was performed for planning the surgical approach to the lesion and for intraoperative guidance. Reconstructions involved volume rendering of a contrast-enhanced dataset to visualize surface venous vasculature. Postoperatively, five of the six patients had complete resections, with one patient having a subtotal resection due to proximity to crucial vasculature. We report that 3DSV is a useful tool for surgical planning, since topographical relationships between lesion location and surface vasculature landmarks are less likely to change with surgical progress.

Introduction: Surgical treatment of moyamoya disease in the adult population commonly employs direct revascularization, the superficial temporal artery to middle cerebral artery (STA-MCA) bypass. Pial synangiosis, a method of indirect revascularization, has been utilized in adult moyamoya patients when STA-MCA bypass is not technically feasible. Although the effectiveness of pial synangiosis has been well described in children, only limited reports have examined its role in adult moyamoya patients. Here we report on our experience with pial synangiosis revascularization for this population. Methods: We reviewed the clinical and radiographic records of all adult moyamoya patients (18 years of age or older), who underwent cerebral revascularization surgery using pial synangiosis at a single institution. Results: From 1985-2010, 66 procedures (6 unilateral, 30 bilateral) were performed on 36 adult moyamoya patients. The mean age at surgery was 28.3 (range: 19 - 51) and 30 were female. Thirty-one patients (86.1%) presented with either stroke or TIA and 3 (8.3%) with hemorrhage. Pre-operative Suzuki grade was III or higher in 50 hemispheres (75.7%) and 3 patients had prior treatments to the affected hemisphere before pial synangiosis surgery. Clinical follow-up was available for an average of 5.8 years (range 0.6-14.1 years), with 26 (72.2%) patients followed for longer than 2 years. Post-operative angiogram was available for 24 patients and 46 revascularized hemispheres, and 39 (84.8%) demonstrated good collateral formation (Matsushima grade A or B). Peri-operative complications included 3 strokes, 5 TIA’s, and 2 seizures, and there was no stroke or hemorrhage during the follow-up period. One patient required additional revascularization surgery 8 months after pial synangiosis. Conclusions: Pial synangiosis is a safe, effective, and durable method of cerebral revascularization in adult moyamoya patients. Our data supports the utilization of pial synangiosis as a treatment option for moyamoya disease in adults, particularly when STA-MCA bypass is not technically feasible.

Diseases and disorders of the central nervous system (CNS) represent a large field of unmet need that significantly impacts the lifespan and quality of life of many patients. The ability to deliver therapeutic proteins from the systemic circulation to the CNS is hampered by the blood-brain barrier (BBB). A number of strategies have been developed to allow therapies to cross the BBB, but to date with limited success. We have developed a novel localized approach to deliver protein and peptide therapeutics to the CNS based on our proprietary Transduced Autologous Restorative Gene Therapy system (TARGT™) platform. TARGT is based on autologous dermal micro-organs (MO) harvested and transduced ex-vivo to produce a therapeutic protein and then re-implanted in the patient. In this study we assessed whether TARGT can survive and deliver sustained localized protein post implantation into the CNS. In rats, MOs, 2×1mm each, were harvested from Lewis rat skin, characterized in-vitro, and then implanted in the Lewis rats’ cisterna magna. The procedure was well-tolerated and without observed behavioral change in all implanted rats. Histopathology of MOs excised several weeks post implantation, demonstrated viable and integrated MOs without signs of implant rejection. In the second phase, rat MOs were processed ex-vivo into TARGT secreting erythropoietin (TARGTEPO) by transduction with Helper Dependent Adenoviral vector encoding human erythropoietin (HDAd-HuEPO). Rat TARGTs secreting human EPO were then implanted into Lewis rats’ cisterna magna. Post implantation, cerebrospinal fluid (CSF) and serum were collected and EPO levels were measured by HuEPO ELISA. Results obtained suggest that implantation was well tolerated with no observed signs of rejection. Measurable human EPO levels were detected in rat CSF for the duration of the experiment. Detectable but low levels of Hu-EPO were also measured in the rat serum, as expected, since CSF drains into the peripheral blood. In pigs we have tested the viability and monoclonal antibody secretion from TARGTs into the CNS. Humira, an established antibody drug, was selected as a proof of concept. Pig MOs were harvested and transduced with the HDAd vector carrying the Humira sequence. Two TARGTHumira were implanted in the pig subdural space at the parietal convexity region and the pig was followed for one week post implantation. Results obtained post implantation suggests no observed pig's behavioral change. Humira was measured in CSF samples taken from the implantation area and the lumbar space. One week post implantation, TARGTs were excised out of the pig brain when they are viable and no signs of inflammation or damage to the brain tissue were observed. These results demonstrate that TARGT is a promising novel therapeutic platform with the potential for treatment of CNS disorders. We are now actively studying TARGTCNS treatment of lysosomal storage diseases and brain malignancies.

Recurrence after endovascular coiling of intracranial aneurysms is reported in up to 42% of cases and is attributed to the lack of endothelialization across the neck. In this study the authors used a novel tissue engineering approach to promote endothelialization by seeding endothelial progenitor cells (EPCs) within a fibrin polymer injected endovascularly into the aneurysm.Experimental aneurysms were created in New Zealand White rabbits and were left untreated, surgically clipped, or embolized with platinum coils, fibrin biopolymer alone, or fibrin combined with autologous cultured EPCs.In aneurysms treated with EPCs, a confluent monolayer of endothelial cells with underlying neointima was demonstrated across the neck at 16 weeks posttreatment, which was not observed with aneurysms treated using the other methods.This novel technique may address reasons for the limited durability of standard coil embolization and provides further avenues for the development of improved devices for the care of patients with aneurysms.

Drug targeting of adult stem cells has been proposed as a strategy for regenerative medicine, but very few drugs are known to target stem cell populations in vivo. Mesenchymal stem/progenitor cells (MSCs) are a multipotent population of cells that can differentiate into muscle, bone, fat, and other cell types in context-specific manners. Bortezomib (Bzb) is a clinically available proteasome inhibitor used in the treatment of multiple myeloma. Here, we show that Bzb induces MSCs to preferentially undergo osteoblastic differentiation, in part by modulation of the bone-specifying transcription factor runt-related transcription factor 2 (Runx-2) in mice. Mice implanted with MSCs showed increased ectopic ossicle and bone formation when recipients received low doses of Bzb. Furthermore, this treatment increased bone formation and rescued bone loss in a mouse model of osteoporosis. Thus, we show that a tissue-resident adult stem cell population in vivo can be pharmacologically modified to promote a regenerative function in adult animals.

proaches (11). We now demonstrate an approach for the in vivo engineering of large predictable volumes of autologous bone without the need for harvestexpansion of cells and use of growth factors. Our approach is based on the manipulation of a deliberately created space within the body, such that it serves as an ''in vivo bioreactor,'' wherein the engineering of the neotissue is achieved by invocation of a healing response within the bioreactor space. Specifically, in the context of bone engineering, we hypothesized that by creating this ''space'' between the surface of a long bone and the membrane rich in pluripotent cells that covers it, namely the periosteum, the cell population and biomolecular signals necessary for the formation of bone could be locally derived. We created such bioreactors in the tibia of New Zealand White rabbits and then provided volume to this space by injecting a biocompatible calcium-alginate gel that crosslinked in situ, and we followed their maturation over 12 weeks. We observed that, as hypothesized, the bioreactor space was reconstituted by functional living bone. Furthermore, the engineered bone was easily harvested without any apparent postoperative morbidity to the subject and transplanted successfully in a contralateral defect. Methods Preparation of Alginate Gel. The 1% (wtvol) alginate gel used in these studies was optimized from a series of 70 gels developed and characterized as reported in detail elsewhere (12, 13). Briefly, gelation was triggered by mixing a 2% (wtvol) sodium alginate (FMC BioPolymer) in 30 mM Hepes containing 150 mM NaCl and 10 mM KCl, with an equal volume of a solution containing 75 mM CaCl2 in 10 mM Hepes containing 150 mM NaCl and 10 mM KCl by using a sterile Y-piece mixer. The gel cured within 1 min and had a Young's modulus of 0.17 MPa. Growth factors (TGF-1 and FGF-2 ,R&D Systems) were included in the formulation at a concentration of 10 ngml where indicated. The growth factor combination and their concentra- tions in the gel were based on our earlier findings that they enhanced cell proliferation and differentiation in periosteal explants organ cultures in vitro (13). Preparation of Hyaluronic Acid (HA)-Based Gel. The HA-based gel used in these studies was prepared by using a previously reported strategy (14). Briefly, HA (Genzyme) was chemically modified to bear aldehyde groups (HA-ALD) by reaction with sodium periodate and hydrazide groups (HA-ADH) by reacting with adipic dihydrazide. HA hydrogels were produced by mixing equal volumes of 2% (wtvol) aqueous solutions of HA-ALD and HA-ADH. Suramin (Bayer, Leverkusen, Germany) was included in free (0.4 molliter) and liposome-encapsulated (0.4 molliter) forms where indicated during the gelation. Suramin

Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n = 40), normal lung specimens (n = 4), normal pleura specimens (n = 5), and MPM and SV40-immortalized mesothelial cell lines (n = 5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma that correlated loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (ie, software) to create and explore complex physiological pathways. Combined, all of these data may advance our understanding of mesothelioma tumorigenesis, pathobiology, or both.

Objective Lesion procedures for psychiatric indications have a history that spans more than a century. This review provides a brief history of psychiatric surgery and addresses the most recent literature on lesion surgery for the treatment of anxiety and mood disorders. Methods Relevant data described in publications from the early 1900s through the modern era regarding lesion procedures for psychiatric indications, both historical and current use, are reported. Results The early procedures of Burkhardt, Moniz, and Freeman are reviewed, followed by descriptions of the more refined techniques of Leksell, Knight, Foltz, White, and Kelly. The application of lesion procedures to obsessive-compulsive disorder, mood disorders, and addiction are discussed. Conclusions Lesioning procedures have informed modern deep brain stimulation targets. Recent lesioning studies demonstrate the efficacy and durability of these procedures in severely disabled patients. Judicious application of these techniques should continue for appropriately selected patients with severe, refractory psychiatric disorders.

OBJECTIVE The posterior meningeal artery (PMA) normally arises from the vertebral artery; however, its origin varies considerably as the result of its embryological development. This gains clinical significance when associated with vascular pathology. CLINICAL PRESENTATION A 65-year-old man presented to his local hospital with a sudden-onset, severe headache. Computed tomography of the head revealed diffuse subarachnoid hemorrhage, mostly in the left posterior fossa. A computed tomographic angiogram demonstrated an anomalous origin of the PMA from the posteroinferior cerebellar artery (PICA). Cerebral angiography showed the PICA to be enlarged, with a reduced caliber at the takeoff of the PMA, which is consistent with possible dissection. INTERVENTION The patient was taken to the operating room for trapping of the dissecting segment of the PMA. A clip was placed across the PMA at its origin from the PICA, and the vessel was coagulated and transected. The PICA was wrapped in muslin gauze. CONCLUSION The variable origin of the PMA and PICA may be the result of the persistence of embryological anastomoses between the arteries, with regression of the normal channel. Physical stress at the junction of the anomalous PMA and the PICA may have contributed to the abnormality of the PMA, consistent with possible dissection. Because the PMA has multiple anastomoses with the arteries of the falx cerebri, the proximal PMA may be occluded with no compromise to its vascular territory.

Bortezomib is a first-in-class proteasome inhibitor approved for the therapy of relapsed, refractory multiple myeloma (MM). Two large registration trials (SUMMIT and APEX) of bortezomib in MM revealed an increase in the serum levels of bone-specific alkaline phosphatase (b-ALP) and osteocalcin (ocn) in bortezomib-responsive patients, raising the prospect that bortezomib may influence the bone marrow (BM) microenvironment in association with its anti-myeloma effect,. However, the precise cellular target of bortezomib within the BM milieu remains unknown. We hypothesized that the observed rise in b-ALP and ocn was the result of direct effects of bortezomib on osteoblast-lineage committed cells. The effect of bortezomib on osteoblastic cells was first evaluated in in vitro. When bortezomib was added to freshly isolated primary BM mononuclear cells, the CFU-Ob (osteoblastic colony-forming units) was unchanged, but the colony size was increased, with a maximum effect observed at 1 nM. In particular, bortezomib increased the number of CD45−/CD51+ cells 1.8 fold (P