Jacob W. Nadler

A neural representation of depth from motion parallax in macaque visual cortex

Perception of depth is a fundamental challenge for the visual system, particularly for observers moving through their environment. The brain makes use of multiple visual cues to reconstruct the three-dimensional structure of a scene. One potent cue, motion parallax, frequently arises during translation of the observer because the images of objects at different distances move across the retina with different velocities. Human psychophysical studies have demonstrated that motion parallax can be a powerful depth cue, and motion parallax seems to be heavily exploited by animal species that lack highly developed binocular vision. However, little is known about the neural mechanisms that underlie this capacity. Here we show, by using a virtual-reality system to translate macaque monkeys (Macaca mulatta) while they viewed motion parallax displays that simulated objects at different depths, that many neurons in the middle temporal area (area MT) signal the sign of depth (near versus far) from motion parallax in the absence of other depth cues. To achieve this, neurons must combine visual motion with extra-retinal (non-visual) signals related to the animal’s movement. Our findings suggest a new neural substrate for depth perception and demonstrate a robust interaction of visual and non-visual cues in area MT. Combined with previous studies that implicate area MT in depth perception based on binocular disparities, our results suggest that area MT contains a more general representation of three-dimensional space that makes use of multiple cues.

Postoperative Cognitive Dysfunction: Minding the Gaps in Our Knowledge of a Common Postoperative Complication in the Elderly.

Postoperative cognitive dysfunction (POCD) is a common complication associated with significant morbidity and mortality in elderly patients. There is much interest in and controversy about POCD, reflected partly in the increasing number of articles published on POCD recently. Recent work suggests surgery may also be associated with cognitive improvement in some patients, termed postoperative cognitive improvement (POCI). As the number of surgeries performed worldwide approaches 250 million per year, optimizing postoperative cognitive function and preventing/treating POCD are major public health issues. In this article, we review the literature on POCD and POCI, and discuss current research challenges in this area.

MT Neurons Combine Visual Motion with a Smooth Eye Movement Signal to Code Depth-Sign from Motion Parallax

The capacity to perceive depth is critical for an observer to interact with his or her surroundings. During observer movement, information about depth can be extracted from the resulting patterns of image motion on the retina (motion parallax). Without extraretinal signals related to observer movement, however, depth-sign (near versus far) from motion parallax can be ambiguous. We previously demonstrated that MT neurons combine visual motion with extraretinal signals to code depth-sign from motion parallax in the absence of other depth cues. In that study, head translations were always accompanied by compensatory tracking eye movements, allowing at least two potential sources of extraretinal input. We now show that smooth eye movement signals provide the critical extraretinal input to MT neurons for computing depth-sign from motion parallax. Our findings demonstrate a powerful modulation of MT activity by eye movements, as predicted by human studies of depth perception from motion parallax.

Joint Representation of Depth from Motion Parallax and Binocular Disparity Cues in Macaque Area MT

Perception of depth is based on a variety of cues, with binocular disparity and motion parallax generally providing more precise depth information than pictorial cues. Much is known about how neurons in visual cortex represent depth from binocular disparity or motion parallax, but little is known about the joint neural representation of these depth cues. We recently described neurons in the middle temporal (MT) area that signal depth sign (near vs far) from motion parallax; here, we examine whether and how these neurons also signal depth from binocular disparity. We find that most MT neurons in rhesus monkeys (Macaca Mulatta) are selective for depth sign based on both disparity and motion parallax cues. However, the depth-sign preferences (near or far) are not always aligned: 56% of MT neurons have matched depth-sign preferences (“congruent” cells) whereas the remaining 44% of neurons prefer near depth from motion parallax and far depth from disparity, or vice versa (“opposite” cells). For congruent cells, depth-sign selectivity increases when disparity cues are added to motion parallax, but this enhancement does not occur for opposite cells. This suggests that congruent cells might contribute to perceptual integration of depth cues. We also found that neurons are clustered in MT according to their depth tuning based on motion parallax, similar to the known clustering of MT neurons for binocular disparity. Together, these findings suggest that area MT is involved in constructing a representation of 3D scene structure that takes advantage of multiple depth cues available to mobile observers.

The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial

BACKGROUND Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimers disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). OBJECTIVE We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. METHODS Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. RESULTS The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aβ levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations). CONCLUSION Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

Anesthetic neuroprotection: antecedents and an appraisal of preclinical and clinical data quality.

Anesthetics have been studied for nearly fifty years as potential neuroprotective compounds in both perioperative and resuscitation medicine. Although anesthetics present pharmacologic properties consistent with preservation of brain viability in the context of an ischemic insult, no anesthetic has been proven efficacious for neuroprotection in humans. After such effort, it could be concluded that anesthetics are simply not neuroprotective in humans. Moreover, pharmacologic neuroprotection with non-anesthetic drugs has also repeatedly failed to be demonstrated in human acute brain injury. Recent focus has been on rectification of promising preclinical neuroprotection data and subsequent failed clinical trials. This has led to consensus guidelines for the process of transferring purported therapeutics from bench to bedside. In this review we first examined the history of anesthetic neuroprotection research. Then, a systematic review was performed to identify major clinical trials of anesthetic neuroprotection. Both the preclinical neuroprotection portfolio cited to justify a clinical trial and the design and conduct of that clinical trial were evaluated using modern standards that include the Stroke Therapy Academic Industry Roundtable (STAIR) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. In publications intended to define anesthetic neuroprotection, we found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. Hence, using current translational research standards, it was not possible to conclude from existing data whether anesthetics ameliorate perioperative ischemic brain injury. Incorporation of advances in translational neuroprotection research conduct may provide a basis for more definitive and potentially successful clinical trials of anesthetics as neuroprotectants.

