Professor Michael Nilsson

Background: Total knee arthroplasty is the standard surgical treatment for end-stage osteoarthritis. Although widely accepted as a successful procedure, approximately 30% of patients are not satisfied due to non-optimal postoperative outcomes. Clinical decision support tools that are able to accurately predict post-surgery outcomes would assist in providing individualized advice or services to help alleviate possible issues, resulting in significant benefits to both the healthcare system and individuals. Methods: Five databases (Ovid Medline, Ovid EMBASE, CINAHL complete, Cochrane Library, and Scopus) were searched for the key phrases ¿knee replacement¿ or ¿knee arthroplasty¿ and ¿decision support tool,¿ ¿decision tool,¿ ¿predict* tool,¿ ¿predict* model,¿ ¿algorithm¿ or ¿nomogram.¿ Searches were limited to peer-reviewed journal articles published between January 2000 and June 2019. Reference lists of included articles were examined. Authors came to a consensus on the final list of included articles. Results: Eighteen articles were included for review. Most models reported low predictive success and inability to externally validate. Both candidate and final predictor variables were inconsistent between studies. Only 1 model was considered strongly predictive (AUROC >0.8), and only 2 studies were able to externally validate their developed model. In general, models that performed well used large patient numbers, were tested on similar demographics, and used either nonlinear input transformations or a completely nonlinear model. Conclusion: Some models do show promise; however, there remains the question of whether the reported predictive success can continue to be replicated. Furthermore, clinical applicability and interpretation of predictive tools should be considered during development.

Background: Cardiorespiratory fitness (CRF) is an important marker of current and future health status. The primary aim of our study was to evaluate the impact of a time-efficient school-based intervention on older adolescents' CRF. Methods: Two-arm cluster randomised controlled trial conducted in two cohorts (February 2018 to February 2019 and February 2019 to February 2020) in New South Wales, Australia. Participants (N=670, 44.6% women, 16.0±0.43 years) from 20 secondary schools: 10 schools (337 participants) were randomised to the Burn 2 Learn (B2L) intervention and 10 schools (333 participants) to the control. Teachers in schools allocated to the B2L intervention were provided with training, resources, and support to facilitate the delivery of high-intensity interval training (HIIT) activity breaks during curriculum time. Teachers and students in the control group continued their usual practice. The primary outcome was CRF (20 m multi-stage fitness test). Secondary outcomes were muscular fitness, physical activity, hair cortisol concentrations, mental health and cognitive function. Outcomes were assessed at baseline, 6 months (primary end-point) and 12 months. Effects were estimated using mixed models accounting for clustering. Results: We observed a group-by-time effect for CRF (difference=4.1 laps, 95% CI 1.8 to 6.4) at the primary end-point (6 months), but not at 12 months. At 6 months, group-by-time effects were found for muscular fitness, steps during school hours and cortisol. Conclusions: Implementing HIIT during curricular time improved adolescents' CRF and several secondary outcomes. Our findings suggest B2L is unlikely to be an effective approach unless teachers embed sessions within the school day. Trial registration number: Australian New Zealand Clinical Trials Registry (ACTRN12618000293268).

Background The association of serum insulin-like growth factor I (s-IGF-I) with favorable outcome after ischemic stroke (IS) beyond 2 years is unknown. We investigated whether the levels of s-IGF-I 3 months post-stroke were associated with functional recovery up to 7 years after IS, considering also mortality and recurrent strokes. Methods Patients (N=324; 65% males; mean age, 55 years) with s-IGF-I levels assessed 3 months after the index IS were included from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The modified Rankin Scale (mRS) was used to evaluate outcomes at 3 months, 2 and 7 years after IS, and recovery was defined as an improvement, no change, or deterioration in the shifts of mRS score. Baseline stroke severity was determined using the National Institutes of Health Stroke Scale (NIHSS). Results The mRS score distributions were better in the above-median s-IGF-I group (>146.7 ng/ml). The s-IGF-I level was not associated with recurrent stroke (N=79) or death (N=44), although it correlated with recovery (r=0.12, P=0.035). In the regression analysis, s-IGF-I associated with recovery between 3 months and 7 years (but not between 2 and 7 years). The associations did not withstand adjustment for age and sex. For comparison, the corresponding associations between 3 months and 2 years withstood all adjustments. Conclusion The association for s-IGF-I with long-term post-stroke recovery persists after 7 years, which is also reflected in the mRS score distributions at all time-points. The effects are however modest, and not driven by mortality or recurrent stroke.

