Electrophysiological Signatures of Visual Recognition Memory across All Layers of Mouse V1.

In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared with novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer 4 (L4) by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDARs) and has been hypothesized to reflect potentiation of thalamocortical (TC) synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells. To shed light on where and how SRP is induced and expressed in male and female mice, the present study had three related aims: (1) to confirm that NMDAR are required specifically in glutamatergic principal neurons of V1, (2) to investigate the consequences of deleting NMDAR specifically in L6, and (3) to use translaminar electrophysiological recordings to characterize SRP expression in different layers of V1. We find that knock-out (KO) of NMDAR in L6 principal neurons disrupts SRP. Current-source density (CSD) analysis of the VEP depth profile shows augmentation of short latency current sinks in layers 3, 4, and 6 in response to phase reversals of familiar stimuli. Multiunit recordings demonstrate that increased peak firing occurs in response to phase reversals of familiar stimuli across all layers, but that activity between phase reversals is suppressed. Together, these data reveal important aspects of the underlying phenomenology of SRP and generate new hypotheses for the expression of experience-dependent plasticity in V1.SIGNIFICANCE STATEMENT Repeated exposure to stimuli that portend neither reward nor punishment leads to behavioral habituation, enabling organisms to dedicate attention to novel or otherwise significant features of the environment. The neural basis of this process, which is so often dysregulated in neurologic and psychiatric disorders, remains poorly understood. Learning and memory of stimulus familiarity can be studied in mouse visual cortex by measuring electrophysiological responses to simple phase-reversing grating stimuli. The current study advances knowledge of this process by documenting changes in visual evoked potentials (VEPs), neuronal spiking activity, and oscillations in the local field potentials (LFPs) across all layers of mouse visual cortex. In addition, we identify a key contribution of a specific population of neurons in layer 6 (L6) of visual cortex.

Cancer survivorship in urban people living with cancer following primary treatment: A secondary analysis of qualitative interview data.

PURPOSE: Urban cancer survivors have been shown to have better opportunities for recovery of health and wellbeing than their rural counterparts. Whilst there is a considerable body of evidence that explores urban people with cancers' experiences and outcomes, there is a dearth of research that explicitly explores 'urban cancer survivorship' in its own right. This study aimed to explore cancer survivorship in urban people living with cancer who have completed primary treatment. METHODS: Secondary analysis of in-depth interview data (n = 18) with adults living with cancer who resided in urban parts of the UK. Data were drawn from a broader study on self-management of people living with cancer. An adapted version of Foster and Fenlon's recovery of health and wellbeing in cancer survivorship framework was used to inform the analysis of the data. RESULTS: Recovery of health and wellbeing was impacted by a variety of contributory factors, which had a largely positive impact. Access to amenities, social support, travel, and healthcare factors were opportunities for urban cancer survivors, whilst pollution, traffic and a lack of green spaces acted as challenges for health management. CONCLUSION: This study demonstrated how urban residency acted as both a barrier and a facilitator to recovery of health and wellbeing in urban cancer survivors following the completion of primary treatment. Area of residence should be taken into account by health providers and policymakers supporting cancer survivorship and the views of those with lived experiences should be included in informing future practice.

A systematic review on the qualitative experiences of people living with lung cancer in rural areas.

PURPOSE: To synthesize the qualitative literature exploring the experiences of people living with lung cancer in rural areas. METHODS: Searches were performed in MEDLINE, CINAHL, and PsycINFO. Articles were screened independently by two reviewers against pre-determined eligibility criteria. Data were synthesized using Thomas and Harden's framework for the thematic synthesis of qualitative research. The CASP qualitative checklist was used for quality assessment and the review was reported in accordance with the ENTREQ and PRISMA checklists. RESULTS: Nine articles were included, from which five themes were identified: (1) diagnosis and treatment pathways, (2) travel and financial burden, (3) communication and information, (4) experiences of interacting with healthcare professionals, (5) symptoms and health-seeking behaviors. Lung cancer diagnosis was unexpected for some with several reporting treatment delays and long wait times regarding diagnosis and treatment. Accessing treatment was perceived as challenging and time-consuming due to distance and financial stress. Inadequate communication of information from healthcare professionals was a common concern expressed by rural people living with lung cancer who also conveyed dissatisfaction with their healthcare professionals. Some were reluctant to seek help due to geographical distance and sociocultural factors whilst others found it challenging to identify symptoms due to comorbidities. CONCLUSIONS: This review provides a deeper understanding of the challenges faced by people with lung cancer in rural settings, through which future researchers can begin to develop tailored support to address the existing disparities that affect this population.

