Recovery from acute hypoxia: A systematic review of cognitive and physiological responses during the 'hypoxia hangover'.

Recovery of cognitive and physiological responses following a hypoxic exposure may not be considered in various operational and research settings. Understanding recovery profiles and influential factors can guide post-hypoxia restrictions to reduce the risk of further cognitive and physiological deterioration, and the potential for incidents and accidents. We systematically evaluated the available evidence on recovery of cognitive and basic physiological responses following an acute hypoxic exposure to improve understanding of the performance and safety implications, and to inform post-hypoxia restrictions. This systematic review summarises 30 studies that document the recovery of either a cognitive or physiological index from an acute hypoxic exposure. Titles and abstracts from PubMed (MEDLINE) and Scopus were searched from inception to July 2022, of which 22 full text articles were considered eligible. An additional 8 articles from other sources were identified and also considered eligible. The overall quality of evidence was moderate (average Rosendal score, 58%) and there was a large range of hypoxic exposures. Heart rate, peripheral blood haemoglobin-oxygen saturation and heart rate variability typically normalised within seconds-to-minutes following return to normoxia or hyperoxia. Whereas, cognitive performance, blood pressure, cerebral tissue oxygenation, ventilation and electroencephalogram indices could persist for minutes-to-hours following a hypoxic exposure, and one study suggested regional cerebral tissue oxygenation requires up to 24 hours to recover. Full recovery of most cognitive and physiological indices, however, appear much sooner and typically within ~2-4 hours. Based on these findings, there is evidence to support a 'hypoxia hangover' and a need to implement restrictions following acute hypoxic exposures. The severity and duration of these restrictions is unclear but should consider the population, subsequent requirement for safety-critical tasks and hypoxic exposure.

Cocoa flavanols protect cognitive function, cerebral oxygenation, and mental fatigue during severe hypoxia.

We tested the hypothesis that ingestion of cocoa flavanols would improve cognition during acute hypoxia equivalent to 5,500 m altitude (partial pressure of end-tidal oxygen = 45 mmHg). Using placebo-controlled double-blind trials, 12 participants ingested 15 mg·kg-1 of cocoa flavanols 90 min before completing cognitive tasks during normoxia and either poikilocapnic or isocapnic hypoxia (partial pressure of end-tidal carbon dioxide uncontrolled or maintained at the baseline value, respectively). Cerebral oxygenation was measured using functional near-infrared spectroscopy. Overall cognition was impaired by poikilocapnic hypoxia (main effect of hypoxia, P = 0.008). Cocoa flavanols improved a measure of overall cognitive performance by 4% compared with placebo (effect of flavanols, P = 0.033) during hypoxia, indicating a change in performance from "low average" to "average." The hypoxia-induced decrease in cerebral oxygenation was two-fold greater with placebo than with cocoa flavanols (effect of flavanols, P = 0.005). Subjective fatigue was increased by 900% with placebo compared with flavanols during poikilocapnic hypoxia (effect of flavanols, P = 0.004). Overall cognition was impaired by isocapnic hypoxia (effect of hypoxia, P = 0.001) but was not improved by cocoa flavanols (mean improvement = 1%; effect of flavanols, P = 0.72). Reaction time was impaired by 8% with flavanols during normoxia and further impaired by 11% during isocapnic hypoxia (effect of flavanols, P = 0.01). Our findings are the first to show that flavanol-mediated improvements in cognition and mood during normoxia persist during severe oxygen deprivation, conferring a neuroprotective effect.NEW & NOTEWORTHY We show for the first time that cocoa flavanols exert a neuroprotective effect during severe hypoxia. Following acute cocoa flavanol ingestion, we observed improvements in cognition, cerebral oxygenation, and subjective fatigue during normoxia and severe poikilocapnic hypoxia. Cocoa flavanols did not improve cognition during severe isocapnic hypoxia, suggesting a possible interaction with carbon dioxide.

The effect of acute normobaric hyperoxia on cognition: A systematic review, meta-analysis and meta-regression.

This systematic review, meta-analysis and meta-regression examined the effect of acute normobaric hyperoxic breathing on cognition in healthy humans. 23 studies were included providing 76 effect estimates (EE). Hyperoxic breathing improved memory accuracy (22 EEs; g = 0.34) and speed (9 EEs; g = 0.59), attention accuracy (7 EEs; g = 0.59) and speed (7 EEs; g = 0.51), reaction speed (8 EEs; g = 0.82), crystallised intelligence (7 EEs; g = 0.73), executive function (6 EEs; g = 0.88) and information processing (10 EEs; g = 0.62). However, the overall quality of evidence was low (average Rosendal score of 47%) and there was a large range of study heterogeneity, with prediction intervals often crossing 0; therefore, reducing the reliability of the magnitude of these favourable effects. Oxygen percentage, 100% compared with 22-99% oxygen, temporal position of administration to task performance, and study quality did not influence the overall weighted mean effects for most cognitive domains. Altogether, despite beneficial results, further high quality research is required prior to recommending hyperoxic breathing to enhance cognition.

Carbon dioxide protects simulated driving performance during severe hypoxia.

PURPOSE: We sought to determine the effect of acute severe hypoxia, with and without concurrent manipulation of carbon dioxide (CO2), on complex real-world psychomotor task performance. METHODS: Twenty-one participants completed a 10-min simulated driving task while breathing room air (normoxia) or hypoxic air (PETO2 = 45 mmHg) under poikilocapnic, isocapnic, and hypercapnic conditions (PETCO2 = not manipulated, clamped at baseline, and clamped at baseline + 10 mmHg, respectively). Driving performance was assessed using a fixed-base motor vehicle simulator. Oxygenation in the frontal cortex was measured using functional near-infrared spectroscopy. RESULTS: Speed limit exceedances were greater during the poikilocapnic than normoxic, hypercapnic, and isocapnic conditions (mean exceedances: 8, 4, 5, and 7, respectively; all p ≤ 0.05 vs poikilocapnic hypoxia). Vehicle speed was greater in the poikilocapnic than normoxic and hypercapnic conditions (mean difference: 0.35 km h-1 and 0.67 km h-1, respectively). All hypoxic conditions similarly decreased cerebral oxyhaemoglobin and increased deoxyhaemoglobin, compared to normoxic baseline, while total hemoglobin remained unchanged. CONCLUSIONS: These findings demonstrate that supplemental CO2 can confer a neuroprotective effect by offsetting impairments in complex psychomotor task performance evoked by severe poikilocapnic hypoxia; however, differences in performance are unlikely to be linked to measurable differences in cerebral oxygenation.

Cerebral haemodynamics during simulated driving: Changes in workload are detectable with functional near infrared spectroscopy.

Motor vehicle operation is a complicated task and substantial cognitive resources are required for safe driving. Experimental paradigms examining cognitive workload using driving simulators often introduce secondary tasks, such as mathematical exercises, or utilise simulated in-vehicle information systems. The effects of manipulating the demands of the primary driving task have not been examined in detail using advanced neuroimaging techniques. This study used a manipulation of the simulated driving environment to test the impact of increased driving complexity on brain activity. Fifteen participants drove in two scenarios reflecting common driving environments differing in the amount of vehicular traffic, frequency of intersections, number of buildings, and speed limit restrictions. Functional near infrared spectroscopy was used to quantify changes in cortical activity; fifty-five optodes were placed over the prefrontal and occipital cortices, commonly assessed areas during driving. Compared to baseline, both scenarios increased oxyhaemoglobin in the bilateral prefrontal cortex and cerebral blood volume in the right prefrontal cortex (all p ≤ 0.05). Deoxyhaemoglobin decreased at the bilateral aspects of the prefrontal cortex but overall tended to increase in the medial aspect during both scenarios (both p ≤ 0.05). Cerebral oxygen exchange significantly declined at the lateral aspects of the prefrontal cortex, with a small but significant increase seen in the medial aspect (both p < 0.05). There were no significant differences for oxyhaemoglobin, deoxyhaemoglobin, or cerebral blood volume (all p > 0.05). This study demonstrates that functional near infrared spectroscopy is capable of detecting changes in cortical activity elicited by simulated driving tasks but may be less sensitive to variations in driving workload aggregated over a longer duration.

Preclinical Evaluation of TSPO and MAO-B PET Radiotracers in an LPS Model of Neuroinflammation.

Discovery of novel PET radiotracers targeting neuroinflammation (microglia and astrocytes) is actively pursued. Employing a lipopolysaccharide (LPS) rat model, this longitudinal study evaluated the translocator protein 18-kDa radiotracer [18F]FEPPA (primarily microglia) and monoamine oxidase B radiotracers [11C]L-deprenyl and [11C]SL25.1188 (astrocytes preferred). Increased [18F]FEPPA binding peaked at 1 week in LPS-injected striatum whereas increased lazabemide-sensitive [11C]L-deprenyl binding developed later. No increase in radiotracer uptake was observed for [11C]SL25.1188. The unilateral intrastriatal LPS rat model may serve as a useful tool for benchmarking PET tracers targeted toward distinct phases of neuroinflammatory reactions involving both microglia and astrocytes.

Synthesis, in vitro and in vivo evaluation of 11C-O-methylated arylpiperazines as potential serotonin 1A (5-HT1A) receptor antagonist radiotracers.

BACKGROUND: Serotonin 1A (5-HT1A) receptors are implicated in the pathogenesis of several psychiatric and neurodegenerative disorders motivating the development of suitable radiotracers for in vivo positron emission tomography (PET) neuroimaging. The gold standard PET imaging agent for this target is [carbonyl-11C]WAY-100635, labeled via a technically challenging multi-step reaction that has limited its widespread use. While several antagonist and agonist-based PET radiotracers for 5-HT 1A receptors have been developed, their clinical translation has been hindered by methodological challenges and/or and non-specific binding. As a result, there is continued interest in the development of new and more selective 5-HT1A PET tracers having a relatively easier and reliable radiosynthesis process for routine production and with favorable metabolism to facilitate tracer-kinetic modeling. The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT1A receptors in the brain. The current study reports the in vitro characterization and radiosyntheses of three candidate 5-HT1A receptor antagonists, DF-100 (1), DF-300 (2) and DF-400 (3), to explore their suitability as potential PET radiotracers. RESULTS: Syntheses of 1-3 and corresponding precursors for radiolabeling were achieved from isonicotinic, picolinic acid or picolino nitrile. In vitro binding studies demonstrated nanomolar affinity of the compounds for 5-HT1A receptors. Binding of 1-3 for other biogenic amines, neurotransmitter receptors, and transporters was negligible with the exception of moderate affinities for α1-adrenergic receptors (4-6-fold less potent than that for 5-HT1A receptor). Radioligands [11C]1-3 were efficiently prepared by 11C-O-methylation of the corresponding phenolic precursor in non-decay corrected radiochemical yields of 7-11% with > 99% chemical and radiochemical purities. Dynamic PET studies in rats demonstrated negligible brain uptake of [11C]1 and [11C]2. In contrast, significant brain uptake of [11C]3 was observed with an early peak SUV of 4-5. However, [11C]3 displayed significant off-target binding attributed to α1-adrenergic receptors based on regional distribution (thalamus>hippocampus) and blocking studies. CONCLUSION: Despite efficient radiolabeling, results from PET imaging experiments limit the application of [11C]3 for in vivo quantification of 5-HT1A receptors. Nevertheless, derivatives of compound 3 may provide a scaffold for alternative PET radiotracers with improved selectivity for 5-HT 1A receptors or α1-adrenergic receptors.

Spatial and temporal variations of PM2.5 mass closure and inorganic PM2.5 in the Southeastern U.S.

