Hypnotic treatment reverses NREM sleep disruption and EEG desynchronization in a mouse model of Fragile X syndrome to rescue memory consolidation deficits.

Fragile X syndrome (FXS) is a highly-prevalent genetic cause of intellectual disability, associated with disrupted cognition and sleep abnormalities. Sleep loss itself negatively impacts cognitive function, yet the contribution of sleep loss to impaired cognition in FXS is vastly understudied. One untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We hypothesized that restoration of sleep-dependent mechanisms could improve functions such as memory consolidation in FXS. We examined whether administration of ML297, a hypnotic drug acting on G-protein-activated inward-rectifying potassium channels, could restore sleep phenotypes and improve disrupted memory consolidation in Fmr1 -/y mice. Using 24-h polysomnographic recordings, we found that Fmr1 -/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM sleep architecture, alterations in NREM EEG spectral power (including reductions in sleep spindles), and reduced EEG coherence between cortical areas. These alterations were reversed in the hours following ML297 administration. Hypnotic treatment following contextual fear or spatial learning also ameliorated disrupted memory consolidation in Fmr1 -/y mice. Hippocampal activation patterns during memory recall was altered in Fmr1 -/y mice, reflecting an altered balance of activity among principal neurons vs. parvalbumin-expressing (PV+) interneurons. This phenotype was partially reversed by post-learning ML297 administration. These studies suggest that sleep disruption could have a major impact on neurophysiological and behavioral phenotypes in FXS, and that hypnotic therapy may significantly improve disrupted cognition in this disorder.

Acetylcholine-gated current translates wake neuronal firing rate information into a spike timing-based code in Non-REM sleep, stabilizing neural network dynamics during memory consolidation.

Sleep is critical for memory consolidation, although the exact mechanisms mediating this process are unknown. Combining reduced network models and analysis of in vivo recordings, we tested the hypothesis that neuromodulatory changes in acetylcholine (ACh) levels during non-rapid eye movement (NREM) sleep mediate stabilization of network-wide firing patterns, with temporal order of neurons' firing dependent on their mean firing rate during wake. In both reduced models and in vivo recordings from mouse hippocampus, we find that the relative order of firing among neurons during NREM sleep reflects their relative firing rates during prior wake. Our modeling results show that this remapping of wake-associated, firing frequency-based representations is based on NREM-associated changes in neuronal excitability mediated by ACh-gated potassium current. We also show that learning-dependent reordering of sequential firing during NREM sleep, together with spike timing-dependent plasticity (STDP), reconfigures neuronal firing rates across the network. This rescaling of firing rates has been reported in multiple brain circuits across periods of sleep. Our model and experimental data both suggest that this effect is amplified in neural circuits following learning. Together our data suggest that sleep may bias neural networks from firing rate-based towards phase-based information encoding to consolidate memories.

Causal role for sleep-dependent reactivation of learning-activated sensory ensembles for fear memory consolidation.

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation.

Temporal differences in ejection between right and left ventricles in chronic pulmonary hypertension: a pulsed Doppler study.

Chronic pulmonary hypertension (cPH) is known to alter right ventricular (RV) deformation and cause mechanical dyssynchrony. Since not all echocardiographic laboratories are equipped with sophisticated imaging tools, we decided to determine if Doppler would be useful to detect temporal differences between the ejection of the right and left ventricle (LV) as a result of cPH using pulsed outflow tract (RVOT and LVOT) spectral signals. Data was collected from 30 patients without PH (Group I: 53 ± 7 years and 31 ± 5 mmHg) and from 40 patients with cPH (Group II: 53 ± 13 years; P = NS and 82 ± 24 mmHg; P < 0.00001). Group II patients had a longer temporal delay from onset between RVOT and LVOT (23 ± 12 ms vs. 0 ± 0 ms; P < 0.0001) with a significantly shorter temporal difference between RVOT and LVOT spectral signals to reach maximum peak of ejection (27 ± 24 ms vs. 61 ± 23 ms; P < 0.0001) than Group I. In addition, Group II had a statistically lower RVOT VTI value (0.14 ± 0.05 cm vs. 0.17 ± 0.03 cm; P < 0.01). Our data seems to suggest that increasing severity of PH mainly affects ejection of the RV resulting in noticeable temporal alterations in both time of onset as well as time to reach maximum peak ejection between RV and LV. More studies are now required to determine the utility of obtaining these measurements prospectively in the follow-up and treatment of cPH patients.

