Effect of neurosurgical residency programs on neurosurgical patient outcomes in a single health care system: a cohort study.

BACKGROUND: The evidence on the benefits and drawbacks of involving neurosurgical residents in the care of patients who undergo neurosurgical procedures is heterogeneous. We assessed the effect of neurosurgical residency programs on the outcomes of such patients in a large single-payer public health care system. METHODS: Ten population-based cohorts of adult patients in Ontario who received neurosurgical care from 2013 to 2017 were identified on the basis of procedural codes, and the cohorts were followed in administrative health data sources. Patient outcomes by the status of the treating hospital (with or without a neurosurgical residency program) within each cohort were compared with models adjusted for a priori confounders and with adjusted multilevel models (MLMs) to also account for hospital-level factors. RESULTS: A total of 46 608 neurosurgical procedures were included. Operative time was 8%-30% longer in hospitals with neurosurgical residency programs in 9 out of 10 cohorts. Thirty-day mortality was lower in hospitals with neurosurgical residency programs for aneurysm repair (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.20-0.44), cerebrospinal fluid shunting (OR 0.52, 95% CI 0.34-0.79), intracerebral hemorrhage evacuation (OR 0.66, 95% CI 0.52-0.84), and posterior lumbar decompression (OR 0.32, 95% CI 0.15-0.65) in adjusted models. The mortality rates remained significantly different only for aneurysm repair (OR 0.19, 95% CI 0.05-0.69) and cerebrospinal shunting (OR 0.42, 95% CI 0.21-0.85) in MLMs. Length of stay was mostly shorter in hospitals with neurosurgical residents, but this finding did not persist in MLMs. Thirty-day reoperation rates did not differ between hospital types in MLMs. For 30-day readmission rates, only extracerebral hematoma decompression was significant in MLMs (OR 1.41, 95% CI 1.07-1.87). CONCLUSION: Hospitals with neurosurgical residents had longer operative times with similar to better outcomes. Most, but not all, of the differences between hospitals with and without residency programs were explained by hospital-level variables rather than direct effects of residents.

Giant sequoia (Sequoiadendron giganteum) in the UK: carbon storage potential and growth rates.

Giant sequoias (Sequoiadendron giganteum) are some of the UK's largest trees, despite only being introduced in the mid-nineteenth century. There are an estimated half a million giant sequoias and closely related coastal redwoods (Sequoia sempervirens) in the UK. Given the recent interest in planting more trees, partly due to their carbon sequestration potential and also their undoubted public appeal, an understanding of their growth capability is important. However, little is known about their growth and carbon uptake under UK conditions. Here, we focus on S. giganteum and use three-dimensional terrestrial laser scanning to perform detailed structural measurements of 97 individuals at three sites covering a range of different conditions, to estimate aboveground biomass (AGB) and annual biomass accumulation rates. We show that UK-grown S. giganteum can sequester carbon at a rate of 85 kg yr-1, varying with climate, management and age. We develop new UK-specific allometric models for S. giganteum that fit the observed AGB with r 2 > 0.93 and bias < 2% and can be used to estimate S. giganteum biomass more generally. This study provides the first estimate of the growth and carbon sequestration of UK open-grown S. giganteum and provides a baseline for estimating their longer-term carbon sequestration capacity.

Role of Rostral Superior Colliculus in Gaze Stabilization during Visual Fixation.

Visual fixation (i.e., holding gaze on a specific visual object or location of interest) has been shown to be influenced by activity in the rostral pole of the intermediate layers of the superior colliculus (SCi)-a sensory-motor integration nucleus in the midbrain involved in visual fixation and saccadic eye movement generation. Neurons in the rostral SCi discharge tonically during visual fixation and pause during saccades to locations beyond their foveal visual-sensory or saccadic-motor response fields. Injection of muscimol to deactivate rostral SCi neurons also leads to an increase in fixation instability. However, the precise role of rostral SCi activity for controlling visual fixation has not been established and is actively debated. Here, we address whether this activity reflects signals related to task demands (i.e., maintaining visual fixation) or foveal visual stimulus properties. Two non-human primates performed an oculomotor task that required fixation of a central fixation point (FP) of varying luminance at the start of each trial. During this fixation period, we measured fixational saccades (≤ 2° of the FP, including microsaccades) and fixation-error saccades (> 2° from the FP) in combination with activity from the rostral SCi. Fixation of the lowest FP luminance increased the latency (onset time relative to initial FP foveation) for both fixational and fixation-error saccades. Fifty percent of the rostral SCi neurons exhibited activity that opposed the change in FP luminance and correlated with delayed fixational saccades and increased fixation-error saccades. Twenty-two percent of rostral SCi neurons exhibited activity that followed the change in FP luminance and correlated with earlier fixational saccades and decreased fixation-error saccades. This suggests the rostral SCi contains both sensory-driven and task-related motor signals related to foveal sensory stimuli and visual fixation. This evidence supports a role for the rostral SCi in gaze stabilization and can help inform artificial computational models of vision.