BACKGROUND: Persons with stroke commonly have residual neurological deficits that seriously hamper mobility. OBJECTIVE: To investigate whether horse-riding therapy (H-RT) and rhythm and music-based therapy (R-MT) affect functional mobility in late phase after stroke. METHODS: This study is part of a randomized controlled trial in which H-RT and R-MT was provided twice weekly for 12 weeks. Assessment included the timed 10-meter walk test (10 mWT), the six-minute walk test (6 MWT) and Modified Motor Assessment Scale (M-MAS). RESULTS: 123 participants were assigned to H-RT (n = 41), R-MT (n = 41), or control (n = 41). Post-intervention, the H-RT group completed the 10 mWT faster at both self-selected (-2.22 seconds [95% CI,-3.55 to-0.88]; p = 0.001) and fast speed (-1.19 seconds [95% CI,-2.18 to-0.18]; p = 0.003), with fewer steps (-2.17 [95% CI,-3.30 to-1.04]; p = 0.002 and-1.40 [95% CI,-2.36 to-0.44]; p = 0.020, respectively), as compared to controls. The H-RT group also showed improvements in functional task performance as measured by M-MAS UAS (1.13 [95% CI, 0.74 to 1.52]; p = 0.001). The gains were partly maintained at 6 months among H-RT participants. The R-MT did not produce any immediate gains. However, 6 months post-intervention, the R-MT group performed better with respect to time;-0.75 seconds [95% CI,-1.36 to-0.14]; p = 0.035) and number of steps-0.76 [95% CI,-1.46 to-0.05]; p = 0.015) in the 10 mWT at self-selected speed. CONCLUSIONS: The present study supports the efficacy of H-RT in producing immediate gains in gait and functional task performance in the late phase after stroke, whereas the effectiveness of R-MT is less clear.

Background. Exercise after stroke improves cardiorespiratory fitness and walking capacity; however, the effect of altering exercise dose (via frequency, intensity, time, and type) on fitness or walking capacity is unclear. Purpose. The purpose of this study was to synthesize the current evidence for the effects of different doses of exercise on cardiorespiratory fitness and walking capacity in people after stroke. Data Sources. Seven relevant electronic databases were searched using keywords relating to stroke and cardiorespiratory fitness. Study Selection. Trials that compared more than 1 dose of exercise for people (? 18 years old) after stroke and measured peak oxygen consumption or 6-minute walk test distance as an outcome were included. Two reviewers independently appraised all trials. Data Extraction. Two reviewers independently extracted data from included articles. Intervention variables were extracted in accordance with the Template for Intervention Description and Replication checklist. Data Synthesis. Data were synthesized narratively. Nine trials involving 279 participants were included. Three of 5 trials comparing exercise intensity showed that higherintensity training was associated with greater improvements in cardiorespiratory fitness. The effects of other exercise dose components (frequency, time, and type) on fitness were not determined. Overall, walking capacity improved as program length increased. Limitations. All trials had a high risk of bias, and most had a high rate of attrition. Most trials included people more than 6 months after stroke and who walked independently, limiting the generalizability of the findings. Conclusions. Exercising at an intensity greater than 70% of heart rate reserve can be more effective in increasing cardiorespiratory fitness after stroke than exercising at lower intensities. More trials that compare exercise doses by manipulating only 1 dose parameter at a time for people after stroke are needed.

Numerous clinical studies have documented the high incidence of cognitive impairment after stroke. However, there is only limited knowledge about the underlying mechanisms. Interestingly, there is emerging evidence suggesting that cognitive function after stroke may be affected due to reduced waste clearance and subsequent accumulation of neurotoxic proteins. To further explore this potential association, we utilised a model of experimental stroke in mice. Specifically, a photothrombotic vascular occlusion targeting motor and sensory parts of the cerebral cortex was induced in young adult mice, and changes in cognition were assessed using a touchscreen platform for pairwise visual discrimination. The results showed that the execution of the visual discrimination task was impaired in mice 10 to 14 days post-stroke compared to sham. Stroke also induced significant neuronal loss within the peri-infarct, thalamus and the CA1 sub-region of the hippocampus. Further, immunohistochemical and protein analyses of the selected brain regions revealed an increased accumulation and aggregation of both amyloid-ß and a-synuclein. These alterations were associated with significant disturbances in the aquaporin-4 protein expression and polarization at the astrocytic end-feet. The results suggest a link between the increased accumulation of neurotoxic proteins and the stroke-induced cognitive impairment. Given that the neurotoxic protein accumulation appeared alongside changes in astrocytic aquaporin-4 distribution, we suggest that the function of the waste clearance pathways in the brain post-stroke may represent a therapeutic target to improve brain recovery.

Background: Accessing suitable fitness programs post-stroke is difficult for many. The feasibility of telehealth delivery has not been previously reported. Objectives: To assess the feasibility of, and level of satisfaction with home-based telehealth-supervised aerobic exercise training post-stroke. Methods: Twenty-one ambulant participants (= 3 months post-stroke) participated in a home-based telehealth-supervised aerobic exercise program (3 d/week, moderate-vigorous intensity, 8-weeks) and provided feedback via questionnaire post-intervention. Session details, technical issues, and adverse events were also recorded. Results: Feasibility was high (83% of volunteers met telehealth eligibility criteria, 85% of sessions were conducted by telehealth, and 95% of participants rated usability favourably). Ninety-five percent enjoyed telehealth exercise sessions and would recommend them to others. The preferred telehealth exercise program parameters were: frequency 3 d/week, duration 20-30 min/session, program length 6-12 weeks. Conclusion: The telehealth delivery of exercise sessions to people after stroke appears feasible and may be considered as a viable alternative delivery means for providing supervised exercise post-stroke.

Experimental stroke leads to microglia activation and progressive neuronal loss at sites of secondary neurodegeneration (SND). These lesions are remote from, but synaptically connected to, primary infarction sites. Previous studies have demonstrated that immune cells are present in sites of infarction in the first hours and days after stroke, and are associated with increased neurodegeneration in peri-infarct regions. However, it is not known whether immune cells are also present in more distal sites where SND occurs. Our study aimed to investigate whether immune cells are present in sites of SND and, if so, how these cell populations compare to those in the peri-infarct zone. Cells were isolated from the thalamus, the main site of SND, and remaining brain tissue 14 days post-stroke. Analysis was performed using flow cytometry to quantify microglia, myeloid cell and lymphocyte numbers. We identified a substantial infiltration of immune cells in the ipsilateral (stroked) compared to the contralateral (control) thalamus, with a significant increase in the percentage of CD4 and CD8 T cells. This result was further quantified using immunofluorescent labelling of fixed tissue. In the remaining ipsilateral hemisphere tissue, there were significant increases in the frequency of CD4 and CD8 T lymphocytes, B lymphocytes, Ly6G neutrophils and both Ly6G Ly6C and Ly6G Ly6C monocytes. Our results indicate that infiltrating immune cells persist in ischemic tissue after the acute ischemic phase, and are increased in sites of SND. Importantly, immune cells have been shown to play pivotal roles in both damage and repair processes after stroke. Our findings indicate that immune cells may also be involved in the pathogenesis of SND and further clinical studies are warranted to characterise the nature of inflammatory cell infiltrates in human disease. + + + + + - LO - HI

Purpose: The purpose of this systematic scoping review was to (1) identify combined somatosensory and motor training interventions for the upper limb and their training components, and (2) review the efficacy of the combined interventions. Methods: Participants were adults post-stroke with somatosensory and/or movement deficits in the upper limb. All studies with interventions combining somatosensory and motor training and targeting the affected upper limb were included. Outcome measures were assessments of somatosensory and/or motor impairment and upper limb function. Results: Ten studies (n = 219) were included, comprising three randomized controlled trials, two pre-post studies with non-randomized comparison groups, three single-case experimental studies, and two case reports. There was heterogeneity across studies with regards to intervention contents and dosage, participant characteristics, and outcome measures. The interventions included combinations of tactile stimulation/discrimination, proprioceptive stimulation/discrimination, haptic object discrimination/recognition, movement training, and functional training. Only one group study, a non-randomized controlled study with multiple active components and the largest dose of treatment, found significant improvements in fine motor and somatosensory measures. Some improvements were found in case studies. Conclusion: There was little consistency across ¿combined somatosensory and motor training¿ interventions and few have been rigorously tested for efficacy across somatosensory, motor and functional outcomes.

Despite the fact that approximately 80% of strokes occur in those aged over 60 years, many pre-clinical stroke studies have been conducted in younger adult rodents, raising debate about translation and generalizability of these results. We were interested in potential age differences in stroke-induced secondary neurodegeneration (SND). SND involves the death of neurons in areas remote from, but connected to, the site of infarction, as well as glial disturbances. Here we investigated potential differences in key parameters of SND in the thalamus, a major site of post-stroke SND. Protein expression profiles in young adult (2¿4 months) and aged (22¿23 months) mice were analyzed 28 days after a cortical stroke. Our results show that age reduced the expression of synaptic markers (PSD 95, Synapsin1) and increased Amyloid ß oligomer accumulation after stroke. Protein expression of several markers of glial activity remained relatively stable across age groups post-stroke. We have identified that age exacerbates the severity of SND after stroke. Our results, however, do not support a view that microglia or astrocytes are the main contributors to the enhanced severity of SND in aged mice.

Secondary neurodegeneration (SND) is an insidious and progressive condition involving the death of neurons in regions of the brain that were connected to but undamaged by the initial stroke. Our group have published compelling evidence that exposure to psychological stress can significantly exacerbate the severity SND, a finding that has considerable clinical implications given that stroke-survivors often report experiencing high and unremitting levels of psychological stress. It may be possible to use one or more targeted pharmacological approaches to limit the negative effects of stress on the recovery process but in order to move forward with this approach the most critical stress signals have to be identified. Accordingly, in the current study we have directed our attention to examining the potential effects of corticosterone, delivered orally at stress-like levels. Our interest is to determine how similar the effects of corticosterone are to stress on repair and remodelling that is known to occur after stroke. The study involved 4 groups, sham and stroke, either administered corticosterone or normal drinking water. The functional impact was assessed using the cylinder task for paw asymmetry, grid walk for sensorimotor function, inverted grid for muscle strength and coordination and open field for anxiety-like behaviour. Biochemically and histologically, we considered disturbances in main cellular elements of the neurovascular unit, including microglia, astrocytes, neurons and blood vessels using both immunohistochemistry and western blotting. In short, we identified that corticosterone delivery after stroke results in significant suppression of key microglial and astroglial markers. No changes were observed on the vasculature and in neuronal specific markers. No changes were identified for sensorimotor function or anxiety-like behaviour. We did, however, observe a significant change in motor function as assessed using the inverted grid walk test. Collectively, these results suggest that pharmacologically targeting corticosterone levels in the future may be warranted but that such an approach is unlikely to limit all the negative effects associated with exposure to chronic stress.

Background and Purpose - This study aimed to assess the efficacy of modafinil, a wakefulness-promoting agent in alleviating post-stroke fatigue =3 months after stroke. We hypothesized that 200 mg of modafinil daily for 6 weeks would result in reduced symptoms of fatigue compared with placebo. Methods - This single-center phase 2 trial used a randomized, double-blind, placebo-controlled, crossover design. The key inclusion criterion was a multidimensional fatigue inventory score of =60. Patients were randomized to either modafinil or placebo for 6 weeks of therapy, then after a 1 week washout period swapped treatment arms for a second 6 weeks of therapy. The primary outcome was the multidimensional fatigue inventory; secondary outcomes included the Montreal cognitive assessment, the Depression, Anxiety, and Stress Scale (DASS), and the Stroke-Specific Quality of Life (SSQoL) scale. The multidimensional fatigue inventory is a self-administered questionnaire with a range of 0 to 100. Treatment efficacy was assessed using linear regression by estimating within-person, baseline-adjusted differences in mean outcomes after therapy. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000350527). Results - A total of 232 stroke survivors were screened and 36 were randomized. Participants receiving modafinil reported a significant decrease in fatigue (multidimensional fatigue inventory, -7.38; 95% CI, -21.76 to -2.99; P<0.001) and improved quality of life (SSQoL, 11.81; 95% CI, 2.31 to 21.31; P=0.0148) compared with placebo. Montreal cognitive assessment and DASS were not significantly improved with modafinil therapy during the study period (P>0.05). Conclusions - Stroke survivors with nonresolving fatigue reported reduced fatigue and improved quality of life after taking 200 mg daily treatment with modafinil.

Background and Purpose - Treatments that improve function in late phase after stroke are urgently needed. We assessed whether multimodal interventions based on rhythm-and-music therapy or horse-riding therapy could lead to increased perceived recovery and functional improvement in a mixed population of individuals in late phase after stroke. Methods - Participants were assigned to rhythm-and-music therapy, horse-riding therapy, or control using concealed randomization, stratified with respect to sex and stroke laterality. Therapy was given twice a week for 12 weeks. The primary outcome was change in participants' perception of stroke recovery as assessed by the Stroke Impact Scale with an intention-to-treat analysis. Secondary objective outcome measures were changes in balance, gait, grip strength, and cognition. Blinded assessments were performed at baseline, postintervention, and at 3- and 6-month follow-up. Results - One hundred twenty-three participants were assigned to rhythm-and-music therapy (n=41), horse-riding therapy (n=41), or control (n=41). Post-intervention, the perception of stroke recovery (mean change from baseline on a scale ranging from 1 to 100) was higher among rhythm-and-music therapy (5.2 [95% confidence interval, 0.79-9.61]) and horse-riding therapy participants (9.8 [95% confidence interval, 6.00-13.66]), compared with controls (-0.5 [-3.20 to 2.28]); P=0.001 (1-way ANOVA). The improvements were sustained in both intervention groups 6 months later, and corresponding gains were observed for the secondary outcomes. Conclusions - Multimodal interventions can improve long-term perception of recovery, as well as balance, gait, grip strength, and working memory in a mixed population of individuals in late phase after stroke. Clinical Trial Registration - URL: http//www.ClinicalTrials.gov. Unique identifier: NCT01372059.

Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.

Exposure to severe stress following stroke is recognised to complicate the recovery process. We have identified that stress can exacerbate the severity of post-stroke secondary neurodegeneration in the thalamus. In this study, we investigated whether exposure to stress could influence the accumulation of the neurotoxic protein Amyloid-b. Using an experimental model of focal cortical ischemia in adult mice combined with exposure to chronic restraint stress, we examined changes within the contra-and ipsilateral thalamus at six weeks post-stroke using Western blotting and immunohistochemical approaches. Western blotting analysis indicated that stroke was associated with a significant enhancement of the 25 and 50 kDa oligomers within the ipsilateral hemisphere and the 20 kDa oligomer within the contralateral hemisphere. Stroked animals exposed to stress exhibited an additional increase in multiple forms of Amyloid-beta oligomers. Immunohistochemistry analysis confirmed that stroke was associated with a significant accumulation of Amyloid-beta within the thalami of both hemispheres, an effect that was exacerbated in stroke animals exposed to stress. Given that Amyloid-beta oligomers, most notably the 30-40 and 50 kDa oligomers, are recognised to correlate with accelerated cognitive decline, our results suggest that monitoring stress levels in patients recovering from stroke may merit consideration in the future.

Cognitive impairment has frequently been shown in patients who seek medical care for stress-related mental health problems. This study aims to extend the current knowledge of cognitive impairments in these patients by focusing on perceived fatigue and effects of distraction during cognitive testing. Executive function and attention were tested in a group of patients with stress-related exhaustion (n = 25) and compared with healthy controls (n = 25). Perceived fatigue was measured before, during and after the test session, and some of the tests were administered with and without standardized auditory distraction. Executive function and complex attention performance were poorer among the patients compared to controls. Interestingly, their performance was not significantly affected by auditory distraction but, in contrast to the controls, they reported a clear-cut increase in mental tiredness, during and after the test session. Thus, patients with stress-related exhaustion manage to perform during distraction but this was achieved at a great cost. These findings are discussed in terms of a possible tendency to adopt a high-effort approach despite cognitive impairments and the likelihood that such an approach will require increased levels of effort, which can result in increased fatigue. We tentatively conclude that increased fatigue during cognitive tasks is a challenge for patients with stress-related exhaustion and plausibly of major importance when returning to work demanding high cognitive performance.

Exposure to psychological stress is known to seriously disrupt the operation of the substantia nigra (SN) and may in fact initiate the loss of dopaminergic neurons within the SN. In this study, we aimed to investigate how chronic stress modified the SN in adult male mice. Using a paradigm of repeated restraint stress (an average of 20¿h per week for 6¿weeks), we examined changes within the SN using western blotting and immunohistochemistry. We demonstrated that chronic stress was associated with a clear loss of dopaminergic neurons within the SN. The loss of dopaminergic neurons was accompanied by higher levels of oxidative stress damage, indexed by levels of protein carbonylation and strong suppression of both microglial and astrocytic responses. In addition, we demonstrated for the first time, that chronic stress alone enhanced the aggregation of a-synuclein into the insoluble protein fraction. These results indicate that chronic stress triggered loss of dopaminergic neurons by increasing oxidative stress, suppressing glial neuroprotective functions and enhancing the aggregation of the neurotoxic protein, a-synuclein. Collectively, these results reinforce the negative effects of chronic stress on the viability of dopaminergic cells within the SN.

Motor function may be enhanced if aerobic exercise is paired with motor training. One potential mechanism is that aerobic exercise increases levels of brain-derived neurotrophic factor (BDNF), which is important in neuroplasticity and involved in motor learning and motor memory consolidation. This study will examine the feasibility of a parallel-group assessor-blinded randomised controlled trial investigating whether task-specific training preceded by aerobic exercise improves upper limb function more than task-specific training alone, and determine the effect size of changes in primary outcome measures. People with upper limb motor dysfunction after stroke will be allocated to either task-specific training or aerobic exercise and consecutive task-specific training. Both groups will perform 60 hours of task-specific training over 10 weeks, comprised of 3 × 1 hour sessions per week with a therapist and 3 × 1 hours of home-based self-practice per week. The combined intervention group will also perform 30 minutes of aerobic exercise (70¿85%HR ) immediately prior to the 1 hour of task-specific training with the therapist. Recruitment, adherence, retention, participant acceptability, and adverse events will be recorded. Clinical outcome measures will be performed pre-randomisation at baseline, at completion of the training program, and at 1 and 6 months follow-up. Primary clinical outcome measures will be the Action Research Arm Test (ARAT) and the Wolf Motor Function Test (WMFT). If aerobic exercise prior to task-specific training is acceptable, and a future phase 3 randomised controlled trial seems feasible, it should be pursued to determine the efficacy of this combined intervention for people after stroke. max

Focal hyperperfusion after acute ischaemic stroke could be of prognostic value depending upon its spatial localisation and temporal dynamics. Factors associated with late stage (12-24 h) perilesional hyperperfusion, identified using arterial spin labelling, are poorly defined. A prospective cohort of acute ischaemic stroke patients presenting within 4.5 h of symptom onset were assessed with multi-modal computed tomography acutely and magnetic resonance imaging at 24 ± 8 h. Multivariate logistic regression analysis and receiver operating characteristics curves were used. One hundred and nineteen hemispheric acute ischaemic stroke patients (mean age = 71 ± 12 years) with 24 h arterial spin labelling imaging were included. Forty-Two (35.3%) patients showed perilesional hyperperfusion on arterial spin labelling at 24 h. Several factors were independently associated with perilesional hyperperfusion: good collaterals (71% versus 29%, P < 0.0001; OR = 5, 95% CI = [1.6, 15.7], P = 0.005), major reperfusion (81% versus 48%, P = < 0.0001; OR = 7.5, 95% CI = [1.6, 35.1], P = 0.01), penumbral salvage (76.2% versus 47%, P = 0.002; OR = 6.6, 95% CI = [1.8, 24.5], P = 0.004), infarction in striatocapsular (OR = 9.5, 95% CI = [2.6, 34], P = 0.001) and in cortical superior division middle cerebral artery (OR = 4.7, 95% CI = [1.4, 15.7], P = 0.012) territory. The area under the receiver operating characteristic curve was 0.91. Our results demonstrate good arterial collaterals, major reperfusion, penumbral salvage, and infarct topographies involving cortical superior middle cerebral artery and striatocapsular are associated with perilesional hyperperfusion.

Exposure to chronic stress following stroke has been shown, both clinically and pre-clinically, to impact negatively on the recovery process. While this phenomenon is well established, the specific mechanisms involved have remained largely unexplored. One obvious signaling pathway through which chronic stress may impact on the recovery process is via corticosterone, and its effects on microglial activity and vascular remodeling. In the current study, we were interested in examining how orally delivered corticosterone at a stress-like concentration impacted on microglial activity and vascular remodeling after stroke. We identified that corticosterone administration for two weeks following stroke significantly increased tissue loss and decreased the weight of the spleen and thymus. We also identified that corticosterone administration significantly altered the expression of the key microglial complement receptor, CD11b after stroke. Corticosterone administration did not alter the expression of the vessel basement membrane protein, Collagen IV after stroke. Together, these results suggest that corticosterone is likely to represent only one of the major stress signals responsible for driving the negative impacts of chronic stress on recovery.

Stroke induces tissue death both at the site of infarction and at secondary sites connected to the primary infarction. This latter process has been referred to as secondary neurodegeneration (SND). Using predominantly fixed tissue analyses, microglia have been implicated in regulating the initial response at both damage sites post-stroke. In this study, we used acute slice based multiphoton imaging, to investigate microglia dynamic process movement in mice 14 days after a photothrombotic stroke. We evaluated the baseline motility and process responses to locally induced laser damage in both the peri-infarct (PI) territory and the ipsilateral thalamus, a major site of post-stroke SND. Our findings show that microglia process extension toward laser damage within the thalamus is lost, yet remains robustly intact within the PI territory. However, microglia at both sites displayed an activated morphology and elevated levels of commonly used activation markers (CD68, CD11b), indicating that the standardly used fixed tissue metrics of microglial ¿activity¿ are not necessarily predictive of microglia function. Analysis of the purinergic P Y receptor, a key regulator of microglia process extension, revealed an increased somal localization on nonresponsive microglia in the thalamus. To our knowledge, this is the first study to identify a non-responsive microglia phenotype specific to areas of SND post-stroke, which cannot be identified by the classical assessment of microglia activation but rather the localization of P Y to the soma. 2 12 2 12

Conclusion: The new mattress and pillow for prone positioning (MPP) is efficient in reducing the apnoea-hypopnoea index (AHI) and oxygen desaturation index (ODI) in most patients with obstructive sleep apnoea (OSA), with satisfactory compliance. Objective: The aim of the present study was to evaluate the effect of the prone body and head sleep position on severity of disease in patients with OSA after 4 weeks of adaptation to a mattress and pillow facilitating prone positioning. Methods: Fourteen patients with mild to severe OSA, 11 men and 3 women with a mean AHI of 26 (min, 6; max, 53) and mean ODI of 21 (min, 6; max, 51) were evaluated. Two polysomnographic (PSG) studies were performed. The first PSG study was without any treatment and the second was after 4 weeks of adaptation to the MPP for prone positioning of the body and the head. Results: Mean AHI and ODI decreased from 26 and 21 to 8 and 7, respectively (p < 0.001) with treatment. The mean time spent in the supine position was reduced from 128 to 10 min (p = 0.02) and the prone time increased from 42 to 174 min (p = 0.02) with the MPP. The mean total sleep time was 390 min during the first PSG study night without treatment and 370 min during the second night with the MPP (p = 0.7). Ten patients (71%) reduced their AHI by at least 50% and reached a value < 10 during treatment. All patients managed to sleep on the MPP for > 4 h per night during the 4-week study.

Sickness behaviors have become the focus of great interest in recent years as they represent a clear case of how peripheral disturbances in immune signaling can disrupt quite complex behaviors. In the current study, we were interested in examining whether we could identify any significant morphological disturbances in microglia associated with these sickness-like behaviors in adult male Sprague-Dawley rats. We chose lipopolysaccharide (LPS 100 µg/kg/i.p.), to induce sickness-like behaviors as it is the most well-validated approach to do so in rodents and humans. We were particularly interested in examining changes in microglia within the prefrontal cortex (PFC) as several recent neuroimaging studies have highlighted significant functional changes in this region following peripheral LPS administration. Paraformaldehyde-fixed tissue was collected from animals 24 h post LPS administration and labeled immunohistochemically with an antibody directed to bind to Iba-1, a protein known to be involved in the structural remodeling of microglia. To analyze changes, we have made use of two recently described image analysis procedures. The first is known as cumulative threshold spectra (CTS) analysis. The second involves the unsupervised digital reconstruction of microglia. We undertook these complementary analysis of microglial cells in the both the pre- and infralimbic divisions of the PFC. Our results indicated that microglial soma size was significantly enlarged, while cell processes had contracted slightly following LPS administration. To our knowledge this study is to first to definitely demonstrate substantial microglial disturbances within the PFC following LPS delivered at a dose that was sufficient to induce significant sickness-like behavior.

BACKGROUND: Physical activity and structural differences in the hippocampus have been linked to educational outcome. We investigated whether a curriculum-based physical activity intervention correlates positively with children's academic achievement, psychological well-being, health-related quality of life (HRQoL), fitness, and structural development of the brain. METHODS: The study had a quasi-experimental design and a control group. National test results were gathered from 545 students, 122 in the intervention school, and 423 in 3 control schools. HRQoL and socioemotional data were collected with child and proxy versions of KIDSCREEN and the Strength and Difficulties Questionnaire. Overall, 79 students in grades 5 and 6 were recruited for an in-depth study, consisting of a submaximal oxygen consumption test and magnetic resonance imaging of the brain. HRQoL and socioemotional data were collected from 349 students (65%), 182 (52%) in the intervention school, and 167 (48%) in one of the control schools. RESULTS: Girls attending the intervention school were more likely to pass national tests in Swedish (odds ratio 5.7) and Mathematics (odds ratio 3.2). The fourth to sixth graders in the intervention school reported lower levels of conduct problems (p<.05), and the girls were also less likely to report hyperactivity (p<.05). Girls reported higher levels of emotional problems (p<.05) than boys. Boys in the intervention group had significantly higher levels of estimated maximal oxygen uptake (p<.05) than controls. No difference in hippocampal structure was seen. CONCLUSIONS: Curriculum-based physical activity in school may improve the academic achievement and psychological health of children, particularly for girls.

There are currently few approaches to transiently manipulate the expression of specific proteins in microglia of the brain. An antibody directed against an extracellular epitope of scavenger receptor class B, type I (SR-BI) was found to be selectively taken up by these cells in the brain. Other antibodies tested were not internalised by microglia. A vector was produced by linking the SR-BI antibody to polyethyleneimine and binding a DNA plasmid encoding green fluorescent protein. Infusions of this vector into the hippocampus produced a widespread transfection of cells, more than 80% of which were immunoreactive for microglial/macrophage markers. Transfection was not detected in cells expressing markers for astrocytes or neurons. Reporter gene expression was most prominent near the infusion site but was seen in tissue up to 4 mm away. DNA bound to polyethyleneimine alone or to a vector containing a different antibody did not produce transfection in the brain. Single injections of the vector containing the SR-BI antibody into the brain also resulted in transfection of microglia, albeit with lower efficiency. Vector modifications to promote lysis of endosomes or entry of DNA into the nucleus did not increase efficiency. The findings clearly demonstrate the capacity of the SR-BI antibody to selectively target brain microglia. This approach offers considerable potential to deliver DNA and other molecules capable of modifying the function of these cells in vivo.

Patients with early-onset dementia are a significantly under-recognized subgroup of patients with an increasing prevalence. Epidemiological studies are limited and studies of modifiable risk factors, such as physical fitness, are lacking. We aimed to investigate the associations between cardiovascular fitness individually and in combination with cognitive performance at age 18 and risk of early-onset dementia and mild cognitive impairment later in life. We performed a population-based cohort study of over 1.1 million Swedish, 18-year-old, male conscripts, who underwent conscription exams between 1968 and 2005. These males were then followed for up to 42 years. Objective data on cardiovascular fitness and cognitive performance were collected during conscription exams and were subsequently linked with hospital registries to calculate later risk of early-onset dementia and mild cognitive impairment using Cox proportional hazards models controlling for several confounders. The scores from the exams were divided into tertiles (low, medium, high) for the analyses. The mean follow-up time for the analyses was 25.7 years (standard deviation: 9.3) and the median was 27 years. In total, 30 195 315 person-years of follow-up were included in the study. In fully adjusted models, both low cardiovascular fitness and cognitive performance (compared to high) at age 18 were associated with increased risk for future early-onset dementia (cardiovascular fitness, n = 662 events: hazard ratio 2.49, 95%, confidence interval 1.87-3.32; cognitive performance, n = 657 events: hazard ratio 4.11, 95%, confidence interval 3.19-5.29) and mild cognitive impairment (cardiovascular fitness, n = 213 events: hazard ratio 3.57, 95%, confidence interval 2.23-5.74; cognitive performance, n = 212 events: hazard ratio 3.23, 95%, confidence interval 2.12-4.95). Poor performance on both cardiovascular fitness and cognitive tests was associated with a >7-fold (hazard ratio 7.34, 95%, confidence interval 5.08-10.58) and a >8-fold (hazard ratio 8.44, 95%, confidence interval 4.64-15.37) increased risk of early-onset dementia and early-onset mild cognitive impairment, respectively. In conclusion, lower cardiovascular fitness and cognitive performance in early adulthood were associated with an increased risk of early-onset dementia and mild cognitive impairment later in life, and the greatest risks were observed for individuals with a combination of low cardiovascular fitness and low cognitive performance. © 2014 The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

BACKGROUND: Despite the emerging body of research on the potential of physical activity to improve learning and academic achievement, conclusive evidence regarding the effects of physical activity on academic achievement is lacking. The objective of this study was to determine the impact of a physical activity intervention program on academic performance. METHODS: A controlled cross-sectional design was used to investigate the hypothesis that the intervention program would increase the proportion of students in grade 5 who achieved the national learning goals in Swedish, mathematics, and English compared with 3 reference schools. Academic results from the years prior to and during the intervention program were analyzed. Logistic regression analyses assessed the odds of achieving the national learning goals when the intervention program was integrated into the elementary curricula. RESULTS: Higher proportions of students in the intervention school achieved the national goals in all 3 subjects compared with the reference schools after initiation of the intervention program. The odds for achieving the national learning goals in the intervention school increased 2-fold (p<.05), whereas these odds either did not change or decreased in the reference schools. CONCLUSION: Promoting physical activity in school by means of a curriculum-based intervention program may improve children's educational outcome. © 2014, American School Health Association.

Objective: To determine physical, cognitive and social activity levels of stroke patients undergoing rehabilitation, and whether these changed over time. Design: Observational study using behavioural mapping techniques to record patient activity over 12 hours on one weekday and one weekend day at baseline (week 1) and again two weeks later (week 2). Setting: A 20-bed mixed rehabilitation unit. Subjects: Fourteen stroke patients. Interventions: None. Main measures: Percentage of day spent in any activity or physical, cognitive and social activities. Level of independence using the Functional Independence Measure (FIM) and mood using the Patient Health Questionniare-9 (PHQ-9). Results: The stroke patients performed any activity for 49%, social activity for 32%, physical activity for 23% and cognitive activity for 4% of the day. Two weeks later, physical activity levels had increased by 4% (95% confidence interval (CI) 1 to 8), but levels of any activity or social and cognitive activities had not changed significantly. There was a significant: (i) positive correlation between change in physical activity and change in FIM score (r = 0.80), and (ii) negative correlation between change in social activity and change in PHQ-9 score (r = -0.72). The majority of activity was performed by the bedside (37%), and most physical (47%) and cognitive (54%) activities performed when alone. Patients undertook 5% (95% CI 2 to 9) less physical activity on the weekends compared with the weekdays. Conclusions: Levels of physical, cognitive and social activity of stroke patients were low and remained so even though level of independence and mood improved. These findings suggest the need to explore strategies to stimulate activity within rehabilitation environments. © The Author(s) 2013.

