Faculty Bibliography

STUDY OBJECTIVES/OBJECTIVE:Obstructive sleep apnea (OSA) prevalence increases with age, but whether OSA-related sleep disruption could interrupt the processing of previously encoded wake information thought to normally occur during sleep in cognitively normal older adults remains unknown. METHODS:Fifty-two older (age = 66.9 ± 7.7 years, 56 % female), community-dwelling, cognitively normal adults explored a 3D maze environment and then performed 3 timed trials before (evening) and after (morning) sleep recorded with polysomnography (PSG) with a 20-minute morning psychomotor vigilance test (PVT). RESULTS:Twenty-two (22) subjects had untreated OSA (Apnea Hypopnea Index (AHI4%) ≥ 5/hour) where severity was mild on average [median (interquartile range (IQR))] AHI4% = 11.0 (20.7)/hour) and 30 subjects had an AHI4% < 5/hour. No significant differences were observed in overnight percent change in completion time or in the pattern of evening pre-sleep maze performance. However, during the morning post-sleep trials, there was a significant interaction between OSA group and morning trial number such that participants with OSA performed worse on average with each subsequent morning trial, whereas those without OSA showed improvements. There were no significant differences in morning PVT performance suggesting that vigilance is unlikely to account for this difference in morning maze performance. Increasing relative frontal slow wave activity (SWA) was associated with better overnight maze performance improvement in participants with OSA (r= 0.51, p = 0.02) but not in those without OSA, and no differences in slow wave activity were observed between groups. CONCLUSIONS:OSA alters morning performance in spatial navigation independent of a deleterious effect on morning vigilance or evening navigation performance. Relative frontal slow wave activity is associated with overnight performance change in older subjects with OSA, but not those without.

Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.

Glutamatergic hilar mossy cells (MCs) have axons that terminate both near and far from their cell body but stay within the DG, making synapses primarily in the molecular layer. The long-range axons are considered the primary projection, and extend throughout the DG ipsilateral to the soma, and project to the contralateral DG. The specificity of MC axons for the inner molecular layer (IML) has been considered to be a key characteristic of the DG. In the present study, we made the surprising finding that dorsal MC axons are an exception to this rule. We used two mouse lines that allow for Cre-dependent viral labeling of MCs and their axons: dopamine receptor D2 (Drd2-Cre) and calcitonin receptor-like receptor (Crlr-Cre). A single viral injection into the dorsal DG to label dorsal MCs resulted in labeling of MC axons in both the IML and middle molecular layer (MML). Interestingly, this broad termination of dorsal MC axons occurred throughout the septotemporal DG. In contrast, long-range axons of ventral MCs terminated in the IML, consistent with the literature. Taken together, these results suggest that dorsal and ventral MCs differ significantly in their axonal projections. Since MC projections in the ML are thought to terminate primarily on GCs, the results suggest a dorsal-ventral difference in MC activation of GCs. The surprising difference in dorsal and ventral MC projections should therefore be considered when evaluating dorsal-ventral differences in DG function.

Pain is a complex, multidimensional experience that involves dynamic interactions between sensory-discriminative and affective-emotional processes. Pain experiences have a high degree of variability depending on their context and prior anticipation. Viewing pain perception as a perceptual inference problem, we propose a predictive coding paradigm to characterize evoked and non-evoked pain. We record the local field potentials (LFPs) from the primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC) of freely behaving rats-two regions known to encode the sensory-discriminative and affective-emotional aspects of pain, respectively. We further use predictive coding to investigate the temporal coordination of oscillatory activity between the S1 and ACC. Specifically, we develop a phenomenological predictive coding model to describe the macroscopic dynamics of bottom-up and top-down activity. Supported by recent experimental data, we also develop a biophysical neural mass model to describe the mesoscopic neural dynamics in the S1 and ACC populations, in both naive and chronic pain-treated animals. Our proposed predictive coding models not only replicate important experimental findings, but also provide new prediction about the impact of the model parameters on the physiological or behavioral read-out-thereby yielding mechanistic insight into the uncertainty of expectation, placebo or nocebo effect, and chronic pain.

INTRODUCTION/BACKGROUND:The term "lactic acidosis" reinforces the misconception that lactate contributes to acidemia. Although it is common to discover an anion gap acidosis with a concomitant elevated lactate concentration, the two are not mutually dependent. CASE REPORT/METHODS:Here we describe two patients exhibiting high lactate concentrations in the setting of metabolic alkalemia. CONCLUSION/CONCLUSIONS:Lactate is not necessarily the direct cause of acid-base disturbances, and there is no fixed relationship between lactate and the anion gap or between lactate and pH. The term "metabolic acidosis with hyperlactatemia" is more specific than "lactic acidosis" and thus more appropriate.

