Barriers and facilitators to the implementation of digital technologies in mental health systems: a qualitative systematic review to inform a policy framework.

BACKGROUND: Despite the potential for improved population mental health and wellbeing, the integration of mental health digital interventions has been difficult to achieve. In this qualitative systematic review, we aimed to identify barriers and facilitators to the implementation of digital technologies in mental healthcare systems, and map these to an implementation framework to inform policy development. METHODS: We searched Medline, Embase, Scopus, PsycInfo, Web of Science, and Google Scholar for primary research articles published between January 2010 and 2022. Studies were considered eligible if they reported barriers and/or facilitators to the integration of any digital mental healthcare technologies. Data were extracted using EPPI-Reviewer Web and analysed thematically via inductive and deductive cycles. RESULTS: Of 12,525 references identified initially, 81 studies were included in the final analysis. Barriers and facilitators were grouped within an implementation (evidence-practice gap) framework across six domains, organised by four levels of mental healthcare systems. Broadly, implementation was hindered by the perception of digital technologies as impersonal tools that add additional burden of care onto both providers and patients, and change relational power asymmetries; an absence of resources; and regulatory complexities that impede access to universal coverage. Facilitators included person-cantered approaches that consider patients' intersectional features e.g., gender, class, disability, illness severity; evidence-based training for providers; collaboration among colleagues; appropriate investment in human and financial resources; and policy reforms that tackle universal access to digital health. CONCLUSION: It is important to consider the complex and interrelated nature of barriers across different domains and levels of the mental health system. To facilitate the equitable, sustainable, and long-term digital transition of mental health systems, policymakers should consider a systemic approach to collaboration between public and private sectors to inform evidence-based planning and strengthen mental health systems. PROTOCOL REGISTRATION: The protocol is registered on PROSPERO, CRD42021276838.

Clopidogrel Administration Impairs Post-Stroke Learning and Memory Recovery in Mice.

Clopidogrel, which is one of the most prescribed antiplatelet medications in the world, is given to stroke survivors for the prevention of secondary cardiovascular events. Clopidogrel exerts its antiplatelet activity via antagonism of the P2Y12 receptor (P2RY12). Although not widely known or considered during the initial clinical trials for clopidogrel, P2RY12 is also expressed on microglia, which are the brain's immune cells, where the receptor facilitates chemotactic migration toward sites of cellular damage. If microglial P2RY12 is blocked, microglia lose the ability to migrate to damaged sites and carry out essential repair processes. We aimed to investigate whether administering clopidogrel to mice post-stroke was associated with (i) impaired motor skills and cognitive recovery; (ii) physiological changes, such as survival rate and body weight; (iii) changes in the neurovascular unit, including blood vessels, microglia, and neurons; and (iv) changes in immune cells. Photothrombotic stroke (or sham surgery) was induced in adult male mice. From 24 h post-stroke, mice were treated daily for 14 days with either clopidogrel or a control. Cognitive performance (memory and learning) was assessed using a mouse touchscreen platform (paired associated learning task), while motor impairment was assessed using the cylinder task for paw asymmetry. On day 15, the mice were euthanized and their brains were collected for immunohistochemistry analysis. Clopidogrel administration significantly impaired learning and memory recovery, reduced mouse survival rates, and reduced body weight post-stroke. Furthermore, clopidogrel significantly increased vascular leakage, significantly increased the number and appearance of microglia, and significantly reduced the number of T cells within the peri-infarct region post-stroke. These data suggest that clopidogrel hampers cognitive performance post-stroke. This effect is potentially mediated by an increase in vascular permeability post-stroke, providing a pathway for clopidogrel to access the central nervous system, and thus, interfere in repair and recovery processes.

Psychological Stress Management and Stress Reduction Strategies for Stroke Survivors: A Scoping Review.

BACKGROUND: Stroke can be a life-changing event, with survivors frequently experiencing some level of disability, reduced independence, and an abrupt lifestyle change. Not surprisingly, many stroke survivors report elevated levels of stress during the recovery process, which has been associated with worse outcomes. PURPOSE: Given the multiple roles of stress in the etiology of stroke recovery outcomes, we aimed to scope the existing literature on stress management interventions that have been trialed in stroke survivors. METHODS: We performed a database search for intervention studies conducted in stroke survivors which reported the effects on stress, resilience, or coping outcome. Medline (OVID), Embase (OVID), CINAHL (EBSCO), Cochrane Library, and PsycInfo (OVID) were searched from database inception until March 11, 2019, and updated on September 1, 2020. RESULTS: Twenty-four studies met the inclusion criteria. There was significant variation in the range of trialed interventions, as well as the outcome measures used to assess stress. Overall, just over half (13/24) of the included studies reported a benefit in terms of stress reduction. Acceptability and feasibility were considered in 71% (17/24) and costs were considered in 17% (4/24) of studies. The management of stress was rarely linked to the prevention of symptoms of stress-related disorders. The overall evidence base of included studies is weak. However, an increase in the number of studies over time suggests a growing interest in this subject. CONCLUSIONS: Further research is required to identify optimum stress management interventions in stroke survivors, including whether the management of stress can ameliorate the negative impacts of stress on health.

The Epidemiology of Major Trauma During the First Wave of COVID-19 Movement Restriction Policies: A Systematic Review and Meta-analysis of Observational Studies.

BACKGROUND: The objective of this systematic review is to investigate changes in the epidemiology of major trauma presentations during the implementation of movement restriction measures to manage the first wave of the SARS-CoV-2 (COVID-19) pandemic. METHODS: A systematic search in six databases, as well as a search of grey literature was performed from January 2020 to August 2021. Estimates were pooled using random-effects meta-analysis. The certainty of evidence was rated according to the GRADE approach. The review is reported using both PRISMA guideline and the MOOSE checklist. RESULTS: In total, 35 studies involving 36,987 patients were included. The number of major trauma admissions overall decreased during social movement restrictions (-24%; p < 0.01; 95% CI [-0.31; -0.17]). A pooled analysis reported no evidence of a change in the severity of trauma admissions (OR:1.17; 95%CI [0.77, 1.79], I2 = 77%). There was no evidence for a change in mortality during the COVID-19 period (OR:0.94, 95%CI [0.80,1.11], I2 = 53%). There was a statistically significant reduction in motor vehicle trauma (OR:0.70; 95%CI [0.61, 0.81], I2 = 91%) and a statistically significant increase in admissions due to firearms and gunshot wounds (OR:1.34; 95%CI [1.11, 1.61], I2 = 73%) and suicide attempts and self-harm (OR:1.41; 95%CI [1.05, 1.89], I2 = 39%). CONCLUSIONS AND RELEVANCE: Although evidence continues to emerge, this systematic review reports some decrease in absolute major trauma volume with unchanged severity and mortality during the first wave of COVID-19 movement restriction policies. Current evidence does not support the reallocation of highly specialised trauma professionals and trauma resources. Registration PROSPERO ID CRD42020224827.

Do P2Y12 receptor inhibitors prescribed poststroke modify the risk of cognitive disorder or dementia? Protocol for a target trial using multiple national Swedish registries.

INTRODUCTION: The target of a class of antiplatelet medicines, P2Y12R inhibitors, exists both on platelets and on brain immune cells (microglia). This protocol aims to describe a causal (based on a counterfactual model) approach for analysing whether P2Y12R inhibitors prescribed for secondary prevention poststroke may increase the risk of cognitive disorder or dementia via their actions on microglia, using real-world evidence. METHODS AND ANALYSIS: This will be a cohort study nested within the Swedish National Health and Medical Registers, including all people with incident stroke from 2006 to 2016. We developed directed acyclic graphs to operationalise the causal research question considering potential time-independent and time-dependent confounding, using input from several experts. We developed a study protocol following the components of the target trial approach described by Hernan et al and describe the data structure that would be required in order to make a causal inference. We also describe the statistical approach required to derive the causal estimand associated with this important clinical question; that is, a time-to-event analysis for the development of cognitive disorder or dementia at 1, 2 and 5-year follow-up, based on approaches for competing events to account for the risk of all-cause mortality. Causal effect estimates and the precision in these estimates will be quantified. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of the University of Gothenburg and Confidentiality Clearance at Statistics Sweden with Dnr 937-18, and an approved addendum with Dnr 2019-0157. The analysis and interpretation of the results will be heavily reliant on the structure, quality and potential for bias of the databases used. When we implement the protocol, we will consider and document any biases specific to the dataset and conduct appropriate sensitivity analyses. Findings will be disseminated to local stakeholders via conferences, and published in appropriate scientific journals.

Patient and clinician characteristics and preferences for increasing participation in placebo surgery trials: a scoping review of attributes to inform a discrete choice experiment.

BACKGROUND: Orthopaedic surgeries include some of the highest volume surgical interventions globally; however, studies have shown that a significant proportion of patients report no clinically meaningful improvement in pain or function after certain procedures. As a result, there is increasing interest in conducting randomised placebo-controlled trials in orthopaedic surgery. However, these frequently fail to reach recruitment targets suggesting a need to improve trial design to encourage participation. The objective of this study was to systematically scope the available evidence on patient and clinician values and preferences which may influence the decision to participate in placebo surgery trial. METHODS: A systematic review was conducted via a literature search in the MEDLINE, Embase, PsycInfo, CINAHL, and EconLit databases as of 19 July 2021, for studies of any design (except commentaries or opinion pieces) based on two key concepts: patient and clinician characteristics, values and preferences, and placebo surgery trials. RESULTS: Of 3424 initial articles, we retained 18 eligible studies. Characteristics, preferences, values, and attitudes of patients (including levels of pain/function, risk/benefit perception, and altruism) and of clinicians (including concerns regarding patient deception associated with placebo, and experience/training in research) influenced their decisions to participate in placebo-controlled trials. Furthermore, some aspects of trial design, including randomisation procedures, availability of the procedure outside of the trial, and the information and consent procedures used, also influenced decisions to participate. CONCLUSION: Participant recruitment is a significant challenge in placebo surgery trials, and individual decisions to participate appear to be sensitive to preferences around treatment. Understanding and quantifying the role patient and clinician preferences may play in surgical trials may contribute to the optimisation of the design and implementation of clinical trials in surgery.

Impact of disease-modifying therapies on MRI and neurocognitive outcomes in relapsing-remitting multiple sclerosis: a protocol for a systematic review and network meta-analysis.

INTRODUCTION: Disease-modifying therapies (DMTs) are the mainstay of treatment for relapsing-remitting multiple sclerosis (RRMS). There is established evidence that DMTs are effective at reducing relapse rate and disease progression in RRMS, but there has been less consideration to the synthesis of MRI and neurocognitive outcomes, which play an increasingly important role in treatment decisions. The aim of this systematic review and network meta-analysis is to examine the relative efficacy, acceptability and tolerability of DMTs for RRMS, using MRI and neurocognitive outcomes. METHODS AND ANALYSIS: We will search electronic databases, including MEDLINE, Embase and the Cochrane Central Register of Controlled Trials, with no date restrictions. We will also search the websites of international regulatory bodies for pharmaceuticals and international trial registries. We will include parallel group randomised controlled trials of DMTs including interferon beta-1a intramuscular, interferon beta-1a subcutaneous, interferon beta-1b, peginterferon beta-1a, glatiramer acetate, natalizumab, ocrelizumab, alemtuzumab, dimethyl fumarate, teriflunomide, fingolimod, cladribine, ozanimod, mitoxantrone and rituximab, either head-to-head or against placebo in adults with RRMS. Primary outcomes include efficacy (MRI outcomes including new T1/hypointense lesions and T2/hyperintense lesions) and acceptability (all-cause dropouts). Secondary outcomes include gadolinium-enhancing lesions, cerebral atrophy and tolerability (dropouts due to adverse events). Neurocognitive measures across three domains including processing speed, working memory and verbal learning will be included as exploratory outcomes. Data will be analysed using a random-effects pairwise meta-analysis and a Bayesian hierarchical random effects network meta-analysis to evaluate the efficacy, acceptability and tolerability of the included DMTs. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. The review will be reported using the Preferred Reporting Items for Systematic Reviews incorporating Network Meta-Analyses statement. ETHICS AND DISSEMINATION: This protocol does not require ethics approval. Results will be disseminated in a peer-reviewed academic journal. PROSPERO REGISTRATION NUMBER: CRD42021239630.

Barriers and facilitators to the integration of digital technologies in mental health systems: A protocol for a qualitative systematic review.

INTRODUCTION: Digital technology has the potential to improve health outcomes and health system performance in fragmented and under-funded mental health systems. Despite this potential, the integration of digital technology tools into mental health systems has been relatively poor. This is a protocol for a synthesis of qualitative evidence that will aim to determine the barriers and facilitators to integrating digital technologies in mental health systems and classify them in contextual domains at individual, organisational and system levels. METHODS AND ANALYSIS: The methodological framework for systematic review of qualitative evidence described in Lockwood et al. will be applied to this review. A draft search strategy was developed in collaboration with an experienced senior health research librarian. A systematic search of Medline, Embase, Scopus, PsycInfo, Web of Science and Google Scholar, as well as hand searching of reference lists and reviews will identify relevant studies for inclusion. Study selection will be carried out independently by two authors, with discrepancies resolved by consensus. The quality of selected studies will be assessed using JBI Critical Appraisal Checklist for Qualitative Research. Data will be charted using JBI QUARI Data Extraction Tool for Qualitative Research. Findings will be defined and classified both deductively in a priori conceptual framework and inductively by a thematic analysis. Results will be reported based on the Enhancing transparency in reporting the synthesis of qualitative research. The level of confidence of the findings will be assessed using GRADE-CERQual. ETHICS AND DISSEMINATION: This study does not require ethics approval. The systematic review will inform policy and practices around improving the integration of digital technologies into mental health care systems.

Opposing Associations of Stress and Resilience With Functional Outcomes in Stroke Survivors in the Chronic Phase of Stroke: A Cross-Sectional Study.

Stroke survivors report significant levels of psychological distress post stroke. To date, most studies conducted have focused on the relationship between psychological stress and functional outcomes in the acute phase of stroke. However, no studies had considered the role of stress over the chronic phase, where stress may continue to exert negative effects on cognitive and psychological processes. Further, the role of potentially modulatory variables, such as psychological resilience, on stroke outcomes has been understudied. The purpose of this study was to consider the relationships between stress and resilience with functional outcomes in long-term survivors of stroke. People (N = 70) who had experienced a stroke between 5 months and 28 years ago were included in the cross-sectional study, along with age-matched controls (N = 70). We measured stress using both the Perceived Stress Scale and biological markers, and resilience using both the Brief Resilience Scale and the Connor-Davidson Resilience Scale. Stroke outcomes were assessed using the Stroke Impact Scale. We found that, compared with age-matched controls, stroke survivors reported greater levels of perceived stress, and lower levels of resilience. In stroke survivors, both perceived stress and resilience were independently associated with stroke outcomes in linear regression models. In particular, these relationships were observed for cognitive outcomes including mood, memory, and communication. The association between stress and stroke outcome did not differ across time post stroke. Given that resilience is a modifiable psychological construct, future research may consider whether strategies directed at enhancing resilience may improve recovery from stroke. Australia and New Zealand Clinical Trials Registry: ACTRN12617000736347.

Attitudes of patients and surgeons towards sham surgery trials: a protocol for a scoping review of attributes to inform a discrete choice experiment.

INTRODUCTION: In order to properly evaluate the efficacy of orthopaedic procedures, rigorous, randomised controlled sham surgery trial designs are necessary. However, randomised controlled trials (RCTs) for surgery involving a placebo are ethically debated and difficult to conduct with many failing to reach their desired sample size and power. A review of the literature on barriers and enablers to recruitment, and patient and surgeon attitudes and preferences towards sham surgery trials, will help to determine the characteristics necessary for successful recruitment. METHODS AND ANALYSIS: This review will scope the diverse literature surrounding sham surgery trials with the aim of informing a discrete choice experiment to empirically test patient and surgeon preferences for different sham surgery trial designs. The scoping review will be conducted in accordance with the methodological framework described in Arksey and O'Malley (2005) and reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols extension for Scoping Reviews. The review will be informed by a systematic search of Medline, Embase, PsycInfo, CINAHL and EconLit databases (from database inception to 21 June 2019), a Google Scholar search, and hand searching of reference lists of relevant studies or reviews. Studies or opinion pieces that involve patient, surgeon or trial characteristics, which influence the decision to participate in a trial, will be included. Study selection will be carried out independently by two authors with discrepancies resolved by consensus among three authors. Data will be charted using a standardised form, and results tabulated and narratively summarised with reference to the research questions of the review. ETHICS AND DISSEMINATION: The findings from this review will inform the design of a discrete choice experiment around willingness to participate in surgical trials, the outcomes of which can inform decision and cost-effectiveness models of sham surgery RCTs. The qualitative information from this review will also inform patient-centred outcomes research. The review will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: CRD42019133296.

Exploration of stress management interventions to address psychological stress in stroke survivors: a protocol for a scoping review.

INTRODUCTION: Several studies have shown that stroke survivors report experiencing high and unremitting levels of stress, which can negatively affect brain repair processes and psychological outcomes and thereby compromise recovery. However, it is presently unclear which interventions have been trialled to manage stress in stroke survivors and whether they translate to clinically relevant outcomes. The aim of this scoping review will be to examine stress management interventions in stroke survivors in order to map the types of interventions trialled, commonly reported stress outcome measures and whether a reduction in stress contributes to reductions in relevant clinical outcomes. METHODS AND ANALYSIS: The methodological framework described in Arksey and O'Malley will be applied to this review. A draft search strategy was developed in collaboration with an experienced senior health research librarian. A systematic search of Medline, Embase, CINAHL, Cochrane library, PsycInfo and Clinicaltrials.gov as well as hand searching of reference lists and reviews will identify relevant studies for inclusion. To be eligible for inclusion, studies must report on the outcomes of an intervention targeting stress management and resilience in stroke survivors. Study selection and critical appraisal of selected studies will be carried out independently by two authors, with discrepancies resolved by consensus. Data will be charted using a standard extraction form. Results will be tabulated and narratively summarised to highlight findings relevant to our research questions and to inform recommendations for future research. ETHICS AND DISSEMINATION: This study does not require ethics approval. This scoping review will provide a synthesis of evidence for stress management interventions in stroke survivors. It will identify and clarify the gaps in stress research specific to stroke pathologies and highlight promising interventions for future research. Findings will be relevant to researchers and healthcare workers and will be disseminated via publications in peer-reviewed journals and presented at conferences.

Exploring the relationship between fatigue and circulating levels of the pro-inflammatory biomarkers interleukin-6 and C-reactive protein in the chronic stage of stroke recovery: A cross-sectional study.

BACKGROUND: The precise mechanisms underlying the aetiology of post-stroke fatigue remain poorly understood. Inflammation has been associated with clinically significant fatigue across a number of neurological disorders; however, at present there is a lack of evidence regarding the association of fatigue and inflammation in the chronic phase of stroke recovery. AIMS: The aim of this study was to examine fatigue in a cohort of stroke survivors in the chronic phase of stroke, compared with matched controls, and to explore associations between the pro-inflammatory cytokine interleukin-6, high-sensitivity C-reactive Protein and fatigue. METHODS: We performed an exploratory cross-sectional study of 70 people in the chronic phase of stroke recovery, and 70 age matched controls. Fatigue was assessed using the Fatigue Assessment Scale. Interleukin-6 was measured in serum using a commercially available enzyme immunoassay kit. Both outcome measures were assessed contemporaneously. RESULTS: Clinically significant fatigue, defined as a score ≥24 on the Fatigue Assessment Scale, was reported by 60% of stroke survivors, and 15.7% of controls. The odds of experiencing clinically significant fatigue was 8.04 times higher among stroke survivors compared to control participants (odds ratio 8.045; 95% CI: 3.608, 17.939; P â€‹< â€‹0.001). The fatigue score was significantly correlated with the level of both interleukin-6 and high-sensitivity c-reactive protein, however once entered into a linear regression model with cardiovascular covariables, this relationship was no longer statistically significant. CONCLUSIONS: This study shows that fatigue may be associated with systemic inflammation in the chronic phase of stroke. The pathological mechanisms underlying post-stroke fatigue and its clinical implications require further study.

Chronic stress-induced disruption of the astrocyte network is driven by structural atrophy and not loss of astrocytes.

Chronic stress is well recognized to decrease the number of GFAP⁺ astrocytes within the prefrontal cortex (PFC). Recent research, however, has suggested that our understanding of how stress alters astrocytes may be incomplete. Specifically, chronic stress has been shown to induce a unique form of microglial remodelling, but it is not yet clear whether astrocytes also undergo similar structural modifications. Such alterations may be significant given the role of astrocytes in modulating synaptic function. Accordingly, in the current study we have examined changes in astrocyte morphology following exposure to chronic stress in adult rats, using three-dimensional digital reconstructions of astrocytes. Our analysis indicated that chronic stress produced profound atrophy of astrocyte process length, branching and volume. We additionally examined changes in astrocyte-specific S100ß, which are both a putative astrocyte marker and a protein whose expression is associated with astrocyte distress. While we found that S100ß levels were increased by stress, this increase was not correlated with atrophy. We further established that while chronic stress was associated with a decrease in astrocyte numbers when GFAP labelling was used as a marker, we could find no evidence of a decrease in the total number of cells, based on Nissl staining, or in the number of S100ß⁺ cells. This finding suggests that chronic stress may not actually reduce astrocyte numbers and may instead selectively decrease GFAP expression. The results of the current study are significant as they indicate stress-induced astrocyte-mediated disturbances may not be due to a loss of cells but rather due to significant remodeling of the astrocyte network.