Fine particulate matter (i.e., PM2.5) has gained extensive attention owing to its adverse effects. The impacts of PM2.5 may vary in time and space due to the spatiotemporal variations of PM2.5 number size distribution and chemical compositions. This research analyzed the latest PM2.5 chemical compositions measurements with an aim to better understand the dynamic changes of PM2.5 in response to emission reductions due to the new regulations. The particulate measurements from the Southeastern Aerosol Research and Characterization (SEARCH) network between 2001 and 2016 were analyzed for the spatiotemporal variations of PM2.5 and inorganic PM2.5 (iPM2.5 = SO42- + NH4+ + NO3-) chemical compositions in the Southeastern United States (U.S.). It was discovered that PM2.5 and iPM2.5 mass concentrations exhibited significant downward trends in 2001-2016. Both PM2.5 and iPM2.5 mass concentrations were higher at urban and inland sites than rural/suburban and coastal sites. The higher iPM2.5 concentrations at agricultural sites were attributed to the influences of ammonia (NH3) emissions from animal feeding operations (AFOs). The iPM2.5 was the dominant contributor to PM2.5 in 2001-2016 at the coastal sites, whereas organic carbon matter (OCM) was the major contributor to PM2.5 after 2011 at the inland sites. Our data analysis suggests that significant decrease of PM2.5 concentrations is attributed to the reductions in nitrogen oxides (NOx) and sulfur dioxide (SO2) emissions in 2001-2016. Findings from this research provide insights into the development of effective PM2.5 control strategies and assessment of air pollutants exposure.

The association of psychosocial risk factors for mental health with a brain marker altered by inflammation: A translocator protein (TSPO) PET imaging study.

Psychiatric disorders associated with psychosocial risk factors, including depression and psychosis, have been shown to demonstrate increased microglia activity. Whilst preclinical studies indicate that psychosocial stress leads to increased levels of microglia in the frontal cortex, no study has yet been performed in humans. This study aimed at investigating whether psychosocial risk factors for depression and/or psychosis would be associated with alterations in a brain marker expressed by microglia, the translocator specific protein (TSPO) in humans. We used [11C]-PBR28 Positron Emission Tomography on healthy subjects exposed to childhood and adulthood psychosocial risk factors (high-risk group, N = 12) and age- and sex-matched healthy controls not exposed to childhood and adulthood psychosocial risk factors (low-risk group, N = 12). The [11C]-PBR28 volume of distribution (VT) and Distribution Volume Ratio (DVR) were measured in the total gray matter, and frontal, parietal, temporal, occipital lobes. Levels of childhood trauma, anxiety and depression were measured using respectively the Childhood Trauma Questionnaire, State-anxiety questionnaire and Beck Depression Inventory. Compared to the low-risk group, the high-risk group did not exhibit significant differences in the mean [11C]-PBR28 VT (F(1,20) = 1.619, p = 0.218) or DVR (F(1,22) = 0.952, p = 0.340) on any region. There were no significant correlations between the [11C]-PBR28 VT and DVRs in total gray matter and frontal lobe and measures of childhood trauma, anxiety and depression. Psychosocial risk factors for depression and/or psychosis are unlikely to be associated with alterations in [11C]-PBR28 binding, indicating that alterations in TSPO expression reported in these disorders is unlikely to be caused by psychosocial risk factors alone.

Generalization of endothelial modelling of TSPO PET imaging: Considerations on tracer affinities.

The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [11C]PBR28, [18F]DPA714 and [11C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [11C]-R-PK11195 data from six healthy subjects. Then, we compared the [11C]-R-PK11195 vascular binding estimates with previously published values for [18F]DPA714 and [11C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [11C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.

A Unified Framework for Plasma Data Modeling in Dynamic Positron Emission Tomography Studies.

OBJECTIVE: Full quantification of dynamic positron emission tomography (PET) data requires the knowledge of tracer concentration in the arterial plasma. However, its accurate measurement is challenging due to the presence of radiolabeled metabolites and measurement noise. Mathematical models are fitted to the plasma data for both radiometabolite correction and data denoising. However, the models used are generally not physiologically informed and not consistently applied across studies even when quantifying the kinetics of the same radiotracer, introducing methodological variability affecting the results interpretation. The aim of this study was to develop and validate a unified framework for the arterial data modeling to achieve an accurate and fully automated description of the plasma tracer kinetics. METHODS: The proposed pipeline employs basis pursuit techniques for estimating both radiometabolites and parent concentration models from the raw plasma measurements, allowing the resulting algorithm to be both robust and flexible to the different quality of data available. The pipeline was tested on four PET tracers ([11C]PBR28, [11C]MePPEP, [11C]WAY-100635, and [11C]PIB) with continuous and discrete blood sampling. RESULTS: Compared to the standard procedure, the pipeline provided similar fit of the parent fraction but yielded a better description of the total plasma radioactivity, which in turn allowed a more accurate fit of the tissue PET data. CONCLUSION: The new method showed superior fits compared to the standard pipeline, for both continuous and discrete arterial sampling protocol, yielding to better description of PET data. SIGNIFICANCE: The proposed pipeline has the potential to standardize the blood data modeling in dynamic PET studies given its robustness, flexibility and easiness of use.

The effects of haloperidol on microglial morphology and translocator protein levels: An in vivo study in rats using an automated cell evaluation pipeline.

BACKGROUND: Altered microglial markers and morphology have been demonstrated in patients with schizophrenia in post-mortem and in vivo studies. However, it is unclear if changes are due to antipsychotic treatment. AIMS: Here we aimed to determine whether antipsychotic medication affects microglia in vivo. METHODS: To investigate this we administered two clinically relevant doses (0.05 mg n=12 and 2.5 mg n=7 slow-release pellets, placebo n=20) of haloperidol, over 2 weeks, to male Sprague Dawley rats to determine the effect on microglial cell density and morphology (area occupied by processes and microglial cell area). We developed an analysis pipeline for the automated assessment of microglial cells and used lipopolysaccharide (LPS) treatment ( n=13) as a positive control for analysis. We also investigated the effects of haloperidol ( n=9) or placebo ( n=10) on the expression of the translocator protein 18 kDa (TSPO) using autoradiography with [3H]PBR28, a TSPO ligand used in human positron emission tomography (PET) studies. RESULTS: Here we demonstrated that haloperidol at either dose does not alter microglial measures compared with placebo control animals ( p > 0.05). Similarly there was no difference in [3H]PBR28 binding between placebo and haloperidol tissue ( p > 0.05). In contrast, LPS was associated with greater cell density ( p = 0.04) and larger cell size ( p = 0.01). CONCLUSION: These findings suggest that haloperidol does not affect microglial cell density, morphology or TSPO expression, indicating that clinical study alterations are likely not the consequence of antipsychotic treatment. The automated cell evaluation pipeline was able to detect changes in microglial morphology induced by LPS and is made freely available for future use.

Brain TSPO imaging and gray matter volume in schizophrenia patients and in people at ultra high risk of psychosis: An [11C]PBR28 study.

Patients with schizophrenia show whole brain and cortical gray matter (GM) volume reductions which are progressive early in their illness. Microglia, the resident immune cells in the CNS, phagocytose neurons and synapses. Some post mortem and in vivo studies in schizophrenia show evidence for elevated microglial activation compared to matched controls. However, it is currently unclear how these results relate to changes in cortical structure. METHODS: Fourteen patients with schizophrenia and 14 ultra high risk for psychosis (UHR) subjects alongside two groups of age and genotype matched healthy controls received [11C]PBR28 PET scans to index TSPO expression, a marker of microglial activation and a 3T MRI scan. We investigated the relationship between the volume changes of cortical regions and microglial activation in cortical GM (as indexed by [11C]PBR28 distribution volume ratio (DVR). RESULTS: The total cortical GM volume was significantly lower in SCZ than the controls [mean (SD)/cm3: SCZ=448.83 (39.2) and controls=499.6 (59.2) (p=0.02) but not in UHR (mean (SD)=503.06 (57.9) and controls=524.46 (45.3) p=0.3). Regression model fitted the total cortical GM DVR values with the cortical regional volumes in SCZ (r=0.81; p<0.001) and in UHR (r=0.63; p=0.02). We found a significant negative correlation between the TSPO signal and total cortical GM volume in SCZ with the highest absolute correlation coefficient in the right superior-parietal cortex (r=-0.72; p=0.006). CONCLUSIONS: These findings suggest that microglial activity is related to the altered cortical volume seen in schizophrenia. Longitudinal investigations are required to determine whether microglial activation leads to cortical gray matter loss.

Kinetic modelling of [11C]PBR28 for 18 kDa translocator protein PET data: A validation study of vascular modelling in the brain using XBD173 and tissue analysis.

The 18 kDa translocator protein (TSPO) is a marker of microglia activation in the central nervous system and represents the main target of radiotracers for the in vivo quantification of neuroinflammation with positron emission tomography (PET). TSPO PET is methodologically challenging given the heterogeneous distribution of TSPO in blood and brain. Our previous studies with the TSPO tracers [11C]PBR28 and [11C]PK11195 demonstrated that a model accounting for TSPO binding to the endothelium improves the quantification of PET data. Here, we performed a validation of the kinetic model with the additional endothelial compartment through a displacement study. Seven subjects with schizophrenia, all high-affinity binders, underwent two [11C]PBR28 PET scans before and after oral administration of 90 mg of the TSPO ligand XBD173. The addition of the endothelial component provided a signal compartmentalization much more consistent with the underlying biology, as only in this model, the blocking study produced the expected reduction in the tracer concentration of the specific tissue compartment, whereas the non-displaceable compartment remained unchanged. In addition, we also studied TSPO expression in vessels using 3D reconstructions of histological data of frontal lobe and cerebellum, demonstrating that TSPO positive vessels account for 30% of the vascular volume in cortical and white matter.

Evaluation of a novel radiotracer for positron emission tomography imaging of reactive oxygen species in the central nervous system.

INTRODUCTION: Few, if any, radiotracers are available for the in vivo imaging of reactive oxygen species (ROS) in the central nervous system. ROS play a critical role in normal cell processes such as signaling and homeostasis but overproduction of ROS is implicated in several disorders. We describe here the radiosynthesis and initial ex vivo and in vivo evaluation of [11C]hydromethidine ([11C]HM) as a radiotracer to image ROS using positron emission tomography (PET). METHODS: [11C]HM and its deuterated isotopologue [11C](4) were produced using [11C]methyl triflate in a one-pot, two-step reaction and purified by high performance liquid chromatography. Ex vivo biodistribution studies were performed after tail vein injections of both radiotracers. To demonstrate sensitivity of uptake to ROS, [11C]HM was administered to rats treated systemically with lipopolysaccharide (LPS). In addition, ex vivo autoradiography and in vivo PET imaging were performed using [11C]HM on rats which had been microinjected with sodium nitroprusside (SNP) to induce ROS. RESULTS: [11C]HM and [11C](4) radiosyntheses were reliable and produced the radiotracers at high specific activities and radiochemical purities. Both radiotracers demonstrated good brain uptake and fast washout of radioactivity, but [11C](4) washout was faster. Pretreatment with LPS resulted in a significant increase in brain retention of radioactivity. Ex vivo autoradiography and PET imaging of rats unilaterally treated with microinjections of SNP demonstrated increased retention of radioactivity in the treated side of the brain. CONCLUSIONS: [11C]HM has the attributes of a radiotracer for PET imaging of ROS in the brain including good brain penetration and increased retention of radioactivity in animal models of oxidative stress.