A Role for Thalamic Projection GABAergic Neurons in Circadian Responses to Light.

The thalamus is an important hub for sensory information and participates in sensory perception, regulation of attention, arousal and sleep. These functions are executed primarily by glutamatergic thalamocortical neurons that extend axons to the cortex and initiate cortico-thalamocortical connectional loops. However, the thalamus also contains projection GABAergic neurons that do not extend axons toward the cortex. Here, we have harnessed recent insight into the development of the intergeniculate leaflet (IGL) and the ventral lateral geniculate nucleus (LGv) to specifically target and manipulate thalamic projection GABAergic neurons in female and male mice. Our results show that thalamic GABAergic neurons of the IGL and LGv receive retinal input from diverse classes of retinal ganglion cells (RGCs) but not from the M1 intrinsically photosensitive retinal ganglion cell (ipRGC) type. We describe the synergistic role of the photoreceptor melanopsin and the thalamic neurons of the IGL/LGv in circadian entrainment to dim light. We identify a requirement for the thalamic IGL/LGv neurons in the rapid changes in vigilance states associated with circadian light transitions.SIGNIFICANCE STATEMENT The intergeniculate leaflet (IGL) and ventral lateral geniculate nucleus (LGv) are part of the extended circadian system and mediate some nonimage-forming visual functions. Here, we show that each of these structures has a thalamic (dorsal) as well as prethalamic (ventral) developmental origin. We map the retinal input to thalamus-derived cells in the IGL/LGv complex and discover that while RGC input is dominant, this is not likely to originate from M1ipRGCs. We implicate thalamic cells in the IGL/LGv in vigilance state transitions at circadian light changes and in overt behavioral entrainment to dim light, the latter exacerbated by concomitant loss of melanopsin expression.

Visual recognition is heralded by shifts in local field potential oscillations and inhibitory networks in primary visual cortex.

Learning to recognize and filter familiar, irrelevant sensory stimuli eases the computational burden on the cerebral cortex. Inhibition is a candidate mechanism in this filtration process, and oscillations in the cortical local field potential (LFP) serve as markers of the engagement of different inhibitory neurons. We show here that LFP oscillatory activity in visual cortex is profoundly altered as male and female mice learn to recognize an oriented grating stimulus-low frequency (∼15 Hz peak) power sharply increases while high frequency (∼65 Hz peak) power decreases. These changes report recognition of the familiar pattern, as they disappear when the stimulus is rotated to a novel orientation. Two-photon imaging of neuronal activity reveals that parvalbumin-expressing inhibitory neurons disengage with familiar stimuli and reactivate to novelty, whereas somatostatin-expressing inhibitory neurons show opposing activity patterns. We propose a model in which the balance of two interacting interneuron circuits shifts as novel stimuli become familiar.SIGNIFICANCE STATEMENT:Habituation, familiarity and novelty detection are fundamental cognitive processes that enable organisms to adaptively filter meaningless stimuli and focus attention on potentially important elements of their environment. We have shown that this process can be studied fruitfully in the mouse primary visual cortex by using simple grating stimuli for which novelty and familiarity are defined by orientation, and by measuring stimulus-evoked and continuous local field potentials. Altered event-related and spontaneous potentials, and deficient habituation, are well-documented features of several neurodevelopmental psychiatric disorders. The paradigm described here will be valuable to interrogate the origins of these signals and the meaning of their disruption more deeply.

The Immediate Early Gene Arc Is Not Required for Hippocampal Long-Term Potentiation.

Memory consolidation is thought to occur through protein synthesis-dependent synaptic plasticity mechanisms such as long-term potentiation (LTP). Dynamic changes in gene expression and epigenetic modifications underlie the maintenance of LTP. Similar mechanisms may mediate the storage of memory. Key plasticity genes, such as the immediate early gene Arc, are induced by learning and by LTP induction. Mice that lack Arc have severe deficits in memory consolidation, and Arc has been implicated in numerous other forms of synaptic plasticity, including long-term depression and cell-to-cell signaling. Here, we take a comprehensive approach to determine if Arc is necessary for hippocampal LTP in male and female mice. Using a variety of Arc knock-out (KO) lines, we found that germline Arc KO mice show no deficits in CA1 LTP induced by high-frequency stimulation and enhanced LTP induced by theta-burst stimulation. Temporally restricting the removal of Arc to adult animals and spatially restricting it to the CA1 using Arc conditional KO mice did not have an effect on any form of LTP. Similarly, acute application of Arc antisense oligodeoxynucleotides had no effect on hippocampal CA1 LTP. Finally, the maintenance of in vivo LTP in the dentate gyrus of Arc KO mice was normal. We conclude that Arc is not necessary for hippocampal LTP and may mediate memory consolidation through alternative mechanisms.SIGNIFICANCE STATEMENT The immediate early gene Arc is critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modeled experimentally by induction of LTP, which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and may regulate memory storage through alternative mechanisms.

Distinct Laminar Requirements for NMDA Receptors in Experience-Dependent Visual Cortical Plasticity.

Primary visual cortex (V1) is the locus of numerous forms of experience-dependent plasticity. Restricting visual stimulation to one eye at a time has revealed that many such forms of plasticity are eye-specific, indicating that synaptic modification occurs prior to binocular integration of thalamocortical inputs. A common feature of these forms of plasticity is the requirement for NMDA receptor (NMDAR) activation in V1. We therefore hypothesized that NMDARs in cortical layer 4 (L4), which receives the densest thalamocortical input, would be necessary for all forms of NMDAR-dependent and input-specific V1 plasticity. We tested this hypothesis in awake mice using a genetic approach to selectively delete NMDARs from L4 principal cells. We found, unexpectedly, that both stimulus-selective response potentiation and potentiation of open-eye responses following monocular deprivation (MD) persist in the absence of L4 NMDARs. In contrast, MD-driven depression of deprived-eye responses was impaired in mice lacking L4 NMDARs, as was L4 long-term depression in V1 slices. Our findings reveal a crucial requirement for L4 NMDARs in visual cortical synaptic depression, and a surprisingly negligible role for them in cortical response potentiation. These results demonstrate that NMDARs within distinct cellular subpopulations support different forms of experience-dependent plasticity.

Treatment Intensity Differences After Early-Stage Breast Cancer (ESBC) Diagnosis Depending on Participation in a Screening Program.

BACKGROUND: While population mammographic screening identifies early-stage breast cancers (ESBCs; ductal carcinoma in situ [DCIS] and invasive disease stages 1-3A), commentaries suggest that harms from overdiagnosis and overtreatment may outweigh the benefits. Apparent benefits to patients with screen-detected cancers may be due to selection bias from exclusion of interval cancers (ICs). Treatment intensity is rarely discussed, with an assumption that all ESBCs are treated similarly. We hypothesized that women diagnosed while in a screening program would receive less-intense treatment than those never or not recently screened (NRS). METHODS: This was a retrospective analysis of all women aged 50-69 years managed for ESBC (invasive or DCIS) during the period 2007-2013 within a single service, comparing treatment according to screening status. Data on demographics, detection, pathology, and treatment were derived from hospital, cancer registry, and screening service records. RESULTS: Overall, 622 patients were active screeners (AS) at diagnosis (569 screen-detected and 53 ICs) and 169 patients were NRS. AS cancers were smaller (17 mm vs. 26 mm, p < 0.0001), less likely to involve nodes (26% vs. 48%, p < 0.0001), and lower grade. For invasive cancer, NRS patients were more likely to be recommended for mastectomies [35% vs. 16%; risk ratio(RR) 2.2, p < 0.0001], axillary dissection (43% vs. 19%; RR 2.3, p < 0.0001), adjuvant chemotherapy (65% vs. 37%; RR 1.7, p < 0.0001), and postmastectomy radiotherapy (58% vs. 39%; RR 1.5, p = 0.04). CONCLUSION: Participants in population screening diagnosed with ESBC receive substantially less-intense treatment than non-participants. Differences persist when potential overdiagnosis is taken into account; these differences should be factored into debates around mammographic screening.

Adaptation of myocardial twist in the remodelled athlete's heart is not related to cardiac output.

NEW FINDINGS: What is the central question of this study? What is the role of heart muscle function in the increased output of remodelled, larger hearts? What is the main finding and its importance? The greater stroke volume of endurance athletes is not associated with enhanced function of the heart muscle (i.e. left ventricular twist, torsion and twist-to-shortening) in normal and low-oxygen environments. These data indicate that, in the process of cardiac adaptation, left ventricular twist may play an important role that is not related to generating a larger output. Since enlarged hearts with low output can develop in disease, the present findings may influence the future interpretation of heart muscle function in patients. ABSTRACT: Despite increased stroke volume (SV), 'athlete's heart' has been proposed to have a similar left ventricular (LV) muscle function - as represented by LV twist - compared with the untrained state. However, the underpinning mechanisms and the associations between SV/cardiac output and LV twist during exercise are unknown. We hypothesised that endurance athletes would have a significantly lower twist-to-shortening ratio (TwSR, a parameter that relates twist to the shortening of heart muscle layers) at rest, but significantly greater LV muscle function during exercise. Eleven endurance trained male runners and 13 untrained males were tested at rest and during supine cycling exercise in normoxia and hypoxia (increased cardiac output but unaltered SV). Despite the expected cardiac remodelling in endurance athletes, LV twist, torsion, TwSR, strain and strain rate ('LV systolic mechanics') did not differ significantly between groups (P > 0.05). Structural remodelling, as per relative wall thickness, and LV twist did not correlate (r2  = 0.04, P = 0.33). In normoxia and hypoxia, exercise increased LV systolic mechanics in both groups (P < 0.001), but with different relationships to SV and cardiac output. Conversely to our hypothesis, hearts of different size had similar LV systolic mechanics, suggesting that similar twist, torsion and TwSR at rest and during exercise irrespective of cardiac output may be an important mechanism in healthy hearts. We hypothesise that the regulatory 'purpose' of LV twist may be related to the sensing of maximal cardiac myofibre stress, which may act as a biologically purposeful limiter to contraction.

ProBac-seq, a bacterial single-cell RNA sequencing methodology using droplet microfluidics and large oligonucleotide probe sets.

Methods that measure the transcriptomic state of thousands of individual cells have transformed our understanding of cellular heterogeneity in eukaryotic cells since their introduction in the past decade. While simple and accessible protocols and commercial products are now available for the processing of mammalian cells, these existing technologies are incompatible with use in bacterial samples for several fundamental reasons including the absence of polyadenylation on bacterial messenger RNA, the instability of bacterial transcripts and the incompatibility of bacterial cell morphology with existing methodologies. Recently, we developed ProBac sequencing (ProBac-seq), a method that overcomes these technical difficulties and provides high-quality single-cell gene expression data from thousands of bacterial cells by using messenger RNA-specific probes. Here we provide details for designing large oligonucleotide probe sets for an organism of choice, amplifying probe sets to produce sufficient quantities for repeated experiments, adding unique molecular indexes and poly-A tails to produce finalized probes, in situ probe hybridization and single-cell encapsulation and library preparation. This protocol, from the probe amplification to the library preparation, requires ~7 d to complete. ProBac-seq offers several advantages over other methods by capturing only the desired target sequences and avoiding nondesired transcripts, such as highly abundant ribosomal RNA, thus enriching for signal that better informs on cellular state. The use of multiple probes per gene can detect meaningful single-cell signals from cells expressing transcripts to a lesser degree or those grown in minimal media and other environmentally relevant conditions in which cells are less active. ProBac-seq is also compatible with other organisms that can be profiled by in situ hybridization techniques.

Implementing the European code of cancer practice in rural settings.

Existing evidence often indicates higher cancer incidence and mortality rates, later diagnosis, lower screening uptake and poorer long-term survival for people living in rural compared to more urbanised areas. Despite wide inequities and variation in cancer care and outcomes across Europe, much of the scientific literature explicitly exploring the impact of rurality on cancer continues to come from Australia and North America. The European Code of Cancer Practice or "The Code" is a citizen and patient-centred statement of the most salient requirements for good clinical cancer practice and has been extensively co-produced by cancer patients, cancer professionals and patient advocates. It contains 10 key overarching Rights that a cancer patient should expect from their healthcare system, regardless of where they live and has been strongly endorsed by professional and patient cancer organisations as well as the European Commission. In this article, we use these 10 fundamental Rights as a framework to argue that (i) the issues and needs identified in The Code are generally more profound for rural people with cancer; (ii) addressing these issues is also more challenging in rural contexts; (iii) interventions and support must explicitly account for the unique needs of rural residents living with and affected by cancer and (iv) new innovative approaches are urgently required to successfully overcome the challenges faced by rural people with cancer and their caregivers. Despite equitable healthcare being a key European policy focus, the needs of rural people living with cancer have largely been neglected.

Physical activity experiences of community-dwelling older adults with physical disabilities: a scoping review of qualitative research.

PURPOSE: The aim of this review was to synthesise qualitative literature on physical activity experiences of community-dwelling older adults with physical disabilities. METHODS: We conducted a scoping review of peer-reviewed, qualitative studies on physical activity with community-dwelling older adults with physical disabilities. We analysed eligible studies identified through electronic database searches (CINAHL Complete, MEDLINE, SPORTDiscus) and manual searches undertaken up to June 2023. RESULTS: Twenty-eight articles with 306 participants were included. As regard the experience of physical activity, although physical activity could elicit pleasure and enjoyment, many reported that physical activity sometimes produced pain. Various outcomes of physical activity were reported, with several physical, psychological, social, and lifestyle benefits prominent. Analyses of barriers and facilitators demonstrated how intrapersonal, interpersonal, environmental, and systems and programme factors influenced physical activity participation among older adults with physical disabilities. DISCUSSION: Our findings contribute to literature on physical activity in older adults with physical disabilities by synthesising qualitative research on physical activity experiences, outcomes, barriers, and facilitators in this population. Findings demonstrate the need for knowledgeable and supportive healthcare and exercise professionals, environments that support physical activity, and activities that promote pleasure and social connections.Implications for RehabilitationPhysical activity is perceived to have wide-ranging benefits for community-dwelling older adults with physical disabilities.Various intrapersonal, interpersonal, environmental, and systems and programme barriers constrain physical activity in physically disabled people.Knowledgeable and supportive healthcare and exercise professionals, accessible environments, and activities that promote pleasure and social connections could enhance engagement in physical activity.

Adherence to swallowing recommendations during (chemo)radiotherapy in head and neck cancer survivors: a scoping review.

PURPOSE OF REVIEW: There is a paucity of knowledge regarding patient adherence to dysphagia recommendations. It is recognized that unique barriers and facilitators contribute to poor treatment adherence in head and neck cancer (HNC) survivors. This review aims to identify the key themes and knowledge gaps regarding adherence to swallowing recommendations in HNC survivors during (chemo)radiotherapy (C)RT. RECENT FINDINGS: Seven studies were identified. Six facilitators to adherence were extracted, namely pain relief, behavioural intervention, attendance at multidisciplinary clinic, individualised swallowing therapy, absence of prophylactic percutaneous endoscopic gastronomy (PEG) and positive social control from a spouse. Barriers to adherence included pain, depression and presence of prophylactic PEG. Adherence to swallowing recommendations positively impacted swallowing outcomes in one study. SUMMARY: Little is known about adherence to swallowing recommendations during (C)RT in HNC survivors. Capturing adherence is challenging. Several knowledge gaps were identified. Further research is needed to better understand the barriers and facilitators from the survivors' perspective. This will inform development of best practice regarding how swallowing recommendations are provided to promote adherence and improve outcomes.

Developing a 'Living with Cancer' programme in a rural and coastal setting: Experiences of collaborative and innovative co-production across an Integrated Health System.

INTRODUCTION: With projected increases in cancer prevalence, and demonstrated unmet need, there is an urgency for a collaborative approach to improving the lives of those living with cancer particularly in rural and coastal areas where cancer survivors face unique challenges. We report on an innovative 'Living with Cancer' (LWC) programme in the rural and coastal English county of Lincolnshire. METHODS: In 2016, the Lincolnshire LWC programme was established to develop person-centred, local support for people living with cancer, their carers and significant others in Lincolnshire. This article reports on the setup of the LWC programme, our innovative approach to delivering cancer care in a rural and coastal setting, as well as our most salient achievements. RESULTS: This work, developed within a policy context of tackling health inequalities and personalised approaches to care, started with stakeholder and community engagement where people described the challenges to living well after cancer and the need to focus on 8 themes further exacerbated by rurality. Recognising the limitations of conventional approaches, led to the development of a strategy underpinned by a shared set of principles and a philosophy of the importance of a transformative, whole-system, place-based, asset-based, and person-centred approaches. The strategy is now being coordinated and delivered across all cancer pathways and Lincolnshire communities. In 2022, permanent funding was secured, and our success was also demonstrated by a national Macmillan Integration Excellence award. DISCUSSION: The initial success of the LWC programme in Lincolnshire is a result of an explicit focus on 'transformation' rather than 'improvement', and a programme not solely situated in an acute setting, which needed a whole systems approach with a focus on person-centred support and community engagement.

