Paul Kalanithi

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

A way to modulate reward-seeking Which brain regions are causally involved in reward-related behavior? Ferenczi et al. combined focal, cell type-specific, optogenetic manipulations with brain imaging, behavioral testing, and in vivo electrophysiology (see the Perspective by Robbins). Stimulation of midbrain dopamine neurons increased activity in a brain region called the striatum and was correlated with reward-seeking across individual animals. However, elevated excitability of an area called the medial prefrontal cortex reduced both striatal responses to the stimulation of dopamine neurons and the behavioral drive to seek the stimulation of dopamine neurons. Finally, modulating the excitability of medial prefrontal cortex pyramidal neurons drove changes in neural circuit synchrony, as well as corresponding anhedonic behavior. These observations resemble imaging and clinical phenotypes observed in human depression, addiction, and schizophrenia. Science, this issue p. 10.1126/science.aac9698; see also p. 10.1126/science.aad9698 Optogenetic and brain imaging approaches reveal a causal brainwide dynamical mechanism for the hedonic-anhedonic transition. [Also see Perspective by Robbins] INTRODUCTION The drive to seek and experience reward is conserved across species and, in mammals, involves interactions between subcortical dopaminergic systems and limbic structures such as the striatum. Impairment of this process, observed across a number of psychiatric conditions, is the clinical symptom of anhedonia (loss of enjoyment). The neural mechanisms underlying anhedonia are unknown but could result from abnormal interactions between cortical and subcortical reward circuits. We sought to test the hypothesis that elevated medial prefrontal cortex (mPFC) excitability (a clinical feature associated with anhedonia) exerts suppressive control over the interactions between two distant subcortical regions: the dopaminergic midbrain and the striatum. RATIONALE Clinical imaging studies have detected elevated activity in the mPFC in human patients with depression, and treatment is associated with normalization of this overactivity and improvement of anhedonic symptoms. Additionally, human studies have identified areas of the brain that respond to reward anticipation and experience, and this response can be suppressed in psychiatric disease. However, the source of this reward signal and the mechanisms underlying its modulation have not been causally demonstrated. We have integrated a diverse set of chronic and acute optogenetic tools with functional magnetic resonance imaging (fMRI) to provide a bridge between the causal, cellular specificity of rodent optogenetics and the brainwide observations that characterize human neuroimaging, with the goal of locally manipulating and globally visualizing neural activity to understand the regulation of reward-seeking behavior. RESULTS We demonstrate that stimulation of midbrain dopamine neurons drives both striatal fMRI blood oxygen level–dependent (BOLD) activity and reward-seeking behavior, and we show that these are correlated across individuals. We additionally find that silencing of dopamine neurons suppresses activity in the striatum, as well as in other brain regions (such as the hypothalamus), and drives avoidance behavior. Having established this bidirectional control of reward-seeking behavior, we then tested for perturbation of this circuitry via elevation of mPFC excitability. We observed suppression of striatal responses to dopamine, as well as the behavioral drive to seek out dopamine neuron stimulation and other natural rewarding stimuli. Finally, we demonstrate that stably elevated mPFC excitability synchronizes corticolimbic BOLD and electrophysiological activity, which in turn can predict anhedonic behavior in individual animals. CONCLUSION Our findings from experiments involving local cell-specific control, simultaneously with global unbiased observation of neural activity, reveal that the mPFC exerts top-down control over midbrain dopaminergic interactions with the striatum and that, when elevated, activity in the mPFC can suppress natural reward-related behavior. Furthermore, we observe that cortical-subcortical neural dynamics work in concert to regulate reward processing. All of these findings have implications for our understanding of natural reward-related physiology and behavior, as well as the pathogenesis of anhedonia. Reward-related signaling between the dopaminergic midbrain and the striatum is under suppressive control by the mPFC. Optogenetic fMRI was used to locally manipulate and globally visualize brainwide neural activity related to reward. Habituated rats were scanned in the awake state (top photographs). We establish that striatal BOLD activity is increased by optogenetic stimulation of dopamine neurons and decreased by optogenetic neural silencing. We demonstrate that focally elevated mPFC excitability suppresses reward-seeking behavior by exerting top-down control over striatal dopamine-induced activity and drives synchrony between specific corticolimbic circuits. 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.

National complication rates and disposition after posterior lumbar fusion for acquired spondylolisthesis.

Study Design. Database study using Nationwide Inpatient Sample (NIS) administrative data from 1993 to 2002. Objective. To determine rates of in-hospital complications and complex disposition for patients undergoing posterior lumbar fusion for degenerative spondylolisthesis, and the association of demographic factors. Summary of Background Data. Spondylolisthesis affects primarily elderly populations. Recent data suggests a benefit of surgical treatment for acquired lumbar spondylolisthesis. However, the risks of these procedures, and the impact of patient demographics on risk, have not been nationally quantified. Methods. Data from 66,601 patients in the NIS (1993–2002) with diagnostic and procedure codes specifying posterior lumbar fusion for acquired spondylolisthesis were included. Patients were grouped by age, sex, race, number of comorbidities, hospital size, and time period of procedure. Multivariate analysis correlated patient and hospital characteristics with complex disposition and complications. Results. Mortality rate was 0.15%. Eleven percent of patients had one or more in-hospital complications; overall complication rate was 13 per 100 operations. Hematoma/seroma (5.4 per 100) was the most common complication, followed by pulmonary (2.6), renal (1.8), and cardiac (1.2) complications. Infection and neurologic injury occurred in <1% of patients. Older patients and those with a number of comorbidities had greater rates of in-hospital complication and complex disposition. Compared to those aged 45 to 64, patients aged 65 to 84 were almost 70% more likely to have complications (OR: 1.67) and 5 times as likely to have complex disposition (OR: 5.84). Having 3 or greater comorbidities, compared to no comorbidities, was also associated with increased risk of complication (OR: 1.6) and complex disposition (OR: 2.3). Conclusion. Posterior lumbar fusion for acquired lumbar spondylolisthesis is safe. However, age and comorbidity independently increase in-hospital complications and complex disposition. These data may improve national estimates of surgical risk, patient selection, informed consent, and cost-efficacy analysis for posterior lumbar fusion operations for acquired spondylolisthesis.

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.

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 (

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

260,208 vs.

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

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.

Von Hippel-Lindau disease in pregnancy: A brief review

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.

Monkey models for brain-machine interfaces: The need for maintaining diversity

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

Is Cauda Equina Syndrome Being Treated Within the Recommended Time Frame

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.

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.

The hormonal and hemodynamic effects of pregnancy accelerate the growth of hemangioblastomas in Von Hippel-Lindau syndrome (VHL), leading to increased symptoms and risk to both the mother and fetus. A review of the literature on the treatment of VHL in pregnancy would suggest surgical intervention should be considered with worsening clinical status. Introducing this review is a description of our patient with VHL, who uniquely presented in pregnancy with a cervical hemangioblastoma.