PURPOSE/OBJECTIVE:To describe an approach for detection of respiratory signals using a transmitted radiofrequency (RF) reference signal called Pilot-Tone (PT) and to use the PT signal for creation of motion-resolved images based on 3D stack-of-stars imaging under free-breathing conditions. METHODS:This work explores the use of a reference RF signal generated by a small RF transmitter, placed outside the MR bore. The reference signal is received in parallel to the MR signal during each readout. Because the received PT amplitude is modulated by the subject's breathing pattern, a respiratory signal can be obtained by detecting the strength of the received PT signal over time. The breathing-induced PT signal modulation can then be used for reconstructing motion-resolved images from free-breathing scans. The PT approach was tested in volunteers using a radial stack-of-stars 3D gradient echo (GRE) sequence with golden-angle acquisition. RESULTS:Respiratory signals derived from the proposed PT method were compared to signals from a respiratory cushion sensor and k-space-center-based self-navigation under different breathing conditions. Moreover, the accuracy was assessed using a modified acquisition scheme replacing the golden-angle scheme by a zero-angle acquisition. Incorporating the PT signal into eXtra-Dimensional (XD) motion-resolved reconstruction led to improved image quality and clearer anatomical depiction of the lung and liver compared to k-space-center signal and motion-averaged reconstruction, when binned into 6, 8, and 10 motion states. CONCLUSION/CONCLUSIONS:PT is a novel concept for tracking respiratory motion. Its small dimension (8 cm), high sampling rate, and minimal interaction with the imaging scan offers great potential for resolving respiratory motion.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein-protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology. Consistent with this, pharmacological or genetic interventions that target dysregulated ion channels effectively restore neuronal excitability, synaptic function and behavioural phenotypes in FXS animal models. Recent studies further support a role for direct and rapid FMRP-channel interactions in regulating ion channel function. This Review lays out the current state of knowledge in the field regarding channelopathies and the pathogenesis of FXS, including promising therapeutic implications.

Introduction: Exertional respiratory symptoms are prominent in patients with environmental lung injury following inhalation of World Trade Center dust. Baseline pulmonary function testing in these patients is frequently normal, leaving symptoms unexplained. Although small airway dysfunction has been identified at rest, its role in producing exertional symptoms is unclear. In this study exercise evaluation with assessment of airway function was employed to uncover mechanisms for exertional dyspnea.
Method(s): 27 subjects were studied: 20 with unexplained dyspnea (normal spirometry) and 6 asymptomatic controls. Baseline pulmonary function testing was conducted along with respiratory oscillometry to assess small airway function. An incremental exercise protocol was performed that included a focused evaluation of airway function: (1) examination of tidal flow vs. volume curves during exercise to assess for dynamic hyperinflation and expiratory flow limitation; and (2) airway reactivity post-exercise using spirometry and oscillometry. Baseline: By design spirometry values were within normal limits in all subjects. Symptomatic individuals tended to have greater mean R5, R20, R5-20, and AX at baseline compared with asymptomatic controls (R5: 4.80+/-1.79 vs. 3.66+/-1.06; R20: 3.52+/-1.12 vs. 2.98+/-0.68; R5-20: 1.28+/-1.02 vs. 0.70+/-0.53; AX: 13.44+/-10.74 vs. 5.48+/-5.21). Exercise: Dyspnea was reproduced with exercise in symptomatic subjects (mean Borg dyspnea score 1.38+/-1.48 at baseline, 4.20+/-2.28 at peak exercise). Asymptomatic controls did not report significant dyspnea (mean Borg dyspnea score 0 at baseline, 1.60+/-1.14 at peak exercise). Expiratory flow limitation during exercise was noted in 13/20 symptomatic subjects compared with 0 controls. Post Exercise: Bronchial hyper-reactivity was evident in post-exercise spirometry (>10% decline in FEV1) in 3/20 symptomatic subjects vs. 1/6 controls; the fall in FEV1 was predominantly attributable to a fall in FVC, consistent with small airway dysfunction. An additional six symptomatic subjects demonstrated isolated small airway hyper-reactivity that was only revealed on oscillometry.
Conclusion(s): In patients with unexplained dyspnea and normal spirometry, symptoms were reproduced during exercise. Focused airway assessment uncovered small airway dysfunction both during and following exercise that contributed to the development of dyspnea

We rapidly classify odors as pleasant or aversive, but the brain circuits underlying how odors motivate approach and avoidance responses are largely unknown. New research describes a direct path from the olfactory bulb to ventral striatum driving odor-mediated reward.