In recent years, the role and physiological regulation of the serine protease tissue-type plasminogen activator (t-PA and its inhibitors, including plasminogen activator inhibitor type-1 (PAI-1, in the brain have received much attention. However, as studies focusing these issues are difficult to perform in humans, a great majority of the studies conducted to date have utilized rodent in vivo and/or in vitro models. In view of the species-specific structural differences present in both the t-PA and the PAI-1 promoters, we have compared the response of these genes in astrocytes of rat and human origin. We reveal marked quantitative and qualitative species-specific differences in gene induction following treatment with various physiological and pathological stimuli. Thus, our findings are of importance for the interpretation of previous and future results related to t-PA and PAI-1 expression. © the authors, publisher and licensee Libertas Academica Limited.

Objective: To analyze the associations between cardiovascular fitness at age 18 years and future risk of epilepsy. Methods: Population-based cohort study of Swedish male conscripts (n = 1,173,079) born in 1950-1987, who were followed for up to 40 years. Data on cardiovascular fitness were collected during conscription exams and linked with hospital registers to calculate later risk of epilepsy using Cox proportional hazard models controlling for several confounders, including familial factors. Results: Epilepsy was recorded in 6,796 individuals during the follow-up time. In fully adjusted models, low and medium cardiovascular fitness (compared with high) at age 18 years was associated with increased risk of future epilepsy (hazard ratio 1.79, 95% confidence interval 1.57-2.03; and hazard ratio 1.36, 95% confidence interval 1.27-1.45, respectively). The associations changed only marginally after adjustment for familial influences and prior severe traumatic brain injury, cerebrovascular disease, or diabetes. Conclusions: Low cardiovascular fitness early in life is associated with an increased risk of epilepsy later in adulthood. These results agree with previous results from animal models. We propose that behaviors that increase cardiovascular fitness may act as positive disease-modifiers for the development of epilepsy. © 2013 American Academy of Neurology.

OBJECTIVE: To investigate the rate of and risk factors for head and neck injury in male soccer. DESIGN: Prospective cohort study. SETTING: Professional soccer. PARTICIPANTS: Twenty-six European teams between 2001/2002 and 2009/2010. ASSESSMENT OF RISK FACTORS: Simple and multiple risk factor analyses were evaluated using Cox regression for player-related variables and logistic regression for match-related variables. MAIN OUTCOME MEASURES: Injury rate (number of time loss injuries per 1000 hours). RESULTS: A total of 136 head and neck injuries were recorded (2.2% of all injuries). The head and neck injury rate was 0.17 (0.06 concussions) per 1000 hours. There was a 20-fold higher rate of head and neck injury during match play compared with training (rate ratio [RR], 20.2; 95% confidence interval [CI], 13.3-30.6) and a 78-fold higher rate of concussions (RR, 78.5; 95% CI, 24.4-252.5). Mean layoff for concussion was 10.5 days, but 27% of the concussed players returned to play within 5 days. Defender was the only significant player-related risk factor for head and neck injuries in the multiple analysis (RR, 1.8; 95% CI, 1.0-3.1), whereas no significant variables were identified for concussions. CONCLUSIONS: Head and neck injuries were relatively uncommon in professional soccer. Defender was the playing position most at risk. More than one-quarter of the concussed players returned to play before what is recommended in the consensus statements by the major sports governing bodies. Copyright © 2013 by Lippincott Williams & Wilkins.

Post-traumatic hypopituitarism (PTHP) has been linked to disability and decreased quality of life. However, no studies have addressed the long-term consequences of PTHP in adults with severe traumatic brain injury (TBI) only. In this study, we evaluated the relationship between pituitary function, quality of life, and functioning in 51 patients (16-65 years of age) with severe TBI who were admitted to Sahlgrenska University Hospital, Gothenburg from 1999 to 2002. The patients were assessed once, 2-10 years after trauma. Data from the time of injury were collected retrospectively to adjust for injury severity. Outcome measures included hormonal testing, the Short Form-36 Health Survey, the Glasgow Outcome Scale-Extended, and a self-report questionnaire specifically designed for this study and based on the International Classification of Functioning, Disability and Health. Of 51 patients, 14 (27.5%) presented with PTHP, and 11 (21.6%) had isolated growth hormone deficiency. Patients with PTHP were more often overweight at follow-up (p=0.01); the higher body mass index was partially explained by PTHP (R change=0.07, p=0.001). Otherwise no significant correlation was found among PTHP, functioning, or patient-reported quality of life. This study - which is unique in the homogeneity of the patients, the long follow-up time, and the use of injury severity as an outcome predictor - did not confirm results from previous studies linking PTHP to a worse outcome. Therefore, screening for PTHP might be restricted to specific subgroups such as overweight patients, indicating growth hormone deficiency. © 2013, Mary Ann Liebert, Inc. 2

Intrinsic Optical Signal imaging is a technique which allows the visualisation and mapping of activity related changes within the brain with excellent spatial and temporal resolution. We analysed a variety of signal and image processing techniques applied to real mouse imaging data. The results were compared in an attempt to overcome the unique issues faced when performing the technique on mice and improve the understanding of post processing options available.