Dynamics of seizure termination in a non-human primate kindling model of mesial temporal lobe epilepsy.

Epilepsy is characterized by recurrent, unprovoked seizures which involve transient neuronal hyperexcitability or hypersynchrony. Focal seizures with impaired awareness (FIAS) are commonly related to mesial temporal lobe epilepsy (mTLE) with hippocampal sclerosis and potentially status epilepticus. How seizures terminate spontaneously remains an unanswered question fundamental to epileptology. To study seizure termination, we induced FIAS in a nonhuman primate (NHP) model with electrical kindling. Kindling stimulation was delivered to the basolateral amygdala once weekly for 30 weeks. Chronic linear microelectrode arrays were implanted in NHP mesial temporal lobe targets: the hippocampus, amygdala and entorhinal cortex. Daily electrophysiologic recordings were obtained from all targets before, during and after stimulation to monitor changes to local field potential activity. We detect prominent changes in electrophysiologic dynamics before after-discharge (AD; subclinical, electrographic seizures which begin after a stimulus) self-termination. Specifically, at seizure termination the power of the extra-focal theta rhythm increased, and the theta phase was shown to couple with the gamma rhythm within the seizure focus. The electrical current threshold for eliciting an after-discharge decreased from >700µA to 15µA. The refractory period, which prevents the induction of seizure events at threshold, was initially 3 minutes in duration. At 30 weeks after FIAS induction the refractory period increased to over 5 minutes in duration. Understanding the electrophysiologic dynamics that reflect endogenous seizure termination mechanisms may be a valuable consideration for refining intervention strategies for treatment of epilepsy. Clinical Relevance- Our findings provide further electrophysiologic description of the endogenous mechanisms behind seizure termination in a healthy brain. This work specifically highlights the importance of considering targets outside the epileptogenic zone for therapeutic intervention.

Systemic D1-R and D2-R antagonists in non-human primates differentially impact learning and memory while impairing motivation and motor performance.

Dopamine (DA) modulates cognition in part via differential activation of D1 and D2 receptors within the striatum and prefrontal cortex, yet evidence for cognitive impairments stemming from DA blockade or deficiency is inconsistent. Given the predominance of D1 over D2 receptors (R) in the prefrontal cortex of primates, D1-R blockade should more strongly influence frontal executive function (including working memory), while D2-R blockade should impair processes more strongly associated with the dorsal striatum (including cognitive flexibility, and learning). To test how systemic DA blockade disrupts cognition, we administered D1-R and D2-R like antagonists to healthy monkeys while they performed a series of cognitive tasks. Two selective DA receptor antagonist drugs (SCH-23390 hydrochloride: D1/D5-R antagonist; or Eticlopride hydrochloride: D2/D3-R antagonist) or placebo (0.9% saline) were systemically administered. Four tasks were used: (1) 'visually guided reaching', to test response time and accuracy, (2) 'reversal learning', to test association learning and attention, (3) 'self-ordered sequential search' to test spatial working memory, and (4) 'delayed match to sample' to test object working memory. Increased reach response times and decreased motivation to work for liquid reward was observed with both the D1/D5-R and D2/D3-R antagonists at the maximum dosages that still enabled task performance. The D2/D3-R antagonist impaired performance in the reversal learning task, while object and spatial working memory performance was not consistently affected in the tested tasks for either drug. These results are consistent with the theory that systemic D2/D3-R antagonists preferentially influence striatum processes (cognitive flexibility) while systemic D1/D5-R administration is less detrimental to frontal executive function.

Reverse Visually Guided Reaching in Patients with Parkinson's Disease.

