Spike Afterhyperpolarizations Govern Persistent Firing Dynamics in Rat Neocortical and Hippocampal Pyramidal Cells.

Persistent firing is commonly reported in both cortical and subcortical neurons under a variety of behavioral conditions. Yet the mechanisms responsible for persistent activity are only partially resolved with support for both intrinsic and synaptic circuit-based mechanisms. Little also is known about physiological factors that enable epochs of persistent firing to continue beyond brief pauses and then spontaneously terminate. In the present study, we used intracellular recordings in rat (both sexes) neocortical and hippocampal brain slices to assess the ionic mechanisms underlying persistent firing dynamics. Previously, we showed that blockade of ether-á-go-go-related gene (ERG) potassium channels abolished intrinsic persistent firing in the presence of low concentrations of muscarinic receptor agonists and following optogenetic activation of cholinergic axons. Here we show the slow dynamics of ERG conductance changes allows persistent firing to outlast the triggering stimulus and even to initiate discharges following ∼7 s poststimulus firing pauses. We find that persistent firing dynamics is regulated by the interaction between ERG conductance and spike afterhyperpolarizations (AHPs). Increasing the amplitude of spike AHPs using either SK channel activators or a closed-loop reactive feedback system allows persistent discharges to spontaneously terminate in both neocortical neurons and hippocampal CA1 pyramidal cells. The interplay between ERG and the potassium channels that mediate spike AHPs grades the duration of persistent firing, providing a novel, generalizable mechanism to explain self-terminating persistent firing modes observed behaving animals.SIGNIFICANCE STATEMENT Many classes of neurons generate prolonged spiking responses to transient stimuli. These discharges often outlast the stimulus by seconds to minutes in some in vitro models of persistent firing. While recent work has identified key synaptic and intrinsic components that enable persistent spiking responses, less is known about mechanisms that can terminate and regulate the dynamics of these responses. The present study identified the spike afterhyperpolarizations as a potent mechanism that regulates the duration of persistent firing. We found that amplifying spike afterpotentials converted bistable persistent firing into self-terminating discharges. Varying the spike AHP amplitude grades the duration of persistent discharges, generating in vitro responses that mimic firing modes associated with neurons associated with short-term memory function.

Modulation of Ether-à-Go-Go Related Gene (ERG) Current Governs Intrinsic Persistent Activity in Rodent Neocortical Pyramidal Cells.

While cholinergic receptor activation has long been known to dramatically enhance the excitability of cortical neurons, the cellular mechanisms responsible for this effect are not well understood. We used intracellular recordings in rat (both sexes) neocortical brain slices to assess the ionic mechanisms supporting persistent firing modes triggered by depolarizing stimuli following cholinergic receptor activation. We found multiple lines of evidence suggesting that a component of the underlying hyperexcitability associated with persistent firing reflects a reduction in the standing (leak) K+ current mediated by Ether-a-go-go-Related Gene (ERG) channels. Three chemically diverse ERG channel blockers (terfenadine, ErgToxin-1, and E-4031) abolished persistent firing and the underlying increase in input resistance in deep pyramidal cells in temporal and prefrontal association neocortex. Calcium accumulation during triggering stimuli appears to attenuate ERG currents, leading to membrane potential depolarization and increased input resistance, two critical elements generating persistent firing. Our results also suggest that ERG current normally governs cortical neuron responses to depolarizing stimuli by opposing prolonged discharges and by enhancing the poststimulus repolarization. The broad expression of ERG channels and the ability of ERG blocks to abolish persistent firing evoked by both synaptic and intracellular step stimuli suggest that modulation of ERG channels may underlie many forms of persistent activity observed in vivoSIGNIFICANCE STATEMENT Persistent activity, where spiking continues beyond the triggering stimulus, is a common phenomenon observed in many types of neurons. Identifying the mechanism underlying this elementary process of memory is a step forward in understanding higher cognitive function including short-term memory. Our results suggest that a reduction in the currents normally mediated by Ether-a-go-go-Related Gene (ERG) K+ channels contributes to persistent firing in neocortical pyramidal cells. ERG currents have been previously studied primarily in the heart; relatively little is known about ERG function in the brain, although mutations in ERG channels have recently been linked to schizophrenia. The present study is among the first to describe its role in neocortex in relation to biophysical correlates of memory function.

Subthalamic Nucleus Activation Occurs Early during Stopping and Is Associated with Trait Impulsivity.

