Publisher Correction: Development of an optogenetic toolkit for neural circuit dissection in squirrel monkeys.

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Development of an optogenetic toolkit for neural circuit dissection in squirrel monkeys.

Optogenetic tools have opened a rich experimental landscape for understanding neural function and disease. Here, we present the first validation of eight optogenetic constructs driven by recombinant adeno-associated virus (AAV) vectors and a WGA-Cre based dual injection strategy for projection targeting in a widely-used New World primate model, the common squirrel monkey Saimiri sciureus. We observed opsin expression around the local injection site and in axonal projections to downstream regions, as well as transduction to thalamic neurons, resembling expression patterns observed in macaques. Optical stimulation drove strong, reliable excitatory responses in local neural populations for two depolarizing opsins in anesthetized monkeys. Finally, we observed continued, healthy opsin expression for at least one year. These data suggest that optogenetic tools can be readily applied in squirrel monkeys, an important first step in enabling precise, targeted manipulation of neural circuits in these highly trainable, cognitively sophisticated animals. In conjunction with similar approaches in macaques and marmosets, optogenetic manipulation of neural circuits in squirrel monkeys will provide functional, comparative insights into neural circuits which subserve dextrous motor control as well as other adaptive behaviors across the primate lineage. Additionally, development of these tools in squirrel monkeys, a well-established model system for several human neurological diseases, can aid in identifying novel treatment strategies.

Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior.

Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions.

Internal carotid artery surgical revascularization in a pediatric patient with Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, episodic lymphopenia, renal failure, and cerebrovascular disease secondary to arteriosclerosis and myointimal hyperplasia. In this paper the authors report the first known application of internal carotid artery (ICA) surgical revascularization to relieve a high-grade focal stenosis of the ICA in a pediatric patient, a 6-year-old boy with SIOD. The clinical presentation, imaging features, operative technique, and postoperative course are described and the molecular genetics, pathophysiology, and treatment considerations in SIOD are discussed.

Rehospitalization and emergency department use rates before and after vagus nerve stimulation for epilepsy: use of state databases to provide longitudinal data across multiple clinical settings.

OBJECTIVES: Data regarding rehospitalization and emergency department (ED) visits following vagus nerve stimulation (VNS) present data analysis challenges. We present a method that uses California's multiple databases to more completely assay VNS efficacy. MATERIALS AND METHODS: The Healthcare Cost and Utilization Project's California Inpatient and Ambulatory Surgery databases were assayed for all VNS surgeries from 2005 to 2009. Patients were selected by epilepsy diagnosis codes and VNS procedure codes. Patients (total N = 629) were tracked across multiple databases using unique identifiers. Thirty-day and one-year post-implantation rates of VNS complication and healthcare visits were abstracted, along with one-year preoperative hospital and ED use. Statistics included correction for multiple comparisons. RESULTS: The one-year reoperation rate for adult patients (N = 536) was 3.9%; during the second year, an additional 3.2% of patients had reoperations. Within the first 30 days, <2% of patients experienced a complication. Four percent of patients were readmitted to a hospital, and 11.6% of patients visited an ED. The most common reason for rehospitalization or ED visit was seizure. In the first year after VNS, total seizure-related visits (hospitalization and ED) were 17% lower (2.12 visits per year to 1.71; p = 0.03). In the second year following VNS, seizure-related visits were 42% lower (2.21 visits per year to 1.27, p = 0.01). Pediatric patients (N = 93) had comparable results. CONCLUSIONS: VNS surgery has low rates of complications and reoperations and is associated with reduced incidence of seizure-related ED visits and hospital admissions in the first and second postoperative years.

A coaxial optrode as multifunction write-read probe for optogenetic studies in non-human primates.

BACKGROUND: Advances in optogenetics have led to first reports of expression of light-gated ion-channels in non-human primates (NHPs). However, a major obstacle preventing effective application of optogenetics in NHPs and translation to optogenetic therapeutics is the absence of compatible multifunction optoelectronic probes for (1) precision light delivery, (2) low-interference electrophysiology, (3) protein fluorescence detection, and (4) repeated insertion with minimal brain trauma. NEW METHOD: Here we describe a novel brain probe device, a "coaxial optrode", designed to minimize brain tissue damage while microfabricated to perform simultaneous electrophysiology, light delivery and fluorescence measurements in the NHP brain. The device consists of a tapered, gold-coated optical fiber inserted in a polyamide tube. A portion of the gold coating is exposed at the fiber tip to allow electrophysiological recordings in addition to light delivery/collection at the tip. RESULTS: Coaxial optrode performance was demonstrated by experiments in rodents and NHPs, and characterized by computational models. The device mapped opsin expression in the brain and achieved precisely targeted optical stimulation and electrophysiology with minimal cortical damage. COMPARISON WITH EXISTING METHODS: Overall, combined electrical, optical and mechanical features of the coaxial optrode allowed a performance for NHP studies which was not possible with previously existing devices. CONCLUSIONS: Coaxial optrode is currently being used in two NHP laboratories as a major tool to study brain function by inducing light modulated neural activity and behavior. By virtue of its design, the coaxial optrode can be extended for use as a chronic implant and multisite neural stimulation/recording.

Optogenetic neuromodulation.

The recent development of optogenetics, a revolutionary research tool in neuroscience, portends an evolution of current clinical neuromodulation tools. A form of gene therapy, optogenetics makes possible highly precise spatial and temporal control of specific neuronal populations. This technique has already provided several new insights relevant to clinical neuroscience, from the physiological substrate of functional magnetic resonance imaging to the mechanism of deep brain stimulation in Parkinson's disease. The increased precision of optogenetic techniques also raises the possibility of eventual human use. Translational efforts have begun in primates, with success reported from multiple labs in rhesus macaques. These developments will remain of ongoing interest to neurologists and neurosurgeons.

Venous thromboembolism after thoracic/thoracolumbar spinal fusion.

OBJECTIVE: Venous thromboembolism (VTE), which includes deep venous thrombosis and pulmonary embolism, is a serious and potentially fatal surgical complication. The goal of our study was to examine preoperative characteristics, incidence, and outcomes of patients with VTE after elective thoracic/thoracolumbar level spine fusion. METHODS: We identified 430,081 patients from the Nationwide Inpatient Sample database who underwent spinal fusion between 2002 and 2008. Patients undergoing thoracic/thoracolumbar level fusion (n = 8617) were found to have the greatest concurrent rate of VTE. We then performed multivariate analyses on this cohort to identify predictors of and outcomes after VTE in patients undergoing thoracic/thoracolumbar level fusion. RESULTS: The overall VTE rate in spinal fusion surgery was 0.40% (cervical = 0.22%, thoracic/thoracolumbar = 1.90%, lumbar/lumbosacral = 0.49%, re-fusions = 0.64%, and fusions not otherwise specified = 0.84%). On multivariate logistic regression analysis of patients undergoing spinal fusion at the thoracic/thoracolumbar level, increasing age, Medicare insurance coverage (vs. private insurance), urban teaching hospital (vs. urban nonteaching hospital), combined anterior/posterior surgical approach (vs. posterior-only approach), and the presence of congestive heart failure or weight loss (Elixhauser comorbidity groups) were each independently associated with an increased odds ratio of VTE complication. VTE after thoracic/thoracolumbar surgery was significantly associated with longer hospital stays (16.6 vs. 6.74 days), increased total hospital costs ($260,208 vs. $115,474), and increased mortality (4.33% vs. 0.33%). CONCLUSIONS: Multivariate logistic regression analysis reveals age, insurance status, hospital type, combined anterior/posterior surgical approach, and the presence of congestive heart failure or weight loss to be independently associated with an increased odds ratio of VTE complication. This complication is associated with increased hospital costs, length of stay, and overall mortality.

Impact of age, injury severity score, and medical comorbidities on early complications after fusion and halo-vest immobilization for C2 fractures in older adults: a propensity score matched retrospective cohort study.

STUDY DESIGN: Propensity score matched retrospective cohort study. OBJECTIVE: To report early complication rates and associated risk factors in patients with C2 fractures who underwent fusion or halo immobilization. SUMMARY OF BACKGROUND DATA: There is limited data on the impact of age, injury severity score, and medical comorbidities on overall complication rates from surgical fixation versus halo-vest immobilization of C2 fractures. METHODS: The Nationwide Inpatient Sample database from 2002 to 2008 was queried to identify cohorts of adult patients (age ≥ 18 years) with C2 fractures without spinal cord injury who were treated with either fusion or halo-vest immobilization. Complication rates, hospital length of stay, and costs were compared in a propensity score matched sample. Multivariate analysis was used to identify predictors of in-hospital complications. RESULTS: A total of 3758 patients (1627 fusion and 2131 halo) were identified. Fusion was associated with greater overall complication rates (20.2% vs. 10.1%, P < 0.0001), increased length of stay (8.9 d vs. 6.4 d, P < 0.0001), higher charges ($80,000 vs. $41,000, P < 0.0001), but a lower rate of nonroutine discharge (52.6% vs. 62.6%, P < 0.0001). There was no difference in mortality between the fusion group (2.75%) and the halo group (3.33%). Age, injury score, and comorbidity increased complication rates by a similar degree (odds ratio) in both cohorts. Patients aged 80 years and older were 3.5 times more likely to have a complication than those younger than 60 years. CONCLUSION: Fusion patients had greater overall complication rates, increased length of stay, and greater resource utilization but were discharged home in a greater proportion. Both fusion and halo were associated with significant (more than 3-fold) increase in complication rates in elderly patients aged 80 years or older. Given the similar mortality rate between the fusion group and the halo group and the higher cost and complication rate in the fusion group, our study supports the use of halo-vest immobilization in patients where operative therapy is contraindicated.

Morbid obesity increases cost and complication rates in spinal arthrodesis.

STUDY DESIGN: A retrospective cross-sectional study of all spinal fusions in California from 2003 to 2007. OBJECTIVE: This study analyzes whether morbid obesity alters rates of complications and charges in patients undergoing spinal fusion. SUMMARY OF BACKGROUND DATA: Prior studies of obesity have focused on lumbar fusion; some identified increases in wound complications. However, these studies typically do not account for comorbidities, do not examine nonlumbar fusions, and usually are small single institution series. METHODS: Our study used the Healthcare Cost and Utilization Project's California State Inpatient Databases (CA-SID) to identify normal weight and morbidly obese patients admitted in California between 2003 and 2007 for 4 types of spinal fusion: anterior cervical fusion (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] procedure code 810.2), posterior cervical fusion (810.3), anterior lumbar fusion (810.6), and posterior lumbar fusion (810.8). Demographic, comorbidity, and complications data were collected. Primary outcome was in-hospital complication; secondary outcomes were total cost, length of stay, and in-hospital mortality. Multivariate logistic regression was performed. RESULTS: In total 84,607 admissions were identified, of which 1455 were morbidly obese. Morbid obesity was associated with 97% higher in-hospital complication rates (13.6% vs. 6.9%), sustained across nearly all complication types (cardiac, renal, pulmonary, wound complications, among others). Mortality among the morbidly obese was slightly higher (0.41 vs. 0.13, P < 0.01) as were average hospital costs ($108,604 vs. $84,861, P < 0.0001). Length of stay was longer as well (4.8 d vs. 3.5 d, P < 0.0001). All effects were less pronounced in posterior cervical fusions. On multivariate analysis, morbid obesity was the most significant predictor of complications in the anterior cervical and posterior lumbar fusion groups (more than age, demography, and other comorbidity). CONCLUSION: Morbid obesity seems to increase the risk of multiple complication types in spinal fusion surgery, most particularly in anterior cervical and posterior lumbar approaches.

Morbidity and mortality of C2 fractures in the elderly: surgery and conservative treatment.

BACKGROUND: Closed C2 fractures commonly occur after falls or other trauma in the elderly and are associated with significant morbidity and mortality. Controversy exists as to best treatment practices for these patients. OBJECTIVE: To compare outcomes for elderly patients with closed C2 fractures by treatment modality. METHODS: We retrospectively reviewed 28 surgically and 28 nonsurgically treated cases of closed C2 fractures without spinal cord injury in patients aged 65 years of age or older treated at Stanford Hospital between January 2000 and July 2010. Comorbidities, fracture characteristics, and treatment details were recorded; primary outcomes were 30-day mortality and complication rates; secondary outcomes were length of hospital stay and long-term survival. RESULTS: Surgically treated patients tended to have more severe fractures with larger displacement. Charlson comorbidity scores were similar in both groups. Thirty-day mortality was 3.6% in the surgical group and 7.1% in the nonsurgical group, and the 30-day complication rates were 17.9% and 25.0%, respectively; these differences were not statistically significant. Surgical patients had significantly longer lengths of hospital stay than nonsurgical patients (11.8 days vs 4.4 days). Long-term median survival was not significantly different between groups. CONCLUSION: The 30-day mortality and complication rates in surgically and nonsurgically treated patients were comparable. Elderly patients faced relatively high morbidity and mortality regardless of treatment modality; thus, age alone does not appear to be a contraindication to surgical fixation of C2 fractures.

Hospital costs, incidence, and inhospital mortality rates of traumatic subdural hematoma in the United States.