In addition to motor symptoms such as difficulty in movement initiation and bradykinesia, patients with Parkinson's disease (PD) display nonmotor executive cognitive dysfunction with deficits in inhibitory control. Preoperative psychological assessments are used to screen for impulsivity that may be worsened by deep brain stimulation (DBS) of the subthalamic nucleus (STN). However, it is unclear whether anti-Parkinson's therapy, such as dopamine replacement therapy (DRT) or DBS, which has beneficial effects on motor function, adversely affects inhibitory control or its domains. The detrimental effects of STN-DBS are more apparent when tasks test the inhibition of habitual prepotent responses or involve complex cognitive loads. Our goal was to use a reverse visually guided reaching (RVGR) task, a hand-based version of the antisaccade task, to simultaneously measure motor performance and response inhibition in subjects with PD. We recruited 55 healthy control subjects, 26 PD subjects receiving treatment with DRTs, and 7 PD subjects receiving treatment with STN-DBS and DRTs. In the RVGR task, a cursor moved opposite to the subject's hand movement. This was compared to visually guided reaching (VGR) where the cursor moved in the same direction as the subject's hand movement. Reaction time, mean speed, and direction errors (in RVGR) were assessed. Reaction times were longer, and mean speeds were slower during RVGR compared to VGR in all three groups but worse in untreated subjects with PD. Treatment with DRTs, DBS, or DBS + DRT improved the reaction time and speed on the RVGR task to a greater extent than VGR. Additionally, DBS or DBS + DRT demonstrated an increase in direction errors, which was correlated with decreased reaction time. These results show that the RVGR task quantifies the benefit of STN-DBS on bradykinesia and the concomitant reduction of proactive inhibitory control. The RVGR task has the potential to be used to rapidly screen for preoperative deficits in inhibitory control and to titrate STN-DBS, to maximize the therapeutic benefits on movement, and minimize impaired inhibitory control.

Distinct sensory- and goal-related signals underlie the gap effect in the superior colliculus.

The removal of a fixation point (FP) prior to the appearance of a saccade target (gap effect) influences pre-motor circuits and reduces saccadic reaction time (SRT). Saccade preparation signals underlying the gap effect have been observed within the intermediate layers of the superior colliculus (SCi). Neurons in the caudal SCi, coding a target location, increase their activity during the gap, while neurons in the rostral SCi, with tonic activity related to visual fixation, decrease activity. However, the gap effect confounds two factors: (1) a goal-driven temporal warning component (upcoming saccade target appearance) and (2) a stimulus-driven sensory component (FP disappearance). These factors combine to reduce SRT and elicit pre-target responses in the SCi. To dissociate warning and sensory effects, we altered the luminance of the FP during the gap period (renamed warning period) such that it could increase, decrease, or stay the same. Faster SRTs resulted with larger decrements in FP luminance. Different categories of SCi warning period activity were evaluated: (1) always increasing or decreasing or (2) sensory-linked responses to changes in FP luminance. In the caudal SCi (at the location coding the target), all activity correlated negatively with SRT (i.e., saccade facilitation), and two categories of activity were observed (always increasing or opposing FP luminance changes). In the rostral SCi, four categories of activity were observed: activity that increased or followed the change in FP luminance correlated positively with SRT (i.e., saccade inhibition), while activity that decreased or opposed FP luminance changes correlated negatively with SRT. Such SCi activity reflected both goal-driven saccade preparation signals and FP sensory properties.

The Dostoyevsky effect: epileptogenesis and memory enhancement after kindling stimulation in the primate basolateral amygdala.

Kindling is an electrical stimulation technique used to lower the threshold for epileptogenic activity in the brain. It can also be used as a tool to investigate electrophysiologic alterations that occur as a result of seizures. Epileptiform activity, like seizures and after-discharges (AD; evoked epileptiform activity), commonly cause memory impairment but rarely, can elicit vivid memory retrieval. We kindled the basolateral amygdala of a non-human primate (NHP) once weekly and had him perform a spatial memory task in a 3D virtual environment before, during and after kindling. AD were associated with an initial average performance increase of 46.6%. The enhancement which followed AD persisted up to 2 days. Memory task performance enhancement was accompanied by significant resetting of hippocampal theta oscillations and robust hippocampal potentiation as measured by field evoked potentials. However, neither lasted throughout the duration of performance enhancement. Sharp-wave ripples (SWR), a local field event that supports episodic memory, were generated more often throughout the period of enhancement. SWR rate increased from 14.38 SWR per min before kindling to 24.22 SWR per min after kindling on average. Our results show that kindling can be associated with improved memory. Memory function appears to depend on the particular induction circuit and the resultant excitation/inhibition ratio of the mesial temporal lobe network. Investigating the electrophysiologic underpinnings of this observed memory enhancement is an important step towards understanding the network alterations that occur after seizures and stimulation.Clinical Relevance- Our findings provide new insight into the effects of kindling stimulation in the primate brain. Kindling can cause increase MTL synchrony and the frequency of spontaneous seizures in a primate. This work highlights important considerations for therapeutic deep brain stimulation.

Retrospective cell lineage reconstruction in humans by using short tandem repeats.

Cell lineage analysis aims to uncover the developmental history of an organism back to its cell of origin. Recently, novel in vivo methods utilizing genome editing enabled important insights into the cell lineages of animals. In contrast, human cell lineage remains restricted to retrospective approaches, which still lack resolution and cost-efficient solutions. Here, we demonstrate a scalable platform based on short tandem repeats targeted by duplex molecular inversion probes. With this human cell lineage tracing method, we accurately reproduced a known lineage of DU145 cells and reconstructed lineages of healthy and metastatic single cells from a melanoma patient who matched the anatomical reference while adding further refinements. This platform allowed us to faithfully recapitulate lineages of developmental tissue formation in healthy cells. In summary, our lineage discovery platform can profile informative somatic mutations efficiently and provides solid lineage reconstructions even in challenging low-mutation-rate healthy single cells.

Muting, not fragmentation, of functional brain networks under general anesthesia.

Changes in resting-state functional connectivity (rs-FC) under general anesthesia have been widely studied with the goal of identifying neural signatures of consciousness. This work has commonly revealed an apparent fragmentation of whole-brain network structure during unconsciousness, which has been interpreted as reflecting a break-down in connectivity and a disruption of the brain's ability to integrate information. Here we show, by studying rs-FC under varying depths of isoflurane-induced anesthesia in nonhuman primates, that this apparent fragmentation, rather than reflecting an actual change in network structure, can be simply explained as the result of a global reduction in FC. Specifically, by comparing the actual FC data to surrogate data sets that we derived to test competing hypotheses of how FC changes as a function of dose, we found that increases in whole-brain modularity and the number of network communities - considered hallmarks of fragmentation - are artifacts of constructing FC networks by thresholding based on correlation magnitude. Taken together, our findings suggest that deepening levels of unconsciousness are instead associated with the increasingly muted expression of functional networks, an observation that constrains current interpretations as to how anesthesia-induced FC changes map onto existing neurobiological theories of consciousness.

The effect of lumbar puncture on the neurodegeneration biomarker neurofilament light in macaque monkeys.

INTRODUCTION: Neurofilament light (NFL) in cerebrospinal fluid (CSF) is elevated in neurodegenerative disease patients, and may track disease progression and treatment. Macaque monkeys are emerging as important translational models of neurodegeneration, and NFL may be a useful biomarker. METHODS: To determine the influence of a previous lumbar puncture (LP) on NFL, we collected CSF at multiple time points in macaque monkeys via LP or cisterna magna puncture. NFL, amyloid beta (Aß40, Aß42), and tau (tTau, pTau) in CSF were measured by standard enzyme-linked immunosorbent assay and multiplex. RESULTS: NFL was significantly elevated at 14 to 23 days after an LP (median increase: 162%). Aß and tau biomarkers remained stable. NFL peaked and decayed over 1 to 2 months after LP. NFL was not elevated after cisterna magna puncture. DISCUSSION: Results suggest damage of the cauda equina during LP may increase NFL. Caution should be taken in interpreting NFL concentration in studies in which repeat LPs are performed.

The transition between active and inactive conformations of Abl kinase studied by rock climbing and Milestoning.

BACKGROUND: Kinases are a family of enzymes that catalyze the transfer of the ɤ-phosphate group from ATP to a protein's residue. Malfunctioning kinases are involved in many health problems such as cardiovascular diseases, diabetes, and cancer. Kinases transitions between multiple conformations of inactive to active forms attracted considerable interest. METHOD: A reaction coordinate is computed for the transition between the active to inactive conformation in Abl kinase with a focus on the DFG-in to DFG-out flip. The method of Rock Climbing is used to construct a path locally, which is subsequently optimized using a functional of the entire path. The discrete coordinate sets along the reaction path are used in a Milestoning calculation of the free energy landscape and the rate of the transition. RESULTS: The estimated transition times are between a few milliseconds and seconds, consistent with simulations of the kinetics and with indirect experimental data. The activation requires the transient dissociation of the salt bridge between Lys271 and Glu286. The salt bridge reforms once the DFG motif is stabilized by a locked conformation of Phe382. About ten residues are identified that contribute significantly to the process and are included as part of the reaction space. CONCLUSIONS: The transition from DFG-in to DFG-out in Abl kinase was simulated using atomic resolution of a fully solvated protein yielding detailed description of the kinetics and the mechanism of the DFG flip. The results are consistent with other computational methods that simulate the kinetics and with some indirect experimental measurements. GENERAL SIGNIFICANCE: The activation of kinases includes a conformational transition of the DFG motif that is important for enzyme activity but is not accessible to conventional Molecular Dynamics. We propose a detailed mechanism for the transition, at a timescale longer than conventional MD, using a combination of reaction path and Milestoning algorithms. The mechanism includes local structural adjustments near the binding site as well as collective interactions with more remote residues.

Pharmacological interventions for the prevention of acute postoperative pain in adults following brain surgery.