Electrophysiological signatures of visual recognition memory across all layers of mouse V1.

In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared to novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer (L) 4 by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDAR) and has been hypothesized to reflect potentiation of thalamocortical synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells. To shed light on where and how SRP is induced and expressed, the present study had three related aims: (1) to confirm that NMDAR are required specifically in glutamatergic principal neurons of V1, (2) to investigate the consequences of deleting NMDAR specifically in L6, and (3) to use translaminar electrophysiological recordings to characterize SRP expression in different layers of V1. We find that knockout of NMDAR in L6 principal neurons disrupts SRP. Current-source density analysis of the VEP depth profile shows augmentation of short latency current sinks in layers 3, 4 and 6 in response to phase reversals of familiar stimuli. Multiunit recordings demonstrate that increased peak firing occurs to in response to phase reversals of familiar stimuli across all layers, but that activity between phase reversals is suppressed. Together, these data reveal important aspects of the underlying phenomenology of SRP and generate new hypotheses for the expression of experience-dependent plasticity in V1. Significance Statement: Repeated exposure to stimuli that portend neither reward nor punishment leads to behavioral habituation, enabling organisms to dedicate attention to novel or otherwise significant features of the environment. The neural basis of this process, which is so often dysregulated in neurological and psychiatric disorders, remains poorly understood. Learning and memory of stimulus familiarity can be studied in mouse visual cortex by measuring electrophysiological responses to simple phase-reversing grating stimuli. The current study advances knowledge of this process by documenting changes in visual evoked potentials, neuronal spiking activity, and oscillations in the local field potentials across all layers of mouse visual cortex. In addition, we identify a key contribution of a specific population of neurons in layer 6 of visual cortex.

Exploratory evidence for differences in GABAergic regulation of auditory processing in autism spectrum disorder.

Altered reactivity and responses to auditory input are core to the diagnosis of autism spectrum disorder (ASD). Preclinical models implicate ϒ-aminobutyric acid (GABA) in this process. However, the link between GABA and auditory processing in humans (with or without ASD) is largely correlational. As part of a study of potential biosignatures of GABA function in ASD to inform future clinical trials, we evaluated the role of GABA in auditory repetition suppression in 66 adults (n = 28 with ASD). Neurophysiological responses (temporal and frequency domains) to repetitive standard tones and novel deviants presented in an oddball paradigm were compared after double-blind, randomized administration of placebo, 15 or 30 mg of arbaclofen (STX209), a GABA type B (GABAB) receptor agonist. We first established that temporal mismatch negativity was comparable between participants with ASD and those with typical development (TD). Next, we showed that temporal and spectral responses to repetitive standards were suppressed relative to responses to deviants in the two groups, but suppression was significantly weaker in individuals with ASD at baseline. Arbaclofen reversed weaker suppression of spectral responses in ASD but disrupted suppression in TD. A post hoc analysis showed that arbaclofen-elicited shift in suppression was correlated with autistic symptomatology measured using the Autism Quotient across the entire group, though not in the smaller sample of the ASD and TD group when examined separately. Thus, our results confirm: GABAergic dysfunction contributes to the neurophysiology of auditory sensory processing alterations in ASD, and can be modulated by targeting GABAB activity. These GABA-dependent sensory differences may be upstream of more complex autistic phenotypes.

A Rapid Systematic Review on the Experiences of Cancer Survivors Residing in Rural Areas during the COVID-19 Pandemic.

The COVID-19 pandemic has caused considerable disruption to cancer care and may have exacerbated existing challenges already faced by cancer survivors from rural areas. This has created a need for a rapid evidence synthesis to inform the development of tailored interventions that address the specific needs of rural cancer survivors who continue to be affected by the pandemic. The review was conducted following guidance from the Cochrane Rapid Review Methods Group. Database searches were performed via the EBSCOHost interface (includes MEDLINE, CINAHL, PsycINFO) on 25 May 2022 and supplemented with searches on Google Scholar. Peer-reviewed articles published after March 2020 that reported primary data on the experiences of cancer survivors residing in rural and remote settings during the pandemic were included. Findings were tabulated and written up narratively. Fourteen studies were included. The COVID-19 pandemic had a mostly detrimental impact on the experiences of rural cancer survivors. People's individual coping mechanisms were challenging for a range of reasons. Specifically, the pandemic impacted on their ability to access testing, treatment, check-ups and supportive care, their ability to maintain and access social support with close friends and family, as well as negative consequences to their finances and emotional wellbeing with some reporting feelings of psychological distress including depression and anxiety. This review provides important insight into the experiences of rural cancer survivors that may help inform tailored support in line with the needs and challenges faced because of the pandemic.