Preventing delirium after cardiothoracic surgery: provocative but preliminary evidence for bispectral index monitoring.

April 2014 • Volume 118 • Number 4 Copyright

The Effect of Propofol vs. Isoflurane Anesthesia on Postoperative Changes in Cerebrospinal Fluid Cytokine Levels: Results from a Randomized Trial

Introduction Aside from direct effects on neurotransmission, inhaled and intravenous anesthetics have immunomodulatory properties. In vitro and mouse model studies suggest that propofol inhibits, while isoflurane increases, neuroinflammation. If these findings translate to humans, they could be clinically important since neuroinflammation has detrimental effects on neurocognitive function in numerous disease states. Materials and methods To examine whether propofol and isoflurane differentially modulate neuroinflammation in humans, cytokines were measured in a secondary analysis of cerebrospinal fluid (CSF) samples from patients prospectively randomized to receive anesthetic maintenance with propofol vs. isoflurane (registered with http://www.clinicaltrials.gov, identifier NCT01640275). We measured CSF levels of EGF, eotaxin, G-CSF, GM-CSF, IFN-α2, IL-1RA, IL-6, IL-7, IL-8, IL-10, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α before and 24 h after intracranial surgery in these study patients. Results After Bonferroni correction for multiple comparisons, we found significant increases from before to 24 h after surgery in G-CSF, IL-10, IL-1RA, IL-6, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α. However, we found no difference in cytokine levels at baseline or 24 h after surgery between propofol- (n = 19) and isoflurane-treated (n = 21) patients (p > 0.05 for all comparisons). Increases in CSF IL-6, IL-8, IP-10, and MCP-1 levels directly correlated with each other and with postoperative CSF elevations in tau, a neural injury biomarker. We observed CSF cytokine increases up to 10-fold higher after intracranial surgery than previously reported after other types of surgery. Discussion These data clarify the magnitude of neuroinflammation after intracranial surgery, and raise the possibility that a coordinated neuroinflammatory response may play a role in neural injury after surgery.

Pilot prospective study of post-surgery sleep and EEG predictors of post-operative delirium

OBJECTIVE Delirium is a common post-operative complication associated with significant costs, morbidity, and mortality. We sought sleep/EEG predictors of delirium present prior to delirium symptoms to facilitate developing and targeting therapies. METHODS Continuous EEG data were obtained in 12 patients post-orthopedic surgery from the day of surgery until delirium assessment on post-operative day 2 (POD2). RESULTS Diminished total sleep time (r=-0.68; p<0.05) and longer latency to sleep onset (r=0.67; p<0.05) on the first night in the hospital were associated with greater POD2 delirium severity. Patients experiencing delirium slept 2.4h less and took 2h longer to fall asleep. Greater waking EEG delta power (r=0.84; p<0.05) on POD1 and less non-REM sleep EEG delta power (r=-0.72; p<0.05) on night 2 also predicted POD2 delirium severity. CONCLUSIONS Loss of sleep on night1 post-surgery is an early predictor of subsequent delirium. EEG Delta Power alterations in waking and sleep appear to be later indicators of impending delirium. Further work is needed to evaluate reproducibility/generalizability and assess whether sleep loss contributes to causing delirium. SIGNIFICANCE This first study to prospectively collect continuous EEG data for an extended period prior to delirium onset identified EEG-derived indices that predict subsequent delirium that could aid in developing and targeting therapies.

A randomised trial of peri‐operative positive airway pressure for postoperative delirium in patients at risk for obstructive sleep apnoea after regional anaesthesia with sedation or general anaesthesia for joint arthroplasty

Previous pilot work has established an association between obstructive sleep apnoea and the development of acute postoperative delirium , but it remains unclear to what extent this risk factor is modifiable in the ‘real world’ peri‐operative setting. In a single‐blind randomised controlled trial, 135 elderly surgical patients at risk for obstructive sleep apnoea were randomly assigned to receive peri‐operative continuous positive airway pressure (CPAP) or routine care. Of the 114 patients who completed the study, 21 (18.4%) experienced delirium. Delirium was equally common in both groups: 21% (12 of 58 subjects) in the CPAP group and 16% (9 of 56 subjects) in the routine care group (OR = 1.36 [95%CI 0.52–3.54], p = 0.53). Delirious subjects were slightly older – mean (SD) age 68.9 (10.7) vs. 64.9 (8.2), p = 0.07 – but had nearly identical pre‐operative STOP‐Bang scores (4.19 (1.1) versus 4.27 (1.3), p = 0.79). Subjects in the CPAP group used their devices for a median (IQR [range]) of 3 (0.25–5 [0–12]) nights pre‐operatively (2.9 (0.1–4.8 [0.0–12.7]) hours per night) and 1 (0–2 [0–2]) nights postoperatively (1.4 (0.0–5.1 [0.0–11.6]) hours per night). Among the CPAP subjects, the residual pre‐operative apnoea–hypopnea index had a significant effect on delirium severity (p = 0.0002). Although we confirm that apnoea is associated with postoperative delirium, we did not find that providing a short‐course of auto‐titrating CPAP affected its likelihood or severity. Voluntary adherence to CPAP is particularly poor during the initiation of therapy.