Chronic stress induced remodeling of the prefrontal cortex: structural re-organization of microglia and the inhibitory effect of minocycline.

Recently, it has been discovered that the working memory deficits induced by exposure to chronic stress can be prevented by treating stressed animals with minocycline, a putative inhibitor of microglial activity. One of the pressing issues that now requires clarification is exactly how exposure to chronic stress modifies microglial morphology, this being a significant issue as microglial morphology is tightly coupled with their function. To examine how chronic stress alters microglial morphology, we digitally reconstructed microglia within the rat medial prefrontal cortex. Our analysis revealed that stress increased the internal complexity of microglia, enhancing ramification (i.e. branching) without altering the overall area occupied by the cell and that this effect was more pronounced in larger cells. We subsequently determined that minocycline treatment largely abolished the pro-ramifying effects of stress. With respect to mechanisms, we could not find any evidence of increased inflammation or neurodegeneration (interleukin-1ß, MHC-II, CD68, terminal deoxynucleotidyl transferase dUTP nick end labeling, and activated caspase-3). We did, however, find that chronic stress markedly increased the expression of ß1-integrin (CD29), a protein previously implicated in microglial ramification. Together, these findings highlight that increased ramification of microglia may represent an important neurobiological mechanism through which microglia mediate the behavioral effects of chronic psychological stress.

A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia.

Selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRI; SNRI) are the first choice pharmacological treatment options for major depression. It has long been assumed that the primary therapeutic mechanism of action of these drugs involves the modulation of monoaminergic systems. However, contemporary investigations have revealed that depression is linked with inflammation, and that SSRI/SNRIs possess significant anti-inflammatory actions. While these anti-inflammatory properties initially only related to work undertaken on cells of the peripheral immune system, it has recently become apparent that these drugs also exert anti-inflammatory effects on microglia, the principal cells within the CNS that regulate and respond to inflammatory factors. The aim of the current study was to compare SSRI/SNRIs in terms of their anti-inflammatory potency, and to determine the specific mechanisms through which these effects are mediated. Accordingly, the current study evaluated the ability of five different SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram) and one SNRI (venlafaxine) to suppress microglial responses to an inflammatory stimulus. Specifically, we examined their ability to alter tumour necrosis factor-α (TNF-α) and nitric oxide (NO) production after 4 and 24 h stimulation with lipopolysaccharide. Our results indicated that the SSRIs potently inhibited microglial TNF-α and NO production. We then investigated whether these effects might involve either ß-adrenoceptor or cAMP signalling. Using the protein kinase A inhibitor Rp-CAMPs, we found evidence to suggest that cAMP signalling is involved in regulating the anti-inflammatory response. These findings suggest that antidepressants may owe at least some of their therapeutic effectiveness to their anti-inflammatory properties.

Repeated social defeat selectively increases δFosB expression and histone H3 acetylation in the infralimbic medial prefrontal cortex.

Exposure to social stress has been linked to the development and maintenance of mood-related psychopathology; however, the underlying neurobiological changes remain uncertain. In this study, we examined numbers of δFosB-immunoreactive cells in the forebrains of rats subjected to 12 episodes of social defeat. This was achieved using the social conflict model whereby animals are introduced into the home cage of older males ("residents") trained to attack and defeat all such "intruders"; importantly, controls were treated identically except that the resident was absent. Our results indicated that the only region in which δFosB-positive cells were found in significantly higher numbers in intruders than in controls was the infralimbic medial prefrontal cortex (mPFC). This same effect was not apparent using another psychological stressor, noise stress. Cells of the infralimbic mPFC also displayed evidence of chromatin remodeling. We found that exposure to repeated episodes of social defeat increased numbers of cells immunoreactive for histone H3 acetylation, but not for histone H3 phosphoacetylation, in the infralimbic mPFC. Collectively, these findings highlight the importance of the infralimbic mPFC in responding to social stress-a finding that provides insight into the possible neurobiological alterations associated with stress-induced psychiatric illness.

Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions.

The current study, in parallel experiments, evaluated the impact of chronic psychological stress on physiological and behavioural measures, and on the activation status of microglia in 15 stress-responsive brain regions. Rats were subjected, for 14 days, to two 30 min sessions of restraint per day, applied at random times each day. In one experiment the effects of stress on sucrose preference, weight gain, core body temperature, and struggling behaviour during restraint, were determined. In the second experiment we used immunohistochemistry to investigate stress-induced changes in ionized calcium-binding adaptor molecule-1 (Iba1), a marker constitutively expressed by microglia, and major histocompatibility complex-II (MHC-II), a marker often expressed on activated microglia, in a total of 15 stress-responsive nuclei. We also investigated cellular proliferation in these regions using Ki67 immunolabelling, to check for the possibility of microglial proliferation. Collectively, the results we obtained showed that chronic stress induced a significant increase in anhedonia, a decrease in weight gain across the entire observation period, a significant elevation in core body temperature during restraint, and a progressive decrease in struggling behaviour within and over sessions. With regard to microglial activation, chronic stress induced a significant increase in the density of Iba1 immunolabelling (nine of 15 regions) and the number of Iba1-positive cells (eight of 15 regions). Within the regions that exhibited an increased number of Iba1-positive cells after chronic stress, we found no evidence of a between group difference in the number of MHC-II or Ki67 positive cells. In summary, these results clearly demonstrate that chronic stress selectively increases the number of microglia in certain stress-sensitive brain regions, and also causes a marked transition of microglia from a ramified-resting state to a non-resting state. These findings are consistent with the view that microglial activation could play an important role in controlling and/or adapting to stress.

Strain differences in coping behaviour, novelty seeking behaviour, and susceptibility to socially conditioned fear: a comparison between Wistar and Sprague Dawley rats.

The aim of the current study was to generate socially conditioned fear in two different strains of rat (Wistar, W and Sprague Dawley, SD) using social conflict, in order to investigate whether the magnitude of the conditioned fear responses in each strain was related to behaviour exhibited prior to or during fear induction (i.e. social conflict). On day one of the study, all intruders were assessed for exploratory activity in a novel environment. Twenty four hours following the novel environment test the locomotor activity of the intruders was assessed, while they underwent a single familiarisation exposure to the arena in which the conflict was subsequently to occur in. Twenty-four hours following familiarisation, intruders underwent either a 10 min social conflict or sham conflict session. One day later we examined the response of the intruders when they were returned to the vacant resident's cage. Upon return to the conflict context, we examined the intruder's ultrasonic distress vocalisations and the extent to which locomotor activity was inhibited. We found that W rats displayed significantly more immobility (i.e. conditioned fear) upon return to context than did SD rats (p < 0.05). Importantly, we observed that the differences in the two strains behaviour upon return to context appeared to be related to their quite different patterns of coping behaviour. The results of the current study indicate that preclinical between-strain comparisons potentially have much to offer in regard to understanding the basis of resilience to social stress.

Individual differences predict susceptibility to conditioned fear arising from psychosocial trauma.

BACKGROUND: Classical Pavlovian fear conditioning has been widely used in preclinical studies to gain insights into anxiety-related disorders. In this study we examined whether pre-existing behavioral differences, and/or behavioral differences displayed during fear induction, predict the severity of the conditioned fear response that can develop after an episode of psychosocial conflict. METHODS: Prior to conditioning, male rats (intruders) were behaviorally assessed using the novel environment exploration and defensive burying tests. These animals were subsequently placed in the territory of an older male (resident) that invariably attacked the intruder. RESULTS: Upon return to this territory 24 h later, intruders moved less than controls and produced more distress vocalizations, indicating conditioned fear to context. Additionally, analyses revealed that both pre-existing behavioral differences, and the animal's response during social conflict, predicted the magnitude of the subsequent conditioned fear response. Specifically, animals that engaged in higher levels of novel environment exploration, that exhibited a greater number of defensive burying behaviors, and that demonstrated higher levels of fighting and guarding during social conflict, displayed less evidence of conditioned fear. CONCLUSION: These findings show that the behavioral variability existent within a normal outbred population can predict the magnitude of the conditioned fear response.