BACKGROUND: Pain following brain surgery can compromise recovery. Several pharmacological interventions have been used to prevent pain after craniotomy; however, there is currently a lack of evidence regarding which interventions are most effective. OBJECTIVES: The objectives are to assess the effectiveness of pharmacological interventions for prevention of acute postoperative pain in adults undergoing brain surgery; compare them in terms of additional analgesic requirements, incidence of chronic headache, sedative effects, length of hospital stay and adverse events; and determine whether these characteristics are different for certain subgroups. SEARCH METHODS: We searched MEDLINE, Embase, CINAHL, CENTRAL, Web of Science and two trial registries together with reference checking and citation searching on 28th of November 2018. SELECTION CRITERIA: We included blinded and non-blinded, randomized controlled trials evaluating pharmacological interventions for the prevention of acute postoperative pain in adults undergoing neurosurgery, which had at least one validated pain score outcome measure. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We calculated mean differences for the primary outcome of pain intensity; any pain scores reported on a 0 to 100 scale were converted to a 0 to 10 scale. MAIN RESULTS: We included 42 completed studies (3548 participants) and identified one ongoing study. Nonsteroidal anti-inflammatories (NSAIDs) Nonsteroidal anti-inflammatories (NSAIDs) reduce pain up to 24 hours (0 to 6 hours, MD -1.16, 95% CI -1.57 to -0.76; 12 hours, MD -0.62, 95% CI -1.11 to -0.14; 24 hours, MD -0.66, 95% CI -1.18 to -0.13; 6 studies, 742 participants; all high-quality evidence). Results for other outcomes were imprecise (additional analgesic requirements: MD 1.29 mg, 95% CI -5.0 to 2.46, 4 studies, 265 participants; nausea and vomiting RR 1.34, 95% CI 0.30 to 5.94, 2 studies, 345 participants; both low-quality evidence). Dexmedetomidine reduces pain up to 12 hours (0 to 6 hours, MD -0.89, 95% CI -1.27 to -0.51, moderate-quality evidence; 12 hours, MD -0.81, 95% CI -1.21 to -0.42, low-quality evidence). It did not show efficacy at 24 hours (MD -0.08, 95% CI -0.32 to 0.16; 2 studies, 128 participants; low-quality evidence). Dexmedetomidine may decrease additional analgesic requirements (MD -21.36 mg, 95% CI -34.63 to -8.1 mg, 2 studies, 128 participants, low-quality evidence). Results for other outcomes were imprecise (nausea and vomiting RR -0.43, 95% CI 0.06 to 3.08, 3 studies, 261 participants; hypotension RR 0.5, 95% CI 0.05 to 5.28, 3 studies, 184 participants; both low-quality evidence). Scalp blocks may reduce pain up to 48 hours (0 to 6 hours, MD -0.98, 95% CI -1.66 to -0.3, 10 studies, 414 participants; 12 hours, MD -0.95, 95% CI -1.53 to -0.37, 8 studies, 294 participants; 24 hours, MD -0.78, 95% CI -1.52 to -0.05, 9 studies, 433 participants, all low-quality evidence; 48 hours, MD -1.34, 95% CI -2.57 to -0.11, 4 studies, 135 participants, very low-quality evidence. When studies with high risk of bias were excluded, significance remained at 12 hours only. Scalp blocks may decrease additional analgesia requirements (SMD -1.11, 95% CI -1.97 to -0.25, 7 studies, 314 participants). Results for other outcomes were imprecise (nausea and vomiting RR 0.66, 95% CI 0.33 to 1.32, 4 studies, 165 participants, very low-quality evidence). Scalp Infiltration may reduce pain postoperatively but efficacy was inconsistent, with a significant effect at 12 and 48 hours only (12 hours, MD -0.71, 95% CI -1.34 to -0.08, 7 studies, 309 participants, low-quality evidence; 48 hours, MD - 1.09, 95% CI -2.13 to - 0.06, 3 studies, 128 participants, moderate-quality evidence). No benefit was observed at other times (0 to 6 hours, MD -0.64, 95% CI -1.28 to -0.00, 9 studies, 475 participants, moderate-quality evidence; 24 hours, MD -0.39, 95% CI -1.06 to 0.27,6 studies, 260 participants, low-quality evidence. Scalp infiltration may reduce additional analgesia requirements MD -9.56 mg, 95% CI -15.64 to -3.49, 6 studies, 345 participants, very low-quality evidence). When studies with high risk of bias were excluded, scalp infiltration lost the pain benefit at 12 hours and effects on additional analgesia requirements, but retained the pain-reducing benefit at 48 hours (MD -0.56, 95% CI -1.20 to -0.32, 2 studies, 100 participants, very low-quality evidence). Results for other outcomes were imprecise (nausea and vomiting, RR 0.74, 95% CI 0.48 to 1.41, 4 studies, 318 participants, low-quality evidence). Pregabalin or gabapentin may reduce pain up to 6 hours (2 studies, 202 participants), MD -1.15,95% CI -1.66 to -0.6, 2 studies, 202 participants, low-quality evidence). One study examined analgesic efficacy at 12 hours showing significant benefit. No analgesia efficacy was shown at later times (24 hours, MD -0.29, 95% CI -0.78 to -0.19; 48 hours, MD - 0.06, 95% CI -0.86 to 0.77, 2 studies, 202 participants, low-quality evidence). Additional analgesia requirements were not significantly less (MD -0.37 (95% CI -1.10 to 0.35, 3 studies, 234 participants, low-quality evidence). Risk of nausea and vomiting was significantly reduced (RR 0.51, 95% CI 0.29 to 0.89, 3 studies, 273 participants, low-quality evidence). Results for other outcomes were imprecise (additional analgesia requirements: MD -0.37, 95% CI -1.10 to 0.35, 3 studies, 234 participants, low-quality evidence). Acetaminophen did not show analgesic benefit (0 to 6 hours, MD -0.35, 95% CI -1.00 to 0.30; 12 hours, MD -0.51, 95% CI -1.04 to 0.03, 3 studies, 332 participants, moderate-quality evidence; 24 hours, MD -0.34, 95% CI -1.20 to 0.52, 4 studies, 439 participants, high-quality evidence). Results for other outcomes remained imprecise (additional analgesia requirements, MD 0.07, 95% CI -0.86 to 0.99, 4 studies, 459 participants, high-quality evidence; length of hospitalizations, MD -3.71, 95% CI -14.12 to 6.7, 2 studies, 335 participants, moderate-quality evidence). AUTHORS' CONCLUSIONS: There is high-quality evidence that NSAIDs reduce pain up to 24 hours postoperatively. The evidence for reductions in pain with dexmedetomidine, pregabalin or gabapentin, scalp blocks, and scalp infiltration is less certain and of very low to moderate quality. There is low-quality evidence that scalp blocks and dexmedetomidine may reduce additional analgesics requirements. There is low-quality evidence that gabapentin or pregabalin may decrease nausea and vomiting, with the caveat that the total number of events for this comparison was low.

Integrated robotics platform with haptic control differentiates subjects with Parkinson's disease from controls and quantifies the motor effects of levodopa.