The subthalamic nucleus (STN) is thought to be a central regulator of behavioral inhibition, which is thought to be a major determinant of impulsivity. Thus, it would be reasonable to hypothesize that STN function is related to impulsivity. However, it has been difficult to test this hypothesis because of the challenges in noninvasively and accurately measuring this structure's signal in humans. We utilized a novel approach for STN signal localization that entails identifying this structure directly on fMRI images for each individual participant in native space. Using this approach, we measured STN responses during the stop signal task in a sample of healthy adult participants. We confirmed that the STN exhibited selective activation during "Stop" trials. Furthermore, the magnitude of STN activation during successful Stop trials inversely correlated with individual differences in trait impulsivity as measured by a personality inventory. Time course analysis revealed that early STN activation differentiated successful from unsuccessful Stop trials, and individual differences in the magnitude of STN activation inversely correlated with stop signal RT, an estimate of time required to stop. These results are consistent with the STN playing a central role in inhibition and related behavioral proclivities, with implications for both normal range function and clinical syndromes of inhibitory dyscontrol. Moreover, the methods utilized in this study for measuring STN fMRI signal in humans may be gainfully applied in future studies to further our understanding of the role of the STN in regulating behavior and neuropsychiatric conditions.

Genetics of early-onset coronary artery disease: from discovery to clinical translation.

PURPOSE OF REVIEW: This review is a comprehensive update on recent discoveries on the genetics of early-onset coronary artery disease (EOCAD), and how those findings can be translated to advance its medical management. RECENT FINDINGS: To date, a total of 266 common variants of modest effect size have been reported to be associated with CAD, but many still warrant functional studies. Rare variants impacting the function of at least 10 genes are now well characterized in Mendelian EOCAD. Estimations of minor allele frequencies in multiple ancestries from large genetic databases have allowed us to estimate the prevalence of Mendelian forms of EOCAD. In fact, the prevalence of Mendelian mutations varies markedly between ancestries, ranging from 1 : 289 to 1 : 153 for familial hypercholesterolemia. Mendelian forms of EOCAD support three major biological pathways, including lipid metabolism, vascular wall integrity and function, and thrombosis. Furthermore, combining common variants of modest effect into polygenic risk scores (PRS) has shown to be effective at identifying individuals at high risk of CAD. SUMMARY: Mendelian forms of EOCAD highlight the importance of lipid metabolism, yet prevalence in many non-European populations remains to be clarified. Polygenic EOCAD affects more individuals and, in many cases, confers a higher risk of EOCAD than rare Mendelian mutations. Thus, sequencing of target genes and the derivation of PRSs can be used to identify high-risk patients, leading to more personalized therapeutic approaches.

Delay Period Activity of the Substantia Nigra during Proactive Control of Response Selection as Determined by a Novel fMRI Localization Method.

The ability to proactively control motor responses, particularly to overcome overlearned or automatic actions, is an essential prerequisite for adaptive, goal-oriented behavior. The substantia nigra (SN), an element of the BG, has figured prominently in current models of response selection. However, because of its small size and proximity to functionally distinct subcortical structures, it has been challenging to test the SN's involvement in response selection using conventional in vivo functional neuroimaging approaches. We developed a new fMRI localization method for directly distinguishing, on echo-planar images, the SN BOLD signal from that of neighboring structures, including the subthalamic nucleus (STN). Using this method, we tested the hypothesis that the SN supports the proactive control of response selection. We acquired high-resolution EPI volumes at 3 T from 16 healthy participants while they completed the Preparing to Overcome Prepotency task of proactive control. There was significantly elevated delay period signal selectively during high- compared with low-control trials in the SN. The STN did not show delay period activity in either condition. SN delay period signal was significantly inversely associated with task performance RTs across participants. These results suggest that our method offers a novel means for measuring SN BOLD responses, provides unique evidence of SN involvement in cognitive control in humans, and suggests a novel mechanism for proactive response selection.

Effect of pharmacologic anti-atherosclerotic therapy on carotid intraplaque neovascularization: A systematic review.

Intraplaque neovascularization (IPN), a key feature of vulnerable carotid plaque, is associated with adverse cardiovascular (CV) events. Statin therapy has been shown to diminish and stabilize atherosclerotic plaque, but its effect on IPN is uncertain. This review investigated the effects of common pharmacologic anti-atherosclerotic therapies on carotid IPN. Electronic databases (MEDLINE, EMBASE and Cochrane Library) were searched from inception until July 13, 2022. Studies evaluating the effect of anti-atherosclerotic therapy on carotid IPN among adults with carotid atherosclerosis were included. Sixteen studies were eligible for inclusion. Contrast-enhanced ultrasound (CEUS) was the most common IPN assessment modality (n=8), followed by dynamic contrast-enhanced MRI (DCE-MRI) (n=4), excised plaque histology (n=3) and superb microvascular imaging (n=2). In fifteen studies, statins were the therapy of interest and one study assessed PCSK9 inhibitors. Among CEUS studies, baseline statin use was associated with a lower frequency of carotid IPN (median OR = 0.45). Prospective studies showed regression of IPN after 6-12 months of lipid-lowering therapy, with more regression observed in treated participants compared to untreated controls. Our findings suggest that lipid-lowering therapy with statins or PCSK9 inhibitors is associated with IPN regression. However, there was no correlation between change in IPN parameters and change in serum lipids and inflammatory markers in statin-treated participants, so it is unclear whether these factors are mediators in the observed IPN changes. Lastly, this review was limited by study heterogeneity and small sample sizes, so larger trials are needed to validate findings.

Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories.

Rare variants are collectively numerous and may underlie a considerable proportion of complex disease risk. However, identifying genuine rare variant associations is challenging due to small effect sizes, presence of technical artefacts, and heterogeneity in population structure. We hypothesize that rare variant burden over a large number of genes can be combined into a predictive rare variant genetic risk score (RVGRS). We propose a method (RV-EXCALIBER) that leverages summary-level data from a large public exome sequencing database (gnomAD) as controls and robustly calibrates rare variant burden to account for the aforementioned biases. A calibrated RVGRS strongly associates with coronary artery disease (CAD) in European and South Asian populations by capturing the aggregate effect of rare variants through a polygenic model of inheritance. The RVGRS identifies 1.5% of the population with substantial risk of early CAD and confers risk even when adjusting for known Mendelian CAD genes, clinical risk factors, and a common variant genetic risk score.

Reduced in vivo visual cortex GABA in schizophrenia, a replication in a recent onset sample.

The GABA deficit hypothesis remains one of the most compelling explanations for the information processing impairments in schizophrenia. However, much of the supportive evidence has been derived from post-mortem studies, whereas in vivo studies have largely yielded inconsistent results. We undertook this single voxel proton magnetic resonance (MRS) GABA study to test in a sample of recent onset patients the replicability of our prior finding of reduced early visual cortex GABA in schizophrenia. We also examined the possibility that antipsychotics could represent a significant confound by studying a small subsample of antipsychotic naïve subjects. 23 adults with recent onset schizophrenia and a demographically matched sample of 31 healthy control subjects underwent MRS using a MEGA PRESS sequence on a 3T MR scanner to measure GABA concentration in early visual cortex. To control for in-scanner head movement confounding the results, we quantified the amount of head movement during GABA scans to identify and exclude from analysis scans with excessive movement. Patients demonstrated significantly reduced GABA levels compared to control subjects, p = 0.029. GABA levels did not differ significantly between patients who were antipsychotic naïve (n = 7) and patients treated with antipsychotics. This replication in a recent onset sample suggest that diminished GABA in the visual cortex is a reliable finding, present in early phase of illness and not confounded by illness chronicity.

Selective attenuation of Ether-a-go-go related K+ currents by endogenous acetylcholine reduces spike-frequency adaptation and network correlation.

Most neurons do not simply convert inputs into firing rates. Instead, moment-to-moment firing rates reflect interactions between synaptic inputs and intrinsic currents. Few studies investigated how intrinsic currents function together to modulate output discharges and which of the currents attenuated by synthetic cholinergic ligands are actually modulated by endogenous acetylcholine (ACh). In this study we optogenetically stimulated cholinergic fibers in rat neocortex and find that ACh enhances excitability by reducing Ether-à-go-go Related Gene (ERG) K+ current. We find ERG mediates the late phase of spike-frequency adaptation in pyramidal cells and is recruited later than both SK and M currents. Attenuation of ERG during coincident depolarization and ACh release leads to reduced late phase spike-frequency adaptation and persistent firing. In neuronal ensembles, attenuating ERG enhanced signal-to-noise ratios and reduced signal correlation, suggesting that these two hallmarks of cholinergic function in vivo may result from modulation of intrinsic properties.

Chronic pain in Canada: have we improved our management of chronic noncancer pain?

BACKGROUND: Chronic noncancer pain (CNCP) is a global issue, not only affecting individual suffering, but also impacting the delivery of health care and the strength of local economies. OBJECTIVES: The current study (the Canadian Chronic Pain Study II [CCPSII]) was designed to assess any changes in the prevalence and treatment of CNCP, as well as in attitudes toward the use of strong analgesics, compared with a 2001 study (the CCPSI), and to provide a snapshot of the current standards of care for pain management in Canada. METHODS: Standard, computer-assisted telephone interview survey methodology was applied in two segments, ie, a general population survey and a survey targeting randomly selected primary care physicians (PCPs) who treat moderate to severe CNCP. RESULTS AND DISCUSSION: The patient-reported prevalence of CNCP within Canada has not markedly changed since 2001 but the duration of suffering has decreased. There have been minor changes in regional distribution and generally more patients receive medical treatment, which includes prescription analgesics. Physicians continue to demonstrate opiophobia in their prescribing practices; however, although this is lessened relating to addiction, abuse remains an important concern to PCPs. Canadian PCPs, in general, are implementing standard assessments, treatment approaches, evaluation of treatment success and tools to prevent abuse and diversion, in accordance with guidelines from the Canadian Pain Society and other pain societies globally, although there remains room for improvement and standardization.

Recurrent genetic defects on chromosome 5q in myeloid neoplasms.

BACKGROUND: Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms. MATERIALS AND METHODS: To define the pathogenic molecular features associated with del(5q), next-generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5. FINDINGS: A number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53, and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations. INTERPRETATION: Our results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution.