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The 2019 Sherrington Prize was awarded on March 20th at the Oxford Neuroscience Symposium
Selective Potentiation of the (α4)3(β2)2 Nicotinic Acetylcholine Receptor Response by NS9283 Analogues.
NS9283, 3-(3-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole, is a selective positive allosteric modulator of (α4)3(β2)2 nicotinic acetylcholine receptors (nAChRs). It has good subtype selective therapeutic potential afforded by its specific binding to the unique α4-α4 subunit interface present in the (α4)3(β2)2 nAChR. However, there is currently a lack of structure activity relationship (SAR) studies aimed at developing a class of congeners endowed with the same profile of activity that can help consolidate the druggability of the α4-α4 subunit interface. In this study, new NS9283 analogues were designed, synthesized, and characterized for their ability to selectively potentiate the ACh activity at heterologous (α4)3(β2)2 nAChRs vs nAChR subtypes (α4)2(β2)3, α5α4β2, and α7. With few exceptions, all the NS9283 analogues exerted positive modulation of the (α4)3(β2)2 nAChR ACh-evoked responses. Above all, those modified at the 3-cyanophenyl moiety by replacement with 3-nitrophenyl (4), 4-cyanophenyl (10), and N-formyl-4-piperidinyl (20) showed the same efficacy as NS9283, although with lower potency. Molecular dynamics simulations of NS9283 and some selected analogues highlighted consistency between potentiation activity and pose of the ligand inside the α4-α4 site with the main interaction being with the complementary (-) side and induction of a significant conformational change of the Trp156 residue in the principal (+) side.
The influence of cortical activity on perception depends on behavioral state and sensory context
The mechanistic link between neural circuit activity and behavior remains unclear. While manipulating cortical activity can bias certain behaviors and elicit artificial percepts, some tasks can still be solved when cortex is silenced or removed. Here, mice were trained to perform a visual detection task during which we selectively targeted groups of visually responsive and co-tuned neurons in L2/3 of primary visual cortex (V1) for two-photon photostimulation. The influence of photostimulation was conditional on two key factors: the behavioral state of the animal and the contrast of the visual stimulus. The detection of low-contrast stimuli was enhanced by photostimulation, while the detection of high-contrast stimuli was suppressed, but crucially, only when mice were highly engaged in the task. When mice were less engaged, our manipulations of cortical activity had no effect on behavior. The behavioral changes were linked to specific changes in neuronal activity. The responses of non-photostimulated neurons in the local network were also conditional on two factors: their functional similarity to the photostimulated neurons and the contrast of the visual stimulus. Functionally similar neurons were increasingly suppressed by photostimulation with increasing visual stimulus contrast, correlating with the change in behavior. Our results show that the influence of cortical activity on perception is not fixed, but dynamically and contextually modulated by behavioral state, ongoing activity and the routing of information through specific circuits.
Integration of population genetics with oceanographic models reveals strong connectivity among coral reefs across Seychelles.
Many countries with tropical reef systems face hard choices preserving coral reefs in the face of climate change on limited budgets. One approach to maximising regional reef resilience is targeting management efforts and resources at reefs that export large numbers of larvae to other reefs. However, this requires reef connectivity to be quantified. To map coral connectivity in the Seychelles reef system we carried out a population genomic study of the Porites lutea species complex using 241 sequenced colonies from multiple islands. To identify oceanographic drivers of this connectivity and quantify variability, we further used a 2 km resolution regional ocean simulation coupled with a larval dispersal model to predict the flow of coral larvae between reef sites. Patterns of admixture and gene flow are broadly supported by model predictions, but the realised connectivity is greater than that predicted from model simulations. Both methods detected a biogeographic dispersal barrier between the Inner and Outer Islands of Seychelles. However, this barrier is permeable and substantial larval transport is possible across Seychelles, particularly for one of two putative species found in our genomic study. The broad agreement between predicted connectivity and observed genetic patterns supports the use of such larval dispersal simulations in reef system management in Seychelles and the wider region.
The effect of universal school-based mindfulness on anhedonia and emotional distress and its underlying mechanisms: A cluster randomised controlled trial via experience sampling in secondary schools.
This cluster randomised controlled trial examined the effectiveness of universal school-based mindfulness training (MT; vs. passive control) to lower anhedonia and emotional distress among mid-adolescents (15-18 years). It further examined three potential mechanisms: dampening of positive emotions, non-acceptance/suppression of negative emotions, and perceived social pressure not to experience/express negative emotions. Adolescents (ncontrol = 136, nintervention = 95) participated in three assessment points (before, after and two/three months after the in-class MT), consisting of Experience Sampling (ES) assessments and self-report questionnaires (SRQs) to corroborate the ES assessments. Analyses were based on general linear modelling and multilevel modelling. Overall, no evidence was found for a significant beneficial and long-lasting impact of the MT on adolescents' mental health. Importantly, some barriers inherently linked to universal MT approaches (low engagement in and mixed attitudes towards the MT) may have tempered the effectiveness of the MT in the current trial. Further research should prioritise overcoming these barriers to optimise programme implementation. Additionally, given the potential complex interplay of moderators at micro- (home practice), meso- (school climate), and macro-level (broader context), research should simultaneously focus on alternative ways of delivering MT at schools to strengthen adolescents' mental health.
Identifying relapse predictors in individual participant data with decision trees.
BACKGROUND: Depression is a highly common and recurrent condition. Predicting who is at most risk of relapse or recurrence can inform clinical practice. Applying machine-learning methods to Individual Participant Data (IPD) can be promising to improve the accuracy of risk predictions. METHODS: Individual data of four Randomized Controlled Trials (RCTs) evaluating antidepressant treatment compared to psychological interventions with tapering ([Formula: see text]) were used to identify predictors of relapse and/or recurrence. Ten baseline predictors were assessed. Decision trees with and without gradient boosting were applied. To study the robustness of decision-tree classifications, we also performed a complementary logistic regression analysis. RESULTS: The combination of age, age of onset of depression, and depression severity significantly enhances the prediction of relapse risk when compared to classifiers solely based on depression severity. The studied decision trees can (i) identify relapse patients at intake with an accuracy, specificity, and sensitivity of about 55% (without gradient boosting) and 58% (with gradient boosting), and (ii) slightly outperform classifiers that are based on logistic regression. CONCLUSIONS: Decision tree classifiers based on multiple-rather than single-risk indicators may be useful for developing treatment stratification strategies. These classification models have the potential to contribute to the development of methods aimed at effectively prioritizing treatment for those individuals who require it the most. Our results also underline the existing gaps in understanding how to accurately predict depressive relapse.
Correction to: Increases in External Sensory Observing Cross‑Sectionally Mediate the Repair of Positive Affect Following Mindfulness‑Based Cognitive Therapy in Individuals with Residual Depression Symptoms (Mindfulness, (2023), 14, 1, (113-127), 10.1007/s12671-022-02032-0)
In the published article, the author wishes to correct the scoring scale for DPES (rating items on 1 to 5 not the standard 1 to 7 scale). In the Measure section, the below should be updated: The measure of PA was a composite of subscales from the Dispositional Positive Emotions Scale (DPES; Shiota et al., 2006), which ask participants to rate to what extent they agree with a variety of statements on a scale from 1 (strongly disagree) to 7 (strongly agree). We chose to focus on the joy subscale (six items; e.g. “On a typical day, many events make me happy”) and the contentment subscale (five items; e.g. “I am generally a contented person”), as these correspond to high and low arousal PA respectively. The 11 items were added together to form a single DPES PA scale, ranging from 11 to 77. The measure of PA was a composite of subscales from the Dispositional Positive Emotions Scale (DPES; Shiota et al., 2006), which ask participants to rate to what extent they agree with a variety of statements about experience of positive emotions. We chose to focus on the joy subscale (six items; e.g. “On a typical day, many events make me happy”) and the contentment subscale (five items; e.g. “I am generally a contented person”), as these correspond to high and low arousal PA respectively. Each item was rated on a scale from 1 (strongly disagree) to 5 (strongly agree). This a minor modification to the original DPES validation papers (Shiota et al., 2006), where each item was rated on a scale from 1 (strongly disagree) to 7 (strongly agree), meaning the current data cannot be directly benchmarked against existing normative data on the DPES. Thus, this erratum is presented to fix the error. The original article has been corrected.
Estimating Vitamin K Antagonist Anticoagulation Benefit in People With Atrial Fibrillation Accounting for Competing Risks: Evidence From 12 Randomized Trials.
BACKGROUND: Patients with atrial fibrillation have a high mortality rate that is only partially attributable to vascular outcomes. The competing risk of death may affect the expected anticoagulant benefit. We determined if competing risks materially affect the guideline-endorsed estimate of anticoagulant benefit. METHODS: We conducted a secondary analysis of 12 randomized controlled trials that randomized patients with atrial fibrillation to vitamin K antagonists (VKAs) or either placebo or antiplatelets. For each participant, we estimated the absolute risk reduction (ARR) of VKAs to prevent stroke or systemic embolism using 2 methods-first using a guideline-endorsed model (CHA2DS2-VASc) and then again using a competing risk model that uses the same inputs as CHA2DS2-VASc but accounts for the competing risk of death and allows for nonlinear growth in benefit. We compared the absolute and relative differences in estimated benefit and whether the differences varied by life expectancy. RESULTS: A total of 7933 participants (median age, 73 years, 36% women) had a median life expectancy of 8 years (interquartile range, 6-12), determined by comorbidity-adjusted life tables and 43% were randomized to VKAs. The CHA2DS2-VASc model estimated a larger ARR than the competing risk model (median ARR at 3 years, 6.9% [interquartile range, 4.7%-10.0%] versus 5.2% [interquartile range, 3.5%-7.4%]; P<0.001). ARR differences varied by life expectancies: for those with life expectancies in the highest decile, 3-year ARR difference (CHA2DS2-VASc model - competing risk model 3-year risk) was -1.3% (95% CI, -1.3% to -1.2%); for those with life expectancies in the lowest decile, 3-year ARR difference was 4.7% (95% CI, 4.5%-5.0%). CONCLUSIONS: VKA anticoagulants were exceptionally effective at reducing stroke risk. However, VKA benefits were misestimated with CHA2DS2-VASc, which does not account for the competing risk of death nor decelerating treatment benefit over time. Overestimation was most pronounced when life expectancy was low and when the benefit was estimated over a multiyear horizon.
Comparative neuroimaging of sex differences in human and mouse brain anatomy.
In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-specific brain development, there have been no attempts to formally compare human and mouse neuroanatomical sex differences to ascertain how well they translate. Addressing this question would shed critical light on the use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use structural magnetic resonance imaging to conduct the first comparative neuroimaging study of sex-specific neuroanatomy of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous regions (r=0.30). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-specific brain development in mice to brain regions that best echo sex-specific brain development in humans.
Multi-night cortico-basal recordings reveal mechanisms of NREM slow-wave suppression and spontaneous awakenings in Parkinson's disease.
Sleep disturbance is a prevalent and disabling comorbidity in Parkinson's disease (PD). We performed multi-night (n = 57) at-home intracranial recordings from electrocorticography and subcortical electrodes using sensing-enabled Deep Brain Stimulation (DBS), paired with portable polysomnography in four PD participants and one with cervical dystonia (clinical trial: NCT03582891). Cortico-basal activity in delta increased and in beta decreased during NREM (N2 + N3) versus wakefulness in PD. DBS caused further elevation in cortical delta and decrease in alpha and low-beta compared to DBS OFF state. Our primary outcome demonstrated an inverse interaction between subcortical beta and cortical slow-wave during NREM. Our secondary outcome revealed subcortical beta increases prior to spontaneous awakenings in PD. We classified NREM vs. wakefulness with high accuracy in both traditional (30 s: 92.6 ± 1.7%) and rapid (5 s: 88.3 ± 2.1%) data epochs of intracranial signals. Our findings elucidate sleep neurophysiology and impacts of DBS on sleep in PD informing adaptive DBS for sleep dysfunction.
Cortical signatures of sleep are altered following effective deep brain stimulation for depression.
Deep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) is an experimental therapy for treatment-resistant depression (TRD). Chronic SCC DBS leads to long-term changes in the electrophysiological dynamics measured from local field potential (LFP) during wakefulness, but it is unclear how it impacts sleep-related brain activity. This is a crucial gap in knowledge, given the link between depression and sleep disturbances, and an emerging interest in the interaction between DBS, sleep, and circadian rhythms. We therefore sought to characterize changes in electrophysiological markers of sleep associated with DBS treatment for depression. We analyzed key electrophysiological signatures of sleep-slow-wave activity (SWA, 0.5-4.5 Hz) and sleep spindles-in LFPs recorded from the SCC of 9 patients who responded to DBS for TRD. This allowed us to compare the electrophysiological changes before and after 24 weeks of therapeutically effective SCC DBS. SWA power was highly correlated between hemispheres, consistent with a global sleep state. Furthermore, SWA occurred earlier in the night after chronic DBS and had a more prominent peak. While we found no evidence for changes to slow-wave power or stability, we found an increase in the density of sleep spindles. Our results represent a first-of-its-kind report on long-term electrophysiological markers of sleep recorded from the SCC in patients with TRD, and provides evidence of earlier NREM sleep and increased sleep spindle activity following clinically effective DBS treatment. Future work is needed to establish the causal relationship between long-term DBS and the neural mechanisms underlying sleep.
Acknowledging religion in cognitive behavioural therapy: The effect on alliance, treatment expectations and credibility in a video-vignette study.
OBJECTIVES: Developing mental health services which are accessible and acceptable to those from minority backgrounds continues to be a priority. In the United Kingdom, individuals who identify with a religion are underrepresented in Talking Therapies services as compared to those with no religion. This necessitates an understanding of how therapy is perceived. This online study explored the impact of explicitly acknowledging religion on anticipated alliance, treatment credibility and expectations of therapy in a non-clinical sample of British Muslims. METHODS: A video-vignette experimental design was used in which participants who self-reported as either high or low in religiosity were randomly allocated to receiving information about cognitive behavioural therapy either with or without an explicit mention of religion as a value in the therapeutic process. RESULTS: One hundred twenty-nine British Muslim adults aged 18-70+ years from various ethnic backgrounds participated in the study. Between-subjects ANOVAs showed that scores on the perceived credibility of therapy and treatment expectations were significantly higher when religion was explicitly mentioned by the 'therapist', but that acknowledging religion did not impact upon anticipated alliance. CONCLUSIONS: These findings suggest that mentioning religion as a value to be considered in therapy has some positive impacts upon how therapy is perceived by British Muslims. Although video vignettes do not provide insight into the complexity of actual therapeutic encounters, acknowledging religion in mental health services more broadly remains an important consideration for improving equity of access and may bear relevance to other minoritized groups.
Online peer-led intervention to improve adolescent wellbeing during the COVID-19 pandemic: a randomised controlled trial.
BACKGROUND: The COVID-19 pandemic and associated lockdown measures have posed a major risk to young people's wellbeing, which might be ameliorated by peer-led programmes. Using a randomised controlled trial (ISRCTN registry, number ISRCTN77941736 https://doi.org/10.1186/ISRCTN77941736 ), we tested the short-term efficacy of an online peer-led intervention designed to equip young people with skills to support their mental health and wellbeing during the COVID-19 pandemic. METHODS: Through schools and social media ads, we recruited one hundred young people (aged 16-18) in the UK, focusing on areas with the highest incidence of COVID cases. In December 2020, participants were randomly allocated (1:1) to immediate 5 day Coping during COVID course (n = 49) or a wait-list (n = 51) through a survey software automated randomisation tool. Our primary outcome was self-reported mental wellbeing, and secondary outcomes included self-reported social connectedness, coping skills, sense of purpose, self-esteem, and self-compassion. We also collected qualitative reports of participants' perceived impact of the course and intentions to use what they have learnt from the course in their life moving forward. Assessments were completed at baseline, 1 week post randomisation (primary endpoint), and 2-weeks post-randomisation. RESULTS: Young people allocated to the peer-led intervention reported significantly greater wellbeing, social connectedness, coping skills, sense of purpose, self-esteem, and self-compassion 1 week and 2 weeks post-randomisation (medium-large effect sizes). Specific benefits to mental health, sense of purpose and connectedness were also emphasised in qualitative reports. CONCLUSIONS: An online, peer-led intervention targeting youth wellbeing during the context of the COVID-19 pandemic brought benefits across a range of outcomes, suggesting that structured programmes that incorporate peer-to-peer support can be a valuable approach to promote young people's wellbeing and foster psychological resources during a health crisis.
Bioelectronic Zeitgebers: targeted neuromodulation to re-establish circadian rhythms.
Existing neurostimulation systems implanted for the treatment of neurodegenerative disorders generally deliver invariable therapy parameters, regardless of phase of the sleep/wake cycle. However, there is considerable evidence that brain activity in these conditions varies according to this cycle, with discrete patterns of dysfunction linked to loss of circadian rhythmicity, worse clinical outcomes and impaired patient quality of life. We present a targeted concept of circadian neuromodulation using a novel device platform. This system utilises stimulation of circuits important in sleep and wake regulation, delivering bioelectronic cues (Zeitgebers) aimed at entraining rhythms to more physiological patterns in a personalised and fully configurable manner. Preliminary evidence from its first use in a clinical trial setting, with brainstem arousal circuits as a surgical target, further supports its promising impact on sleep/wake pathology. Data included in this paper highlight its versatility and effectiveness on two different patient phenotypes. In addition to exploring acute and long-term electrophysiological and behavioural effects, we also discuss current caveats and future feature improvements of our proposed system, as well as its potential applicability in modifying disease progression in future therapies.
An Influenza A virus can evolve to use human ANP32E through altering polymerase dimerization.
Human ANP32A and ANP32B are essential but redundant host factors for influenza virus genome replication. While most influenza viruses cannot replicate in edited human cells lacking both ANP32A and ANP32B, some strains exhibit limited growth. Here, we experimentally evolve such an influenza A virus in these edited cells and unexpectedly, after 2 passages, we observe robust viral growth. We find two mutations in different subunits of the influenza polymerase that enable the mutant virus to use a novel host factor, ANP32E, an alternative family member, which is unable to support the wild type polymerase. Both mutations reside in the symmetric dimer interface between two polymerase complexes and reduce polymerase dimerization. These mutations have previously been identified as adapting influenza viruses to mice. Indeed, the evolved virus gains the ability to use suboptimal mouse ANP32 proteins and becomes more virulent in mice. We identify further mutations in the symmetric dimer interface which we predict allow influenza to adapt to use suboptimal ANP32 proteins through a similar mechanism. Overall, our results suggest a balance between asymmetric and symmetric dimers of influenza virus polymerase that is influenced by the interaction between polymerase and ANP32 host proteins.
The effects of pramipexole on motivational vigour during a saccade task: a placebo-controlled study in healthy adults.
Motivation allows us to energise actions when we expect reward and is reduced in depression. This effect, termed motivational vigour, has been proposed to rely on central dopamine, with dopaminergic agents showing promise in the treatment of depression. This suggests that dopaminergic agents might act to reduce depression by increasing the effects of reward or by helping energise actions. The aim of the current study was to investigate whether the dopamine agonist pramipexole enhanced motivational vigour during a rewarded saccade task. In addition, we asked whether the effects of pramipexole on vigour differ between reward contingent on performance and guaranteed reward. Healthy adult participants were randomised to receive either pramipexole (n = 19) or placebo (controls n = 18) for 18 days. The vigour of saccades was measured twice, once before the administration of study medication (Time 1) and after taking it for 12-15 days (Time 2). To separate motivation by contingency vs. reward, saccadic vigour was separately measured when (1) rewards were contingent on performance (2) delivered randomly with matched frequency, (3) when reward was guaranteed, (4) when reward was not present at all. Motivation increased response vigour, as expected. Relative to placebo, pramipexole also increased response vigour. However, there was no interaction, meaning that the effects of reward were not modulated by drug, and there was no differential drug effect on contingent vs. guaranteed rewards. The effect of pramipexole on vigour could not be explained by a speed/accuracy trade-off, nor by autonomic arousal as indexed by pupillary dilation. Chronic D2 stimulation increases general vigour, energising movements in healthy adults irrespective of extrinsic reward.
A Prospective, Observational, Noninterventional Clinical Study of Participants With Choroideremia: The NIGHT Study.
PURPOSE: The NIGHT study aimed to assess the natural history of choroideremia (CHM), an X-linked inherited chorioretinal degenerative disease leading to blindness, and determine which outcomes would be the most sensitive for monitoring disease progression. DESIGN: A prospective, observational, multicenter cohort study. METHODS: Males aged ≥18 years with genetically confirmed CHM, visible active disease within the macular region, and best-corrected visual acuity (BCVA) ≥34 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline were assessed for 20 months. The primary outcome was the change in BCVA over time at Months 4, 8, 12, 16, and 20. A range of functional and anatomical secondary outcome measures were assessed up to Month 12, including retinal sensitivity, central ellipsoid zone (EZ) area, and total area of fundus autofluorescence (FAF). Additional ocular assessments for safety were performed. RESULTS: A total of 220 participants completed the study. The mean BCVA was stable over 20 months. Most participants (81.4% in the worse eye and 77.8% in the better eye) had change from baseline > -5 ETDRS letters at Month 20. Interocular symmetry was low overall. Reductions from baseline to Month 12 were observed (worse eye, better eye) for retinal sensitivity (functional outcome; -0.68 dB, -0.48 dB), central EZ area (anatomical outcome; -0.276 mm2, -0.290 mm2), and total area of FAF (anatomical outcome; -0.605 mm2, -0.533 mm2). No assessment-related serious adverse events occurred. CONCLUSIONS: Retinal sensitivity, central EZ area, and total area of FAF are more sensitive than BCVA in measuring the natural progression of CHM.