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Abstract Patients with schizophrenia exhibit structural and functional dysconnectivity but the relationship to the well-documented cognitive impairments is less clear. This study investigates associations between structural and functional connectivity and executive functions in antipsychotic-naïve patients experiencing schizophrenia. Sixty-four patients with schizophrenia and 95 matched controls underwent cognitive testing, diffusion weighted imaging and resting state functional magnetic resonance imaging. In the primary analyses, groupwise interactions between structural connectivity as measured by fixel-based analyses and executive functions were investigated using multivariate linear regression analyses. For significant structural connections, secondary analyses examined whether functional connectivity and associations with executive functions also differed for the two groups. In group comparisons, patients exhibited cognitive impairments across all executive functions compared to controls (p

Background: Findings of reward disturbances in unaffected relatives of patients with schizophrenia suggest reward disturbances as an endophenotype for schizophrenia. Twin studies, where 1 twin has been diagnosed with a schizophrenia spectrum disorder, can further explore this. Methods: We used Danish registries to identify twin pairs with at least 1 twin having a schizophrenia spectrum disorder diagnosis and control twin pairs matched on age, sex, and zygosity. The analyses included data from 34 unaffected co-twins (16 females), 42 probands with schizophrenia spectrum disorder (17 females), and 83 control twins (42 females). Participants performed a modified incentive delay task during functional magnetic resonance imaging. Whole-brain group differences were analyzed by performing comparisons between co-twins and control twins. Correlations with cognitive flexibility were tested. Results: Compared with control twins, co-twins showed no differences in striatal regions, but increased signal in the dorsolateral prefrontal cortex (DLPFC) during missed target contrast was observed. In co-twins, increased DLPFC signal was associated with lower intra-extra dimensional set-shifting scores indicative of higher cognitive flexibility. Conclusions: Unaffected co-twins did not have decreased striatal activity during anticipation as previously reported for patients with schizophrenia. Instead, they showed increased activity in the DLPFC during evaluation of missed target contrast, which correlated with their level of cognitive flexibility. Unaffected co-twins had no diagnosis at a mean age of 40 years. This could indicate that greater cognitive flexibility and increased activity in the right DLPFC during processing of unexpected negative outcome represents a compensatory resilience mechanism in predisposed twins.

Background: The mechanisms underlying the antidepressant effect and cognitive side effects of Electroconvulsive Therapy (ECT) remain elusive. The measurement of cerebral perfusion provides an insight into brain physiology. Objective: We investigated ECT-related perfusion changes in depressed patients and tested whether these changes correlate with clinical effects. Methods: A sample of 22 in-patients was examined at three time points: 1) within two days before, 2) within one week after, and 3) six months after an ECT series. Cerebral perfusion was quantified using arterial spin labeling magnetic resonance imaging. The primary regions of interest were the bilateral dorsolateral prefrontal cortices (DL-PFC) and hippocampi. The depression severity was assessed by the six-item Hamilton Depression Rating Scale, and cognitive performance by the Screen for Cognitive Impairment in Psychiatry. A linear mixed model and partial correlation were used for statistical analyses. Results: Following an ECT series, perfusion decreased in the right (−6.0%, p = .01) and left DL-PFC (−5.6%, p = .001). Perfusion increased in the left hippocampus (4.8%, p = .03), while on the right side the increase was insignificant (2.3%, p = .23). A larger perfusion reduction in the right DL-PFC correlated with a better antidepressant effect, and a larger perfusion increase in the right hippocampus with worse cognitive impairment. Conclusion: ECT-induced attenuation of prefrontal activity may be related to clinical improvement, whereas a hippocampal process triggered by the treatment is likely associated with cognitive side effects.

Cerebral small vessel disease (SVD) is a major cause of cognitive impairment in older people. As secondary endpoints in a phase-2 randomised clinical trial, we tested the effects of single administration of a widely-used PDE5 inhibitor, tadalafil, on cognitive performance in older people with SVD. In a double-blinded, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥ 7 days apart (randomised to order of treatment). The Montreal Cognitive Assessment (MOCA) was administered at baseline, alongside a measure to estimate optimal intellectual ability (Test of Premorbid Function). Then, before and after treatment, a battery of neuropsychological tests was administered, assessing aspects of attention, information processing speed, working memory and executive function. Sixty-five participants were recruited and 55 completed the protocol (N = 55, age: 66.8 (8.6) years, range 52–87; 15/40 female/male). Median MOCA score was 26 (IQR: 23, 27], range 15–30). No significant treatment effects were seen in any of the neuropsychological tests. There was a trend towards improved performance on Digit Span Forward (treatment effect 0.37, C.I. 0.01, 0.72; P = 0.0521). We did not identify significant treatment effects of single-administration tadalafil on neuropsychological performance in older people with SVD. The trend observed on Digit Span Forward may help to inform future studies. Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT00123456, https://eudract.ema.europa.eu. Unique identifier: 2015–001,235–20NCT00123456.

Background and aimsGlucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) are widely used for the treatment of type 2 diabetes, and recent studies indicate that they may be cardio- and neuroprotective. The safety and effect of a single dose of exenatide, a short-acting GLP-1RA, on cerebral and peripheral arterial function remain unknown.MethodsIn this randomized, double-blind pilot trial, we assigned elderly healthy volunteers without diabetes and no previous history of stroke to receive a single dose of subcutaneous exenatide (5 μg) or placebo. Primary outcome was immediate changes over time in blood flow velocity of the middle cerebral arteries (VMCA) assessed by repeated transcranial Doppler measurements. Secondary outcomes were changes in peripheral arterial function with finger plethysmography, ankle-brachial index (ABI), and inflammatory- and endothelial-specific biomarkers.ResultsHealthy volunteers (13 women and 17 men) were included: (mean ± standard deviation) age: 62 ± 8 years; body weight: 79.6 ± 12.7 kg; VMCA: 65.3 ± 10.7 cm/s; fasting plasma glucose: 5.5 ± 0.5 mmol/L; HbA1c: 33.9 ± 4.1 mmol/mol (5.3 ± 0.38%). No differences between exenatide and placebo group were seen regarding VMCA (p = 0.058), systolic ABI (p = 0.71), plethysmography (p = 0.45), tumor necrosis factor (p = 0.33), interleukin-6 (p = 0.11), interleukin-1β (p = 0.34), vascular cell adhesion molecule 1 (p = 0.73), intercellular adhesion molecule 1 (p = 0.74), or E-selectin (p = 0.31). No severe adverse events were observed.ConclusionA single dose of exenatide did not change cerebral blood flow velocity or peripheral vessel function in elderly healthy volunteers. The medication was safe to use in persons without diabetes allowing us to investigate this drug further in search of the neuroprotective mechanisms.Clinical Trial Registrationhttps://clinicaltrials.gov, Identifier NCT02838589.

BackgroundThe clinical high-risk for psychosis (CHR-P) paradigm was introduced to detect individuals at risk of developing psychosis and to establish preventive strategies. While current prediction of outcomes in the CHR-P state is based mostly on the clinical assessment of presenting features, several emerging biomarkers have been investigated in an attempt to stratify CHR-P individuals according to their individual trajectories and refine the diagnostic process. However, heterogeneity across subgroups is a key challenge that has limited the impact of the CHR-P prediction strategies, as the clinical validity of the current research is limited by a lack of external validation across sites and modalities. Despite these challenges, electroencephalography (EEG) biomarkers have been studied in this field and evidence suggests that EEG used in combination with clinical assessments may be a key measure for improving diagnostic and prognostic accuracy in the CHR-P state. The PSYSCAN EEG study is an international, multi-site, multimodal longitudinal project that aims to advance knowledge in this field.MethodsParticipants at 6 international sites take part in an EEG protocol including EEG recording, cognitive and clinical assessments. CHR-P participants will be followed up after 2 years and subcategorised depending on their illness progression regarding transition to psychosis. Differences will be sought between CHR-P individuals and healthy controls and between CHR-P individuals who transition and those who do not transition to psychosis using data driven computational analyses.DiscussionThis protocol addresses the challenges faced by previous studies of this kind to enable valid identification of predictive EEG biomarkers which will be combined with other biomarkers across sites to develop a prognostic tool in CHR-P. The PSYSCAN EEG study aims to pave the way for incorporating EEG biomarkers in the assessment of CHR-P individuals, to refine the diagnostic process and help to stratify CHR-P subjects according to risk of transition. This may improve our understanding of the CHR-P state and therefore aid the development of more personalized treatment strategies.

Post-traumatic stress disorder (PTSD) is a heterogenous condition and the underlying neurobiology is still poorly understood. In this study, we tested the hypothesis that PTSD is associated with microstructural changes in white matter (WM) fibre tracts that connect regions involved in emotional processing, memory, attention, and language. Furthermore, we examined how different response patterns to individualized trauma-provoking stimuli related to underlying WM microstructure. Sixty-nine trauma-affected male refugees with PTSD (N = 38) or without PTSD (N = 31) underwent clinical assessments and diffusion-weighted magnetic resonance imaging (DWI) of the whole brain at 3 Tesla. Diffusion tensor metrics were computed from DWI data and used to characterize regional white-matter microstructure. An automated tract segmentation method was used to extract diffusion tensor metrics from subject-based reconstructions of tract segments (ROI), including uncinate fasciculus (UF), cingulum bundle (CB), superior longitudinal fasciculus (SLF) in three subdivisions (SLF I - III), and fibre bundles connecting orbito-frontal cortex to striatum (OF-ST). Outside the scanner we obtained measures of immediate (state) arousal, avoidance and dissociation symptoms assessed in response to auditory exposure to a personal traumatic memory. Using mean FA of the middle part of each ROI, mixed ANOVA revealed a significant interaction between group, ROI and hemisphere. Post-hoc comparisons showed that, relative to refugees without PTSD, refugees with PTSD had lower FA in right CB, left SLF-I, bilateral OF-ST and bilateral SLF-II. Mean FA scaled negatively with avoidance in right CB while mean FA in bilateral UF scaled positively with individual scores reflecting dissociation symptoms. The results support a pathophysiological model of PTSD that implicates limbic structures, prefrontal cortex and striatum. The results also emphasize the need to consider PTSD’s multifaceted manifestations when searching for functional-structural relationships.

Background: Brain structural alterations and cognitive dysfunction are independent predictors for poor clinical outcome in schizophrenia, and the associations between these domains remains unclear. We employed a novel, multiblock partial least squares correlation (MB-PLS-C) technique and investigated multivariate cortico-cognitive patterns in patients with treatment-resistant schizophrenia (TRS) and matched healthy controls (HC). Method: Forty-one TRS patients (age 38.5 ± 9.1, 30 males (M)), and 45 HC (age 40.2 ± 10.6, 29 M) underwent 3T structural MRI. Volumes of 68 brain regions and seven variables from CANTAB covering memory and executive domains were included. Univariate group differences were assessed, followed by the MB-PLS-C analyses to identify group-specific multivariate patterns of cortico-cognitive coupling. Supplementary three-group analyses, which included 23 non-affected first-degree relatives (NAR), were also conducted. Results: Univariate tests demonstrated that TRS patients showed impairments in all seven cognitive tasks and volume reductions in 12 cortical regions following Bonferroni correction. The MB-PLS-C analyses revealed two significant latent variables (LVs) explaining > 90% of the sum-of-squares variance. LV1 explained 78.86% of the sum-of-squares variance, describing a shared, widespread structure-cognitive pattern relevant to both TRS patients and HCs. In contrast, LV2 (13.47% of sum-of-squares variance explained) appeared specific to TRS and comprised a differential cortico-cognitive pattern including frontal and temporal lobes as well as paired associates learning (PAL) and intra-extra dimensional set shifting (IED). Three-group analyses also identified two significant LVs, with NARs more closely resembling healthy controls than TRS patients. Conclusions: MB-PLS-C analyses identified multivariate brain structural-cognitive patterns in the latent space that may provide a TRS signature.

Age has been shown to have an impact on both grey (GM) and white matter (WM) volume, with a steeper slope of age-related decline in schizophrenia compared to healthy controls. In schizophrenia, the relation between age and brain volume is further complicated by factors such as lower intelligence, antipsychotic medication, and cannabis use, all of which have been shown to have independent effects on brain volume.In a study of first-episode, antipsychotic-naïve schizophrenia patients (N = 54) and healthy controls (N = 56), we examined the effects of age on whole brain measures of GM and WM volume, and whether these relationships were moderated by schizophrenia and intelligence (IQ). Secondarily, we examined lifetime cannabis use as a moderator of the relationship between age and brain volume.Schizophrenia patients had lower GM volumes than healthy controls but did not differ on WM volume. We found an age effect on GM indicating that increasing age was associated with lower GM volumes, which did not differ between groups. IQ did not have a direct effect on GM, but showed a trend-level interaction with age, suggesting a greater impact of age with lower IQ. There were no age effects on WM volume, but a direct effect of IQ, with higher IQ showing an association with larger WM volume. Lifetime cannabis use did not alter these findings significantly.This study points to effects of schizophrenia on GM early in the illness, before antipsychotic treatment is initiated, suggesting that WM changes may occur later in the disease process. Keywords: Schizophrenia, Age, Grey matter volume, White matter volume, Intelligence, Cannabis

Background: Psychological traumatic experiences can lead to posttraumatic stress disorder (PTSD). Secondary psychotic symptoms are not common but may occur. Objectives: Since psychotic symptoms of schizophrenia have been related to aberrant reward processing in the striatum, using the same paradigm we investigate whether the same finding extends to psychotic and anhedonic symptoms in PTSD. Methods: A total of 70 male refugees: 18 PTSD patients with no secondary psychotic symptoms (PTSD-NSP), 21 PTSD patients with secondary psychotic symptoms (PTSD-SP), and 31 healthy controls (RHC) were interviewed and scanned with functional magnetic resonance imaging (fMRI) during a monetary incentive delay task. Using region of interest analysis of the prefrontal cortex and ventral striatum, we investigated reward-related activity. Results: Compared to RHC, participants with PTSD had decreased neural activity during monetary reward. Also, participants with PTSD-SP exhibited decreased activity in the associative striatum relative to participants with PTSD-NSP during processing of motivational reward anticipation which correlated with severity of psychotic symptoms. However, the difference between the two PTSD groups disappeared when PTSD severity and trauma exposure were accounted for. Conclusions: Anhedonia and secondary psychotic symptoms in PTSD are characterized by dysfunctional reward consumption and anticipation processing, respectively. The latter may reflect a mechanism by which abnormal reward signals in the basal ganglia facilitates psychotic symptoms across psychiatric conditions.

Patients with chronic schizophrenia often display enlarged striatal volumes, and antipsychotic drugs may contribute via the dopamine D2/3 receptor (D2/3R) blockade. Separating the effects of disease from medication is challenging due to the lack of a proper placebo-group. To address this, we conducted a longitudinal study of antipsychotic-naïve, first-episode schizophrenia patients to test the hypothesis that selective blockade of D2/3R would induce a dose-dependent striatal volume increase. Twenty-one patients underwent structural magnetic resonance imaging (sMRI), single-photon emission computed tomography (SPECT), and symptom severity ratings before and after six weeks of amisulpride treatment. Twenty-three matched healthy controls underwent sMRI and baseline SPECT. Data were analyzed using repeated measures and multiple regression analyses. Correlations between symptom severity decrease, volume changes, dose and receptor occupancy were explored. Striatal volumes did not differ between patients and controls at baseline or follow-up, but a significant group-by-time interaction was found (p = 0.01). This interaction was explained by a significant striatal volume increase of 2.1% in patients (Cohens d = 0.45). Striatal increase was predicted by amisulpride dose, but not by either D2/3R occupancy or baseline symptom severity. A significant reduction in symptom severity was observed at a mean dose of 233.3 (SD = 109.9) mg, corresponding to D2/3R occupancy of 44.65%. Reduction in positive symptoms correlated significantly with striatal volume increase, driven by reductions in hallucinations. Our data demonstrate a clear link between antipsychotic treatment and striatal volume increase in antipsychotic-naïve schizophrenia patients. Moreover, the treatment-induced striatal volume increase appears clinically relevant by correlating to reductions in core symptoms of schizophrenia.

Background Symptoms of anhedonia are often central to posttraumatic stress disorder (PTSD), but it is unclear how anhedonia is affected by processes induced by reliving past traumatic memories. Methods Sixty-nine male refugees (PTSD = 38) were interviewed and scanned with functional magnetic resonance imaging while viewing positive, neutral and Scrambled Pictures after being read personalized scripts evoking an emotionally neutral memory and a traumatic memory. We further measured postprovocation state symptoms, physiological measures and PTSD symptoms. We tested whether neural activity associated with positive picture viewing in participants with PTSD was differentially affected by symptom provocation compared to controls. Results For the pictures > scrambled contrast (Positive contrast), PTSD participants had significantly less activity than controls in fusiform gyrus, right inferior temporal gyrus and left middle occipital gyrus. The Positive contrast activity in fusiform gyrus scaled negatively with anhedonia symptoms in PTSD participants after controlling for total PTSD severity. Relative to the emotionally Neutral Script, the Trauma Script decreased positive picture viewing activity in posterior cingulate cortex, precuneus and left calcarine gyrus, but there was no difference between PTSD participants and controls. Conclusions We found reduced responsiveness of higher visual processing of emotionally positive pictures in PTSD. The significant correlation found between positive picture viewing activity and anhedonia suggests the reduced responsiveness to be due to the severity of anhedonia.

Objective(s): The present study was conducted to examine the effect of sleep deprivation (SD) on the anti-apoptotic pathways in Parkinsonian rats. Materials and Methods: Male Wistar rats (n = 40) were assigned to four groups (10 animals each): sham surgery (Sham), 6-hydroxydopamine (6-OHDA)-lesioned (OH), 6-OHDA-lesioned plus grid control (OH+GC), 6-OHDA-lesioned plus SD (OH+SD). Parkinson’s disease (PD) model was induced by the unilateral intra-striatal infusion of 6-OHDA (10 µg/rat). SD (4 hr/day, for 14 days) was induced using a multiple platforms water tank. On the last day of interventions, animals were subjected to open field test for horizontal motor performance assessment. Also, brain-derived neurotrophic factor (BDNF), Bcl-2 and Bax were assessed in the striatum of study groups. Results: SD obscured the motor deficits of PD animals observed in open field test. BDNF level and Bcl2/Bax ratio significantly increased in the OH group, and SD reduced their levels in the PD animals. Conclusion: SD suppressed the anti-apoptotic compensatory responses in the striatum; therefore, it may accelerate continual neuronal cell death in PD.

Abstract Background Open heart surgery is associated with high occurrence of atrial fibrillation (AF), subsequently increasing the risk of post-operative ischemic stroke. Concomitant with open heart surgery, a cardiac ablation procedure is commonly performed in patients with known AF, often followed by left atrial appendage closure with surgery (LAACS). However, the protective effect of LAACS on the risk of cerebral ischemia following cardiac surgery remains controversial. We have studied whether LAACS in addition to open heart surgery protects against post-operative ischemic brain injury regardless of a previous AF diagnosis. Methods One hundred eighty-seven patients scheduled for open heart surgery were enrolled in a prospective, open-label clinical trial and randomized to concomitant LAACS vs. standard care. Randomization was stratified by usage of oral anticoagulation (OAC) planned to last at least 3 months after surgery. The primary endpoint was a composite of post-operative symptomatic ischemic stroke, transient ischemic attack or imaging findings of silent cerebral ischemic (SCI) lesions. Results During a mean follow-up of 3.7 years, 14 (16%) primary events occurred among patients receiving standard surgery vs. 5 (5%) in the group randomized to additional LAACS (hazard ratio 0.3; 95% CI: 0.1–0.8, p = 0.02). In per protocol analysis (n = 141), 14 (18%) primary events occurred in the control group vs. 4 (6%) in the LAACS group (hazard ratio 0.3; 95% CI: 0.1–1.0, p = 0.05). Conclusions In a real-world setting, LAACS in addition to elective open-heart surgery was associated with lower risk of post-operative ischemic brain injury. The protective effect was not conditional on AF/OAC status at baseline. Trial registration LAACS study, clinicaltrials.gov NCT02378116, March 4th 2015, retrospectively registered.

Abstract Background Cerebral small vessel disease is a common cause of vascular cognitive impairment in older people, with no licensed treatment. Cerebral blood flow is reduced in small vessel disease. Tadalafil is a widely prescribed phosphodiesterase-5 inhibitor that increases blood flow in other vascular territories. The aim of this trial is to test the hypothesis that tadalafil increases cerebral blood flow in older people with small vessel disease. Methods/design Perfusion by Arterial Spin labelling following Single dose Tadalafil In Small vessel disease (PASTIS) is a phase II randomised double-blind crossover trial. In two visits, 7-30 days apart, participants undergo arterial spin labelling to measure cerebral blood flow and a battery of cognitive tests, pre- and post-dosing with oral tadalafil (20 mg) or placebo. Sample size: 54 participants are required to detect a 15% increase in cerebral blood flow in subcortical white matter (p

This study investigates the association between intelligence and brain power responses to a passive audiovisual stimulation. We measure the power of gamma-range steady-state responses (SSRs) as well as intelligence and other aspects of neurocognitive function in 40 healthy males born in 1953. The participants are a part of a Danish birth cohort study and the data therefore include additional information measured earlier in life. Our main power measure is the difference in power between a visual stimulation and a combined audiovisual stimulation. We hypothesize and establish empirically that the power measure is associated with intelligence. In particular, we find a highly significant correlation between the power measure and present intelligence scores. The association is robust to controlling for size-at-birth measures, length of education, speed of processing as well as a range of other potentially confounding factors. Interestingly, we find that intelligence scores measured earlier in life (childhood, youth, late midlife), are also correlated with the present-day power measure, suggesting a deep connection between intelligence and the power measure. Finally, we find that the power measure has a high sensitivity for detection of an intelligence score below the average.

Background: High-intensity interval training (HIIT) is superior to moderate-intensity continuous training in improving cardiorespiratory fitness in patients with cardiovascular disease, but is it safe, feasible and effective in patients with stroke? We investigated feasibility and effect of early, home-based HIIT in patients with lacunar stroke combined with usual care vs. usual care, only.Methods: Patients with minor stroke (severity: 55/58 point on the Scandinavian Stroke Scale) were randomized to HIIT or usual care in a randomized, controlled trial. We measured the following outcomes at baseline and post-intervention: cardiorespiratory fitness monitored as power output from the Graded Cycling Test with Talk Test (GCT-TT; primary outcome), physical activity, fatigue, depression, well-being, stress, cognition, endothelial function, blood pressure, body mass index, and biomarkers.Results: We included 71 patients (mean age 63.7 ± 9.2), 49 men, 31 in intervention group. Home-based HIIT was feasible with no reported adverse events in relation to the intervention. No significant change between the groups in GCT-TT power output was detected (p = 0.90). The change in time spent on vigorous-intensity activity was 2 h/week and 0.6 h/week, intervention and usual care, respectively (p = 0.045). There were no significant differences between groups in the remaining secondary outcomes.Conclusion: HIIT was feasible and safe in patients with lacunar stroke. Patients can engage early in home-based HIIT when involved in choosing exercise modality and guided by weekly motivational phone calls. Within 3 months, HIIT did, however, not yield effect on cardiorespiratory fitness. We await further evaluation of long-term effects of this intervention on continued regular physical exercise and cardiovascular event.Clinical Trial Registration:https://clinicaltrials.gov, identifier NCT02731235

Background: The effects of physical exercise in patients with lacunar stroke, seem promising in secondary prevention and only few studies have investigated the effect of high-intensity interval training in patients with lacunar stroke. This study will be investigating whether high-intensity interval training improves cardiovascular fitness as well as cognitive- and endothelial function and potentially attenuating the risk of recurrent stroke. Methods: A randomized controlled trial evaluating 12 weeks of home-based, high-intensity interval training compared with usual care. The intervention group will be exercising 15 min a day, 5 days a week, for 12 weeks. Outcomes will be evaluated at baseline, three, six and twelve months post-stroke with ‘The Graded Cycling Test with Talk Test’ as the primary outcome registered as power output in Watts. Additionally, an annually register-based follow-up will be performed for 5 years from date of inclusion with a composite endpoint of cardiovascular disease or death. Secondary outcomes will be: physical activity, endothelial response, mental well-being, cognition, mood, fatigue, stress, and MRI scan. Discussion: This study is going to show if early initiated home-based high-intensity interval training is feasible and effective in patients with lacunar stroke. A self-chosen aerobic exercise modality allows a realistic implementation of practice, together with greater chance of long-term adherence. A limitation of the study is that recruitment bias cannot be ruled out, as there may be a preferential enrolment of patients who are self-motivated to engage in exercise. Keywords: High-intensity interval training, Lacunar stroke, Risk factors, Secondary prevention

Progressive loss of brain tissue is seen in some patients with schizophrenia and might be caused by increased levels of glutamate and resting cerebral blood flow (rCBF) alterations. Animal studies suggest that the normalisation of glutamate levels decreases rCBF and prevents structural changes in hippocampus. However, the relationship between glutamate and rCBF in anterior cingulate cortex (ACC) of humans has not been studied in the absence of antipsychotics and illness chronicity. Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist that transiently induces schizophrenia-like symptoms and neurobiological disturbances in healthy volunteers (HVs). Here, we used S-ketamine challenge to assess if glutamate levels were associated with rCBF in ACC in 25 male HVs. Second, we explored if S-ketamine changed the neural activity as reflected by rCBF alterations in thalamus (Thal) and accumbens that are connected with ACC. Glutamatergic metabolites were measured in ACC with magnetic resonance (MR) spectroscopy and whole-brain rCBF with pseudo-continuous arterial spin labelling on a 3-T MR scanner before, during, and after infusion of S-ketamine (total dose 0.375 mg/kg). In ACC, glutamate levels were associated with rCBF before (p

Although dementia is associated with both global and regional cerebral blood flow (CBF) changes, little is known about cerebral perfusion in the early pre-clinical stages of cognitive decline preceding overt cognitive dysfunction. The aim of this study was to investigate the association of early sub-clinical cognitive decline with CBF.The study participants were recruited from a cohort of Danish men born in 1953. Based on a regression model we selected men who performed better (Group A, n = 94) and poorer (Group B, n = 95) on cognitive testing at age 57 than expected from testing at age 20. Participants underwent supplementary cognitive testing, blood sampling and MRI including measurements of regional and global CBF.Regional CBF was lower in group B than in group A in the posterior cingulate gyrus and the precuneus. The associations were attenuated when corrected for global atrophy, but remained significant in regions of interest based analysis adjusting for regional gray matter volume and vascular risk factors. No influence of group on global CBF was observed.We conclude that early sub-clinical cognitive decline is associated with reduced perfusion in the precuneus and posterior cingulate gyrus independently of regional atrophy and vascular risk factors, but cannot be statistically separated from an association with global atrophy.

Hemispheric asymmetry of a wide range of functions is a hallmark of the human brain. The visual system has traditionally been thought of as symmetrically distributed in the brain, but a growing body of evidence has challenged this view. Some highly specific visual tasks have been shown to depend on hemispheric specialization. However, the possible lateralization of cerebral responses to a simple checkerboard visual stimulation has not been a focus of previous studies. To investigate this, we performed two sessions of blood-oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in 54 healthy subjects during stimulation with a black and white checkerboard visual stimulus. While carefully excluding possible non-physiological causes of left-to-right bias, we compared the activation of the left and the right cerebral hemispheres and related this to grey matter volume, handedness, age, gender, ocular dominance, interocular difference in visual acuity, as well as line-bisection performance. We found a general lateralization of cerebral activation towards the right hemisphere of early visual cortical areas and areas of higher-level visual processing, involved in visuospatial attention, especially in top-down (i.e., goal-oriented) attentional processing. This right hemisphere lateralization was partly, but not completely, explained by an increased grey matter volume in the right hemisphere of the early visual areas. Difference in activation of the superior parietal lobule was correlated with subject age, suggesting a shift towards the left hemisphere with increasing age. Our findings suggest a right-hemispheric dominance of these areas, which could lend support to the generally observed leftward visual attentional bias and to the left hemifield advantage for some visual perception tasks.

Both cerebral hypoperfusion and vascular risk factors have been implicated in early aging of the brain and the development of neurodegenerative disease. However, the current knowledge of the importance of cardiovascular health on resting brain perfusion is limited. The aim of the present study was to elucidate the relation between brain perfusion variability and risk factors of endothelial dysfunction and atherosclerosis in healthy aged subjects.Thirty-eight healthy subjects aged 50-75 years old were included. Mean global brain perfusion was measured using magnetic resonance phase contrast mapping and regional brain perfusion by use of arterial spin labeling.Mean global brain perfusion was inversely correlated with caffeine and hematocrit, and positively with end-tidal PCO2. Furthermore, the mean global brain perfusion was inversely correlated with circulating homocysteine, but not with asymmetric dimethylarginine, dyslipidemia or the carotid intima-media thickness. The relative regional brain perfusion was associated with circulating homocysteine, with a relative parietal hypoperfusion and a frontal hyperperfusion. No effect on regional brain perfusion was observed for any of the other risk factors. A multiple regression model including homocysteine, caffeine, hematocrit and end-tidal PCO2, explained nearly half of the observed variability.Both intrinsic and extrinsic factors influenced global cerebral perfusion variation between subjects. Further, the results suggest that the inverse relation between homocysteine and brain perfusion is owing to other mechanisms, than reflected by asymmetric dimethylarginine, and that homocysteine may be a marker of cerebral perfusion in aging brains.

Monitoring of industrial processes is a critical capability in industry and in government to ensure reliability of production cycles, quick emergency response, and national security. Process monitoring allows users to gauge the progress of an organization in an industrial process or predict the degradation or aging of machine parts in processes taking place at a remote location. Similar to many data science applications, we usually only have access to limited raw data, such as satellite imagery, short video clips, event logs, and signatures captured by a small set of sensors. To combat data scarcity, we leverage the knowledge of Subject Matter Experts (SMEs) who are familiar with the actions of interest. SMEs provide expert knowledge of the essential activities required for task completion and the resources necessary to carry out each of these activities. Various process mining techniques have been developed for this type of analysis; typically such approaches combine theoretical process models built based on domain expert insights with ad-hoc integration of available pieces of raw data. Here, we introduce a novel mathematically sound method that integrates theoretical process models (as proposed by SMEs) with interrelated minimal Hidden Markov Models (HMM), built via nonnegative tensor factorization. Our method consolidates: (a) theoretical process models, (b) HMMs, (c) coupled nonnegative matrix-tensor factorizations, and (d) custom model selection. To demonstrate our methodology and its abilities, we apply it on simple synthetic and real-world process models. [ABSTRACT FROM AUTHOR]