Right ventricular outflow tract spectral signal: a useful marker of right ventricular systolic performance and pulmonary hypertension severity.

AIMS: Right ventricular outflow tract (RVOT) acceleration shortens with chronic pulmonary hypertension (cPH). However, the overall value of this spectral Doppler signal in the assessment of PH patients is not well understood. METHODS AND RESULTS: Markers of RV systolic performance, time to onset, time to peak, and total duration of the RVOT systolic spectral Doppler signal were examined. Group I consisted of 28 patients without PH [50 +/- 15 years and mean pulmonary artery systolic pressure (PASP) of 30 +/- 8 mmHg] and Group II included 52 patients with cPH (56 +/- 14 years and mean PASP of 80 +/- 27 mmHg; P < 0.0001). As expected, Group II patient's markers showed worse RV performance. In addition, Group II had a longer time to onset, a shorter time to peak, and a shorter total duration of the RVOT systolic signal than Group I. Both time to onset (r = 0.66 vs. r = -0.53; P < 0.0001) and time to peak (r = 0.65 vs. r = 0.50; P < 0.0001) of the RVOT signal correlated better with PH than RV fractional area change. Conversely, RV fractional area change correlated better with total duration of RVOT ejection (r = 0.66 vs. r = 0.58; P < 0.0001) than with PASP. CONCLUSION: Timing of onset and peak of the RVOT systolic spectral signal appears to be useful in characterizing the severity of the PASP, while the total duration of RVOT ejection is a better predictor of the systolic performance of the RV in PH patients. More studies are now required to determine the clinical utility of prospectively measuring RVOT in cPH.

Noncardiac surgery and the risk of death and other cardiovascular events in patients with hypertrophic cardiomyopathy.

BACKGROUND: There is a paucity of reports evaluating the perioperative risk of noncardiac surgery in patients with hypertrophic cardiomyopathy (HCM). HYPOTHESIS: The study was undertaken to evaluate the incidence of acute myocardial infarction (MI) and all-cause inhospital mortality following noncardiac surgery in patients with HCM. METHODS: We searched the National Hospital Discharge Survey database for patients with a diagnosis of HCM who had undergone noncardiac surgery. Cases were matched by age, gender, and year of surgery. Death or acute MI were used as endpoints for analysis. RESULTS: From 1996 to 2002, 227 patients with HCM were matched with 554 controls (representing national estimates of 25,874 HCM and 50,326 controls patients). Patients with HCM were more likely than controls to have a history of atrial fibrillation (22.7 vs. 10.6%, p < 0.001) and of congestive heart failure (CHF) (24.2 vs. 14.1%, p < 0.001). The in-hospital incidence of death or MI was higher in patients with HCM than in controls (6.7 vs. 2.5%, p < 0.001 for death and 2.2 vs. 0.3%, p < 0.001 for MI). After correcting for age, gender, race, presence of hypertension, diabetes mellitus, history of coronary artery-disease, history of CHF, atrial fibrillation, and ventricular arrhythmias in a multivariate binary logistic regression model, the presence of HCM increased the odds of death by 61% (odds ratio [OR] = 1.61, 95% confidence interval [CI] 1.46-1.77, p < 0.001), and almost tripled the odds of the combined endpoint of death or MI (OR = 2.82, 95% CI 2.59-3.07, p < 0.001). CONCLUSION: The presence of HCM significantly increases the risk of death and MI associated with noncardiac surgery. Patients with HCM undergoing elective procedures may require more careful preoperative assessment and perioperative monitoring. The impact of the severity of HCM on outcomes of noncardiac surgery needs further study.