OBJECT: This study provides the first US national data regarding frequency, cost, and mortality rate of traumatic subdural hematoma (SDH), and identifies demographic factors affecting morbidity and death in patients with traumatic SDH undergoing surgical drainage. METHODS: A retrospective analysis was conducted by querying the Nationwide Inpatient Sample, the largest all-payer database of nonfederal community hospitals. All cases of traumatic SDH were identified using ICD-9 codes. The study consisted of 2 parts: 1) trends data, which were abstracted from the years 1993-2006, and 2) univariate analysis and multivariate logistic regression of demographic variables on inhospital complications and deaths for the years 1993-2002. RESULTS: Admissions for traumatic SDH increased 154% from 17,328 in 1993 to 43,996 in 2006. Inhospital deaths decreased from 16.4% to 11.6% for traumatic SDH. Average costs increased 67% to $47,315 per admission. For the multivariate regression analysis, between 1993 and 2002, 67,864 patients with traumatic SDH underwent operative treatment. The inhospital mortality rate was 14.9% for traumatic SDH drainage, with an 18% inhospital complication rate. Factors affecting inhospital deaths included presence of coma (OR = 2.45) and more than 2 comorbidities (OR = 1.60). Increased age did not worsen the inhospital mortality rate. CONCLUSIONS: Nationally, frequency and cost of traumatic SDH cases are increasing rapidly.

Charlson score is a robust predictor of 30-day complications following spinal metastasis surgery.

STUDY DESIGN: Retrospective chart review. OBJECTIVE: To identify predictors of 30-day complications after the surgical treatment of spinal metastasis. SUMMARY OF BACKGROUND DATA: Surgical treatment of spinal metastasis is considered palliative with the aim of reducing or delaying neurologic deficit. Postoperative complication rates as high as 39% have been reported in the literature. Complications may impact patient quality of life and increase costs; therefore, an understanding of which preoperative variables best predict 30-day complications will help risk-stratify patients and guide therapeutic decision making and informed consent. METHODS: We retrospectively reviewed 200 cases of spinal metastasis surgically treated at Stanford Hospital between 1999 and 2009. Multiple logistic regression was performed to determine which preoperative variables were independent predictors of 30-day complications. RESULTS: Sixty-eight patients (34%) experienced one or more complications within 30 days of surgery. The most common complications were respiratory failure, venous thromboembolism, and pneumonia. On multivariate analysis, Charlson Comorbidity Index score was the most significant predictor of 30-day complications. Patients with a Charlson score of two or greater had over five times the odds of a 30-day complication as patients with a score of zero or one. CONCLUSION: After adjusting for demographic, oncologic, neurologic, operative, and health factors, Charlson score was the most robust predictor of 30-day complications. A Charlson score of two or greater should be considered a surgical risk factor for 30-day complications, and should be used to risk-stratify surgical candidates. If complications are anticipated, medical staff can prepare in advance, for instance, scheduling aggressive ICU care to monitor for and treat complications. Finally, Charlson score should be controlled for in future spinal metastasis outcomes studies and compared to other comorbidity assessment tools.

Predictors of survival after surgical treatment of spinal metastasis.

BACKGROUND: Surgery for spinal metastasis is a palliative treatment aimed at improving patient quality of life by alleviating pain and reversing or delaying neurologic dysfunction, but with a mean survival time of less than 1 year and significant complication rates, appropriate patient selection is crucial. OBJECTIVE: To identify the most significant prognostic variables of survival after surgery for spinal metastasis. METHODS: Chart review was performed on 200 surgically treated spinal metastasis patients at Stanford Hospital between 1999 and 2009. Survival analysis was performed and variables entered into a Cox proportional hazards model to determine their significance. RESULTS: Median overall survival was 8.0 months, with a 30-day mortality rate of 3.0% and a 30-day complication rate of 34.0%. A Cox proportional hazards model showed radiosensitivity of the tumor (hazard ratio: 2.557, P<.001), preoperative ambulatory status (hazard ratio: 2.355, P=.0001), and Charlson Comorbidity Index (hazard ratio: 2.955, P<.01) to be significant predictors of survival. Breast cancer had the best prognosis (median survival, 27.1 months), whereas gastrointestinal tumors had the worst (median survival, 2.66 months). CONCLUSION: We identified the Charlson Comorbidity Index score as one of the strongest predictors of survival after surgery for spinal metastasis. We confirmed previous findings that radiosensitivity of the tumor and ambulatory status are significant predictors of survival.

Is cauda equina syndrome being treated within the recommended time frame?