BACKGROUND: The use of integrated robotic technology to quantify the spectrum of motor symptoms of Parkinson's Disease (PD) has the potential to facilitate objective assessment that is independent of clinical ratings. The purpose of this study is to use the KINARM exoskeleton robot to (1) differentiate subjects with PD from controls and (2) quantify the motor effects of dopamine replacement therapies (DRTs). METHODS: Twenty-six subjects (Hoehn and Yahr mean 2.2; disease duration 0.5 to 15 years) were evaluated OFF (after > 12 h of their last dose) and ON their DRTs with the Unified Parkinson's Disease Rating Scale (UPDRS) and the KINARM exoskeleton robot. Bilateral upper extremity bradykinesia, rigidity, and postural stability were quantified using a repetitive movement task to hit moving targets, a passive stretch task, and a torque unloading task, respectively. Performance was compared against healthy age-matched controls. RESULTS: Mean hand speed was 41% slower and 25% fewer targets were hit in subjects with PD OFF medication than in controls. Receiver operating characteristic (ROC) area for hand speed was 0.94. The torque required to stop elbow movement during the passive stretch task was 34% lower in PD subjects versus controls and resulted in an ROC area of 0.91. The torque unloading task showed a maximum displacement that was 29% shorter than controls and had an ROC area of 0.71. Laterality indices for speed and end total torque were correlated to the most affected side. Hand speed laterality index had an ROC area of 0.80 against healthy controls. DRT administration resulted in a significant reduction in a cumulative score of parameter Z-scores (a measure of global performance compared to healthy controls) in subjects with clinically effective levodopa doses. The cumulative score was also correlated to UPDRS scores for the effect of DRT. CONCLUSIONS: Robotic assessment is able to objectively quantify parkinsonian symptoms of bradykinesia, rigidity and postural stability similar to the UPDRS. This integrated testing platform has the potential to aid clinicians in the management of PD and help assess the effects of novel therapies.

Acute myeloid leukemia immunopeptidome reveals HLA presentation of mutated nucleophosmin.

Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapeutic approaches. Here we sought to study the HLA Class I and II immunopeptidome of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry to evaluate for endogenous mutation-bearing HLA ligands from common shared AML mutations. We identified two endogenous, mutation-bearing HLA Class I ligands from nucleophosmin (NPM1). The ligands, AVEEVSLRK from two patient samples and C(cys)LAVEEVSL from OCI-AML3, are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous HLA ligands from mutated NPM1 supports future studies evaluating immunotherapeutic approaches against this shared target, for this subset of patients with AML.

Refinements of Equipment and Methodology to Reduce Risk during Pole-guided Chair Transfer of Nonhuman Primates.

Neurophysiologic studies of NHP commonly involve their transfer from a housing enclosure to a laboratory by using a mobile chair. This transfer should be performed in a manner that is safe and minimizes stress for both animal and handler. The risk of harm associated with attempting to transfer these animals is increased when they are mature and naïve. We have modified previous chair designs and transfer methodologies to reduce this risk by maintaining a constant barrier between NHP and handler while providing control to the handler to facilitate chairing. Chair modifications were built inhouse, and a commercial, hydraulic lift table was used to dock the primate chair to home cages of different heights. The docking chair method was used with 8 adult, male rhesus macaques. A graduate student transferred the animals without complications. These modifications did not compromise existing features of the chair, they did not require training time in addition to that for the standard chairing method in our facility, and they improved safety. These refinements to a commonly used chair and transfer methodology support rapid habituation, safe transfer and reduced stress for both animal and handler. The refinements we describe mitigate the potential risk of harm during NHP transfers and thus advance animal welfare.

Microstimulation-induced inhibition of thalamic reticular nucleus in non-human primates.