Rapid systematic review on developing web-based interventions to support people affected by cancer.

OBJECTIVE: To systematically identify and explore the existing evidence to inform the development of web-based interventions to support people affected by cancer (PABC). DESIGN: A rapid review design was employed in accordance with the guidance produced by the Cochrane Rapid Reviews Methods Group and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. A rapid review was chosen due to the need for a timely evidence synthesis to underpin the subsequent development of a digital resource (Shared Lives: Cancer) as part of an ongoing funded project. METHODS AND OUTCOMES: Keyword searches were performed in MEDLINE to identify peer-reviewed literature that reported primary data on the development of web-based interventions designed to support PABC. The review included peer-reviewed studies published in English with no limits set on publication date or geography. Key outcomes included any primary data that reported on the design, usability, feasibility, acceptability, functionality and user experience of web-based resource development. RESULTS: Ten studies were identified that met the pre-specified eligibility criteria. All studies employed an iterative, co-design approach underpinned by either quantitative, qualitative or mixed methods. The findings were grouped into the following overarching themes: (1) exploring current evidence, guidelines and theory, (2) identifying user needs and preferences and (3) evaluating the usability, feasibility and acceptability of resources. Resources should be informed by the experiences of a wide range of end-users taking into consideration current guidelines and theory early in the design process. Resource design and content should be developed around the user's needs and preferences and evaluated through usability, feasibility or acceptability testing using quantitative, qualitative or mixed methods. CONCLUSION: The findings of this rapid review provide novel methodological insights into the approaches used to design web-based interventions to support PABC. Our findings have the potential to inform and guide researchers when considering the development of future digital health resources. TRIAL REGISTRATION NUMBER: The review protocol was registered on the Open Science Framework (https://osf.io/ucvsz).

Relevance of sleep and associated structural changes in GBA1 mouse to human rapid eye movement behavior disorder.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a REM parasomnia that often predicts the later occurrence of alpha-synucleinopathies. Variants in the gene encoding for the lysosomal enzyme glucocerebrosidase, GBA, strongly increase the risk of RBD. In a GBA1-mouse model recently shown to mimic prodromal stages of α-synucleinopathy, we now demonstrate striking REM and NREM electroencephalographic sleep abnormalities accompanied by distinct structural changes in the more widespread sleep neurocircuitry.

Stimulus-Selective Response Plasticity in Primary Visual Cortex: Progress and Puzzles.

Stimulus-selective response plasticity (SRP) is a robust and lasting modification of primary visual cortex (V1) that occurs in response to exposure to novel visual stimuli. It is readily observed as a pronounced increase in the magnitude of visual evoked potentials (VEPs) recorded in response to phase-reversing grating stimuli in neocortical layer 4. The expression of SRP at the individual neuron level is equally robust, but the qualities vary depending on the neuronal type and how activity is measured. This form of plasticity is highly selective for stimulus features such as stimulus orientation, spatial frequency, and contrast. Several key insights into the significance and underlying mechanisms of SRP have recently been made. First, it occurs concomitantly and shares core mechanisms with behavioral habituation, indicating that SRP reflects the formation of long-term familiarity that can support recognition of innocuous stimuli. Second, SRP does not manifest within a recording session but only emerges after an off-line period of several hours that includes sleep. Third, SRP requires not only canonical molecular mechanisms of Hebbian synaptic plasticity within V1, but also the opposing engagement of two key subclasses of cortical inhibitory neuron: the parvalbumin- and somatostatin-expressing GABAergic interneurons. Fourth, pronounced shifts in the power of cortical oscillations from high frequency (gamma) to low frequency (alpha/beta) oscillations provide respective readouts of the engagement of these inhibitory neuronal subtypes following familiarization. In this article we will discuss the implications of these findings and the outstanding questions that remain to gain a deeper understanding of this striking form of experience-dependent plasticity.