Background: Resting cerebral blood flow (rCBF) in striatum and thalamus is increased in medicated patients with psychosis, but whether this is caused by treatment or illness pathology is unclear. Specifically, effects of partial dopamine agonism, sex, and clinical correlates on rCBF are sparsely investigated. We therefore assessed rCBF in antipsychotic-naïve psychosis patients before and after aripiprazole monotherapy and related findings to sex and symptom improvement. Methods: We assessed rCBF with the pseudo-Continuous Arterial Spin Labeling (PCASL) sequence in 49 first-episode patients (22.6 ± 5.2 years, 58% females) and 50 healthy controls (HCs) (22.3 ± 4.4 years, 63% females) at baseline and in 29 patients and 49 HCs after six weeks. RCBF in striatum and thalamus was estimated with a region-of-interest (ROI) approach. Psychopathology was assessed with the positive and negative syndrome scale. Results: Baseline rCBF in striatum and thalamus was not altered in the combined patient group compared with HCs, but female patients had lower striatal rCBF compared with male patients (p = 0.009). Treatment with a partial dopamine agonist increased rCBF significantly in striatum (p = 0.006) in the whole patient group, but not significantly in thalamus. Baseline rCBF in nucleus accumbens was negatively associated with improvement in positive symptoms (p = 0.046), but baseline perfusion in whole striatum and thalamus was not related to treatment outcome. Conclusions: The findings suggest that striatal perfusion is increased by partial dopamine agonism and decreased in female patients prior to first treatment. This underlines the importance of treatment effects and sex differences when investigating the neurobiology of psychosis. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) has been proposed as a sensitive biomarker of traumatic white matter injury, which could potentially serve as a tool for prognostic assessment and for studying microstructural changes during recovery from traumatic brain injury (TBI). However, there is a lack of longitudinal studies on TBI that follow DTI changes over time and correlate findings with long-term clinical outcome. We performed a prospective longitudinal study of 30 adult patients admitted for subacute rehabilitation following severe traumatic brain injury. DTI and conventional MRI were acquired at mean 8 weeks (5–11 weeks), and repeated in 23 of the patients at mean 12 months (9–15 months) post-trauma. Using a region-of-interest-based approach, DTI parameters were compared to those of healthy matched controls, scanned during the same time period and rescanned with a similar interval as that of patients. At the initial scan, fractional anisotropy was reduced in all the investigated white matter regions in patients compared to controls (P ≤ 0.01) due to decreased diffusivity parallel (λ∥) and increased diffusivity perpendicular (λ⊥) to axonal fibre direction. Fractional anisotropy in the cerebral peduncle correlated with ∼1 year Glasgow outcome scale score (r = 0.60, P0.001) and in this sample predicted dichotomized outcome with 76% accuracy when taken alone, and with 100% accuracy in combination with clinical evaluation by functional independence measure at the time of the first scan. At follow-up DTI, fractional anisotropy in patients had increased in the internal capsule and in centrum semiovale (P ≤ 0.01) due to an interval increase of λ∥ with unchanged λ⊥. In these regions, fractional anisotropy and λ∥ reached normal or supranormal levels, primarily in patients with favourable outcome. In the cerebral peduncle and in corpus callosum, λ∥ and λ⊥ both increased during the scan interval and, particularly in patients with unfavourable outcome, fractional anisotropy remained depressed. No significant DTI parameter changes over time were found in controls, or in CSF of patients. These findings support that DTI is a clinically relevant biomarker in TBI, which may have prognostic value and also might serve as a tool for revealing changes in the neural tissue during recovery. [ABSTRACT FROM AUTHOR]

Background: Aberrant anticipation of motivational salient events and processing of outcome evaluation in striatal and prefrontal regions have been suggested to underlie psychosis. Altered glutamate levels have likewise been linked to schizophrenia. Glutamatergic abnormalities may affect the processing of motivational salience and outcome evaluation. It remains unresolved, whether glutamatergic dysfunction is associated with the coding of motivational salience and outcome evaluation in antipsychotic-naïve patients with first-episode psychosis. Methods: Fifty-one antipsychotic-naïve patients with first-episode psychosis (22 ± 5.2 years, female/male: 31/20) and 52 healthy controls (HC) matched on age, sex, and parental education underwent functional magnetic resonance imaging and magnetic resonance spectroscopy (3T) in one session. Brain responses to motivational salience and negative outcome evaluation (NOE) were examined using a monetary incentive delay task. Glutamate levels were estimated in the left thalamus and anterior cingulate cortex using LCModel. Results: Patients displayed a positive signal change to NOE in the caudate (p = 0.001) and dorsolateral prefrontal cortex (DLPFC; p = 0.003) compared to HC. No group difference was observed in motivational salience or in levels of glutamate. There was a different association between NOE signal in the caudate and DLPFC and thalamic glutamate levels in patients and HC due to a negative correlation in patients (caudate: p = 0.004, DLPFC: p = 0.005) that was not seen in HC. Conclusions: Our findings confirm prior findings of abnormal outcome evaluation as a part of the pathophysiology of schizophrenia. The results also suggest a possible link between thalamic glutamate and NOE signaling in patients with first-episode psychosis. [ABSTRACT FROM AUTHOR]

Cerebral small vessel disease (SVD) is common in older people and is associated with lacunar stroke, white matter hyperintensities (WMH) and vascular cognitive impairment. Cerebral blood flow (CBF) is reduced in SVD, particularly within white matter. Here we quantified test–retest reliability in CBF measurements using pseudo-continuous arterial spin labelling (pCASL) in older adults with clinical and radiological evidence of SVD (N=54, mean (SD): 66.9 (8.7) years, 15 females/39 males). We generated whole-brain CBF maps on two visits at least 7 days apart (mean (SD): 20 (19), range 7-117 days). Test–retest reliability for CBF was high in all tissue types, with intra-class correlation coefficient [95%CI]: 0.758 [0.616, 0.852] for whole brain, 0.842 [0.743, 0.905] for total grey matter, 0.771 [0.636, 0.861] for deep grey matter (caudate-putamen and thalamus), 0.872 [0.790, 0.923] for normal-appearing white matter (NAWM) and 0.780 [0.650, 0.866] for WMH (all p<0.001). ANCOVA models indicated significant decline in CBF in total grey matter, deep grey matter and NAWM with increasing age and diastolic blood pressure (all p<0.001). CBF was lower in males relative to females (p=0.013 for total grey matter, p=0.004 for NAWM). We conclude that pCASL has high test–retest reliability as a quantitative measure of CBF in older adults with SVD. These findings support the use of pCASL in routine clinical imaging and as a clinical trial endpoint. All data come from the PASTIS trial, prospectively registered at: https://eudract.ema.europa.eu (2015-001235-20, registered 13/05/2015), http://www.clinicaltrials.gov (NCT02450253, registered 21/05/2015). [ABSTRACT FROM AUTHOR]

Principal component analysis (PCA) is often applied for analyzing data in the most diverse areas. This work reports, in an accessible and integrated manner, several theoretical and practical aspects of PCA. The basic principles underlying PCA, data standardization, possible visualizations of the PCA results, and outlier detection are subsequently addressed. Next, the potential of using PCA for dimensionality reduction is illustrated on several real-world datasets. Finally, we summarize PCA-related approaches and other dimensionality reduction techniques. All in all, the objective of this work is to assist researchers from the most diverse areas in using and interpreting PCA. [ABSTRACT FROM AUTHOR]

Background: The clinical high-risk for psychosis (CHR-P) paradigm was introduced to detect individuals at risk of developing psychosis and to establish preventive strategies. While current prediction of outcomes in the CHR-P state is based mostly on the clinical assessment of presenting features, several emerging biomarkers have been investigated in an attempt to stratify CHR-P individuals according to their individual trajectories and refine the diagnostic process. However, heterogeneity across subgroups is a key challenge that has limited the impact of the CHR-P prediction strategies, as the clinical validity of the current research is limited by a lack of external validation across sites and modalities. Despite these challenges, electroencephalography (EEG) biomarkers have been studied in this field and evidence suggests that EEG used in combination with clinical assessments may be a key measure for improving diagnostic and prognostic accuracy in the CHR-P state. The PSYSCAN EEG study is an international, multi-site, multimodal longitudinal project that aims to advance knowledge in this field. Methods: Participants at 6 international sites take part in an EEG protocol including EEG recording, cognitive and clinical assessments. CHR-P participants will be followed up after 2 years and subcategorised depending on their illness progression regarding transition to psychosis. Differences will be sought between CHR-P individuals and healthy controls and between CHR-P individuals who transition and those who do not transition to psychosis using data driven computational analyses. Discussion: This protocol addresses the challenges faced by previous studies of this kind to enable valid identification of predictive EEG biomarkers which will be combined with other biomarkers across sites to develop a prognostic tool in CHR-P. The PSYSCAN EEG study aims to pave the way for incorporating EEG biomarkers in the assessment of CHR-P individuals, to refine the diagnostic process and help to stratify CHR-P subjects according to risk of transition. This may improve our understanding of the CHR-P state and therefore aid the development of more personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The typical onset of schizophrenia coincides with the maturational peak in cognition; however, for a significant proportion of patients the onset is before age 18 and after age 30 years. While cognitive deficits are considered core features of schizophrenia, few studies have directly examined the impact of age of illness onset on cognition. Methods: The aim of the study was to examine if the effects of age on cognition differ between healthy controls (HCs) and patients with schizophrenia at illness onset. We examined 156 first-episode antipsychotic-naïve patients across a wide age span (12–43 years), and 161 age- and sex-matched HCs. Diagnoses were made according to ICD-10 criteria. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), and IQ was estimated using subtests from the Wechsler adult- or child-intelligence scales. Multivariate analysis of covariance (MANCOVA) was used to examine linear and quadratic effects of age on cognitive scores and interactions by group, including sex and parental socioeconomic status as covariates. Results: There was a significant overall effect of age on BACS and IQ (p < 0.001). Significant group-by-age interactions for verbal memory (for age-squared, p = 0.009), and digit sequencing (for age, p = 0.01; age-squared, p < 0.001), indicated differential age-related trajectories between patients and HCs. Conclusions: Cognitive functions showing protracted maturation into adulthood, such as verbal memory and verbal working memory, may be particularly impaired in both early- and late-schizophrenia onset. Our findings indicate a potential interaction between the timing of neurodevelopmental maturation and a possible premature age effect in late-onset schizophrenia. [ABSTRACT FROM AUTHOR]

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined. [ABSTRACT FROM AUTHOR]