The thalamic reticular nucleus (TRN) modulates activity in the thalamus and controls excitatory input from corticothalamic and thalamocortical glutamatergic projections. It is made up of GABAergic neurons which project topographically to the thalamus. The TRN also receives inhibitory projections from the globus pallidus and the substantia nigra pars reticulata. Photostimulation of the TRN results in local inhibition in rat slice preparations but the effects of local stimulation in vivo are not known. This study aimed to characterize stimulation-evoked responses in the TRN of non-human primates (NHPs). Microelectrodes were inserted into the TRN and neurons were stimulated at 5, 10, 15, and 20 µA using 0.5 s trains at 100 Hz and the subsequent response was recorded from the same electrode. Stimulation in surrounding nuclei and the internal capsule was used for mapping the anatomical borders of the TRN. Stimulation as low as 10 µA resulted in predominantly inhibition, recorded in both single units and background unit activity (BUA). The duration of inhibition (~ 1-3 s) increased with increasing stimulation amplitude and was significantly increased in BUA when single units were present. At 20 µA of current, 93% of the single units (41/44) and 92% of BUA sites (67/73) were inhibited. Therefore, microstimulation of the NHP TRN with low currents results in current-dependent inhibition of single units and BUA. This finding may be useful to further aid in localization of deep thalamic and subthalamic nuclei during brain surgery.

Differential effects of D1 and D2 dopamine agonists on memory, motivation, learning and response time in non-human primates.

Dopamine (DA) plays a critical role in cognition, motivation and information processing. DA action has been shown to both improve and/or impair cognition across different receptor types, species, subjects and tasks. This complex relationship has been described as an inverted U-shaped function and may be due to the differential effects of DA receptor activation in the striatum and prefrontal cortex. We have investigated the effects of selective DA agonists on cognitive performance in healthy monkeys using a touch screen running tasks from the CAmbridge Neuropsychological Test Automated Battery (CANTAB). One of two DA agonist drugs or placebo was administered prior to each daily CANTAB session: Dihydrexidine hydrochloride (selective D1 agonist, 0.4-0.9 mg/kg), or sumanirole maleate (selective D2 agonist 0.05-0.3 mg/kg). Three CANTAB tasks were tested: (a) "self-ordered sequential search task" which tested spatial working memory, (b) "reversal learning task," which tested association learning, cognitive flexibility and attention and (c) "visually guided reaching task," which tested reaction time and accuracy. At high dosages, the D2 agonist improved spatial working memory performance, while impairing reversal learning and slowing reach response latency. No consistent cognitive effects were observed with the D1 agonist across the dosages tested. A significant decrease in trial completion rate was observed at the higher dosages of both the D1 and D2 agonists which were consistent with decreased motivation. These results are consistent with task-specific effects of a D2 agonist as well as dose specific insensitivities of a D1 agonist on cognitive and motor behaviors in a healthy monkey.

Evidence for a task-dependent switch in subthalamo-nigral basal ganglia signaling.

Basal ganglia (BG) can either facilitate or inhibit movement through excitatory and inhibitory pathways; however whether these opposing signals are dynamically regulated during healthy behavior is not known. Here, we present compelling neurophysiological evidence from three complimentary experiments in non-human primates, indicating task-specific changes in tonic BG pathway weightings during saccade behavior with different cognitive demands. First, simultaneous local field potential recording in the subthalamic nucleus (STN; BG input) and substantia nigra pars reticulata (SNr; BG output) reveals task-dependent shifts in subthalamo-nigral signals. Second, unilateral electrical stimulation of the STN, SNr, and caudate nucleus results in strikingly different saccade directionality and latency biases across the BG. Third, a simple artificial neural network representing canonical BG signaling pathways suggests that pathway weightings can be altered by cortico-BG input activation. Overall, inhibitory pathways (striato-pallidal-subthalamo-nigral) dominate during goal-driven behavior with instructed rewards, while facilitatory pathways (striato-nigral and subthalamo-pallidal-nigral) dominate during unconstrained (free reward) conditions.

Superior colliculus encodes visual saliency before the primary visual cortex.

Models of visual attention postulate the existence of a bottom-up saliency map that is formed early in the visual processing stream. Although studies have reported evidence of a saliency map in various cortical brain areas, determining the contribution of phylogenetically older pathways is crucial to understanding its origin. Here, we compared saliency coding from neurons in two early gateways into the visual system: the primary visual cortex (V1) and the evolutionarily older superior colliculus (SC). We found that, while the response latency to visual stimulus onset was earlier for V1 neurons than superior colliculus superficial visual-layer neurons (SCs), the saliency representation emerged earlier in SCs than in V1. Because the dominant input to the SCs arises from V1, these relative timings are consistent with the hypothesis that SCs neurons pool the inputs from multiple V1 neurons to form a feature-agnostic saliency map, which may then be relayed to other brain areas.