Selective Reduction of AMPA Currents onto Hippocampal Interneurons Impairs Network Oscillatory Activity

Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4HC−/− mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125–250 Hz) in the CA1 region of GluA4HC−/− mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4HC−/− mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance

Reduction of claustrophobia during magnetic resonance imaging: methods and design of the "CLAUSTRO" randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Magnetic resonance (MR) imaging has been described as the most important medical innovation in the last 25 years. Over 80 million MR procedures are now performed each year and on average 2.3% (95% confidence interval: 2.0 to 2.5%) of all patients scheduled for MR imaging suffer from claustrophobia. Thus, prevention of MR imaging by claustrophobia is a common problem and approximately 2,000,000 MR procedures worldwide cannot be completed due to this situation. Patients with claustrophobic anxiety are more likely to be frightened and experience a feeling of confinement or being closed in during MR imaging. In these patients, conscious sedation and additional sequences (after sedation) may be necessary to complete the examinations. Further improvements in MR design appear to be essential to alleviate this situation and broaden the applicability of MR imaging. A more open scanner configuration might help reduce claustrophobic reactions while maintaining image quality and diagnostic accuracy.</p> <p>Methods/Design</p> <p>We propose to analyze the rate of claustrophobic reactions, clinical utility, image quality, patient acceptance, and cost-effectiveness of an open MR scanner in a randomized comparison with a recently designed short-bore but closed scanner with 97% noise reduction. The primary aim of this study is thus to determine whether an open MR scanner can reduce claustrophobic reactions, thereby enabling more examinations of claustrophobic patients without incurring the safety issues associated with conscious sedation. In this manuscript we detail the methods and design of the prospective "CLAUSTRO" trial.</p> <p>Discussion</p> <p>This randomized controlled trial will be the first direct comparison of open vertical and closed short-bore MR systems in regards to claustrophobia and image quality as well as diagnostic utility.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00715806">NCT00715806</a></p

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Local field potentials during sharp wave/ripples in <i>GluA4^HC−/−</i> mice.

<p>(A) Representative examples of SWRs recorded during a rest trial in a control and a <i>GluA4^HC−/−</i> mouse. Top trace: raw signal. Bottom trace: band-pass filtered (125–250 Hz) signal. (B) Mean length of SWR epochs and frequency of SWR occurrence in control and <i>GluA4^HC−/−</i> mice. (C) Mean time-frequency representation of power centered on the peak power of each SWR epoch. (D) Mean power spectrum of SWRs in control and <i>GluA4^HC−/−</i> mice. (E) Mean peak ripple frequency and mean peak power during SWRs in control and <i>GluA4^HC−/−</i> mice. (F) Mean waveform of ripples centered on the peak power of each SWR epoch and aligned on the positive-to-negative zero-crossing. (G) Mean ripple amplitude in control and <i>GluA4^HC−/−</i> mice. *: <i>p</i><0.05.</p

GluA4 ablation in the dorsal hippocampus.

<p>(A) Cre-mediated recombination of the <i>ROSA26</i> reporter gene after AAV-Cre injection into the dorsal hippocampus. Coronal sections at two anteroposterior levels of the hippocampus (left two panels) and a third section at higher magnification of the CA1 hippocampal region (right panel) showing pan-neuronal X-gal staining. Scale bar: 150 µm. (B) Representative Western blot from the dorsal hippocampus in control and <i>GluA4^HC−/−</i> mice. (C) Quantification of GluA4 expression level in the dorsal hippocampus from Western blot analysis. Data are expressed as percentage of control levels (mean ± SEM). (D) Representative Western blot of the ventral hippocampus in control and <i>GluA4^HC−/−</i> mice. (E) Quantification of GluA4 expression level in the ventral hippocampus from Western blot analysis. Abbreviations: so, stratum oriens; sr, stratum radiatum. ***: <i>p</i><10⁻¹⁰.</p

Spatial firing during trials in the open field and the zigzag maze.