BACKGROUND: Cauda equina syndrome (CES) is a rare but devastating medical condition requiring urgent surgery to halt or reverse neurological compromise. Controversy exists as to how soon surgery must be performed after diagnosis, and clinical and medicolegal factors make this question highly relevant to the spine surgeon. It is unclear from the literature how often CES patients are treated within the recommended time frame. OBJECTIVE: To determine whether CES patients are being treated in compliance with the current guideline of surgery within 48 hours and to assess incidence, demography, comorbidities, and outcome measures of CES patients. METHODS: We searched the 2003 to 2006 California State Inpatient Databases to identify degenerative lumbar disk disorder patients surgically treated for CES. An International Classification of Disease, ninth revision, clinical modification, diagnosis code was used to identify CES patients with advanced disease. RESULTS: The majority (88.74%) of California's CES patients received surgery within the recommended 48-hour window after diagnosis. The incidence of CES in surgically treated degenerative lumbar disk patients was 1.51% with an average of 397 cases per year in California. CES patients had worse outcomes and used more healthcare resources than other surgically treated degenerative lumbar disk patients; this disparity was more pronounced for patients with advanced CES. CES patients treated after 48 hours had 3 times the odds of a nonroutine discharge as patients treated within 48 hours (odds ratio = 3.082; P < .001). CONCLUSION: In California, patients are being treated within the recommended 48-hour time frame.

Monkey models for brain-machine interfaces: the need for maintaining diversity.

Brain-machine interfaces (BMIs) aim to help disabled patients by translating neural signals from the brain into control signals for guiding prosthetic arms, computer cursors, and other assistive devices. Animal models are central to the development of these systems and have helped enable the successful translation of the first generation of BMIs. As we move toward next-generation systems, we face the question of which animal models will aid broader patient populations and achieve even higher performance, robustness, and functionality. We review here four general types of rhesus monkey models employed in BMI research, and describe two additional, complementary models. Given the physiological diversity of neurological injury and disease, we suggest a need to maintain the current diversity of animal models and to explore additional alternatives, as each mimic different aspects of injury or disease.

Socioeconomic Trends in Deep Brain Stimulation (DBS) Surgery.

OBJECTIVE: We evaluated trends in deep brain stimulation (DBS) for the 14-year period from 1993 to 2006. MATERIALS AND METHODS: We utilized the Nationwide Inpatient Sample data base from the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. RESULTS: A total of 34,792 patients underwent DBS surgery from 1993 to 2006. There were 756 DBS cases performed in 1993 compared with 4200 DBS procedures performed in 2006. Significant increases in nationwide DBS volume coincided with regulatory approval for new indications-Parkinson's disease and dystonia, respectively. Cost of DBS surgery increased from $38,840 in 1993 to $69,329 in 2006. The majority of cases were done in metropolitan areas (97%) at large academic centers (91%) at a national bill of $291 MM. CONCLUSIONS: Future studies will need to include the socioeconomic impact of the technology on disease status, patient access, and costs as it expands to novel indications.

A socioeconomic survey of spinal cord stimulation (SCS) surgery.

OBJECTIVE: We evaluated trends in inpatient spinal cord stimulation (SCS) for the 14-year period from 1993 to 2006. MATERIALS AND METHODS: We utilized the Nationwide Inpatient Sample data base from the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. RESULTS: A total of 57,486 patients underwent inpatient placement of SCS systems from 1993 to 2006. Length of stay steadily decreased from 4.0 days in 1993 to 2.1 days in 2006. Average cost increased from $15,342 in 1993 to nearly $58,088 in 2006. The National Bill for SCS surgery in 2006 alone totaled nearly $215MM. Medicare accounted for 35% of payers, while private insurance accounted for 41% of claims. CONCLUSIONS: Given the expense of these systems, it is important to assess not only the efficacy of novel neuromodulatory interventions, but also their cost. Future studies should be designed with these important outcome measures in mind.

Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome.

Corticobasal ganglia neuronal ensembles bring automatic motor skills into voluntary control and integrate them into ongoing motor behavior. A 5% decrease in caudate (Cd) nucleus volume is the most consistent structural finding in the brain of patients with Tourette syndrome (TS), but the cellular abnormalities that underlie this decrease in volume are unclear. In this study the density of different types of interneurons and medium spiny neurons (MSNs) in the striatum was assessed in the postmortem brains of 5 TS subjects as compared with normal controls (NC) by unbiased stereological analyses. TS patients demonstrated a 50%-60% decrease of both parvalbumin (PV)+ and choline acetyltransferase (ChAT)+ cholinergic interneurons in the Cd and the putamen (Pt). Cholinergic interneurons were decreased in TS patients in the associative and sensorimotor regions but not in the limbic regions of the striatum, such that the normal gradient in density of cholinergic cells (highest in associative regions, intermediate in sensorimotor and lowest in limbic regions) was abolished. No significant difference was present in the densities of medium-sized calretinin (CR)+ interneurons, MSNs, and total neurons. The selective deficit of PV+ and cholinergic striatal interneurons in TS subjects may result in an impaired cortico/thalamic control of striatal neuron firing in TS.