Biometric validation of a virtual reality-based psychomotor test for motor skill training.

Psychomotor tests have been applied in clinical therapy and laboratory research as tools for evaluating motor and cognitive skills. Some studies have developed computerized versions of such tests using virtual reality (VR) systems with haptic interface controls. These systems allow for increased flexibility in test delivery and accuracy in performance assessment. In this study, a VR-based computer simulation of the block design (BD) test (a standardized psychomotor task as part of an adult IQ test) was developed and compared with the physical version of the test. Performance was evaluated based on four types of muscle activation collected using electromyography (EMG), time spent in completing the task, and subjective ratings of workload. Results verified the VR-based task as physically comparable to the conventional BD test. The validated computerized psychomotor task may be applied for both experimental and clinical use in future studies.

Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness.

RATIONALE: Psychosocial stressors are a well-documented risk factor for mental illness. Neuroinflammation, in particular elevated microglial activity, has been proposed to mediate this association. A number of preclinical studies have investigated the effect of stress on microglial activity. However, these have not been systematically reviewed before. OBJECTIVES: This study aims to systematically review the effects of stress on microglia, as indexed by the histological microglial marker ionised calcium binding adaptor molecule 1 (Iba-1), and consider the implications of these for the role of stress in the development of mental disorders. METHODS: A systematic review was undertaken using pre-defined search criteria on PubMed and EMBASE. Inclusion and data extraction was agreed by two independent researchers after review of abstracts and full text. RESULTS: Eighteen studies met the inclusion criteria. These used seven different psychosocial stressors, including chronic restraint, social isolation and repeated social defeat in gerbils, mice and/or rats. The hippocampus (11/18 studies) and prefrontal cortex (13/18 studies) were the most frequently studied areas. Within the hippocampus, increased Iba-1 levels of between 20 and 200 % were reported by all 11 studies; however, one study found this to be a duration-dependent effect. Of those examining the prefrontal cortex, ∼75 % found psychosocial stress resulted in elevated Iba-1 activity. Elevations were also consistently seen in the nucleus accumbens, and under some stress conditions in the amygdala and paraventricular nucleus. CONCLUSIONS: There is consistent evidence that a range of psychosocial stressors lead to elevated microglial activity in the hippocampus and good evidence that this is also the case in other brain regions. These effects were seen with early-life/prenatal stress, as well as stressors in adulthood. We consider these findings in terms of the two-hit hypothesis, which proposes that early-life stress primes microglia, leading to a potentiated response to subsequent stress. The implications for understanding the pathoaetiology of mental disorders and the development of new treatments are also considered.

Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [(11)C]PBR28 PET Brain Imaging Study.

OBJECTIVE: The purpose of this study was to determine whether microglial activity, measured using translocator-protein positron emission tomography (PET) imaging, is increased in unmedicated persons presenting with subclinical symptoms indicating that they are at ultra high risk of psychosis and to determine whether microglial activity is elevated in schizophrenia after controlling for a translocator-specific genetic polymorphism. METHOD: The authors used the second-generation radioligand [(11)C]PBR28 and PET to image microglial activity in the brains of participants at ultra high risk for psychosis. Participants were recruited from early intervention centers. The authors also imaged a cohort of patients with schizophrenia and matched healthy subjects for comparison. In total, 50 individuals completed the study. At screening, participants were genotyped to account for the rs6971 polymorphism in the gene encoding the 18Kd translocator protein. The main outcome measure was total gray matter [(11)C]PBR28 binding ratio, representing microglial activity. RESULTS: [(11)C]PBR28 binding ratio in gray matter was elevated in ultra-high-risk participants compared with matched comparison subjects (Cohen's d >1.2) and was positively correlated with symptom severity (r=0.730). Patients with schizophrenia also demonstrated elevated microglial activity relative to matched comparison subjects (Cohen's d >1.7). CONCLUSIONS: Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity. These findings suggest that neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical symptoms.