<p>(A) Representative examples of firing rate maps in the open field from 10 simultaneously recorded pyramidal cells in a control and a <i>GluA4^HC−/−</i> mouse. Numbers above each map indicate the peak firing rate in Hz. (B) Spatial information score in the open field for pyramidal cells in control and <i>GluA4^HC−/−</i> mice (mean ± SEM). (C) Sparsity score in the open field for pyramidal cells in control and <i>GluA4^HC−/−</i> mice. (D) Peak firing rate of firing fields in the open field. (E) Mean place field size in the open field. (F) Stability of place firing rate maps across two trials in the open field. Representative recording of one cell during two trials in the open field (1 hr inter-trial interval, left panel). Stability of place firing rate maps with different spatial information scores (right panel). (G) Representative examples of firing rate maps in the zigzag maze from 4 pyramidal cells recorded in a control and a <i>GluA4^HC−/−</i> mouse. South- and northbound runs (indicated by arrows) are plotted separately (top and bottom rows). Numbers above each map indicate the peak firing rate in Hz. (H) Spatial information score in the zigzag maze for pyramidal cells in the zigzag maze. (I) Sparsity score in the zigzag maze for pyramidal cells. (J) Peak firing rate in the 2-dimensional firing rate maps in the zigzag maze for pyramidal cells of control and <i>GluA4^HC−/−</i> mice. (K) Mean size of the firing fields detected in 1-dimensional firing rate maps of the zigzag maze. *: <i>p</i><0.05, ***: <i>p</i><10<i>⁻</i>⁷.</p

Cell activity during sharp wave/ripples in <i>GluA4^HC−/−</i> mice.

<p>(A) Firing rate of pyramidal cells during SWRs. Time 0 represents the peak power of SWRs. The inset shows the mean firing rate during SWRs. (B) Same as A but for interneurons. (C) Proportion of SWRs in which a pyramidal fire from 0 to 5 spikes. Pyramidal cells in <i>GluA4^HC−/−</i> mice were more likely than that of control mice to fire between 1 to 5 spikes during a SWR. (D) Polar plot of the preferred ripple phase and ripple vector length of pyramidal cells (left) and interneurons (right) in control and <i>GluA4^HC−/−</i> mice. Each dot represents a neuron. Phase 0 is the positive-to-negative zero-crossing of the ripple. The ripple vector length of each cells is equal to the distance between the dot and the the center of the plot. The short lines in the right-top corner indicate the mean preferred phase of the recorded neurons. (E) Mean firing probability at different ripple phases for pyramidal cells (left) and interneurons (right) in control and <i>GluA4^HC−/−</i> mice. Abbreviations: Int., interneurons; Pyr., pyramidal cells. **: <i>p</i><0.01, ***: <i>p</i><10<i>⁻</i>⁵.</p

Theta oscillations in <i>GluA4^HC−/−</i> mice.

<p> (A) Representative examples of theta oscillations recorded during exploratory trials in control and <i>GluA4^HC−/−</i> mice. Top trace: raw signal. Bottom trace: band-pass filtered (5–14 Hz) signal. (B) Mean power spectra in the theta frequency range when mice ran at different speed. The peak power and peak frequency was similar in the control and <i>GluA4^HC−/−</i> mice. (C) Polar plot of the preferred theta phase and theta vector length of pyramidal cells in control and <i>GluA4^HC−/−</i> mice. Each dot represents a neuron. Phase 0 is the positive-to-negative zero-crossing of the theta oscillation. The theta vector length of each cells is equal to the distance between the dot and the center of the plot. The short lines in the right-top corner indicate the mean preferred phase of the recorded neurons. (D) Mean theta vector length for all pyramidal cells in control and <i>GluA4^HC−/−</i> mice. (E) Distribution of preferred theta phase for pyramidal cells in control and <i>GluA4^HC−/−</i> mice. (F) Mean firing probability at different theta phases for pyramidal cells. (G–J) Same as C–F but for interneurons. Abbreviations: Int., interneurons; Pyr., pyramidal cells. **: <i>p</i><0.005.</p