Publications by authors named "Egill Rostrup"

109 Publications

Automatic continuous EEG signal analysis for diagnosis of delirium in patients with sepsis.

Clin Neurophysiol 2021 Sep 9;132(9):2075-2082. Epub 2021 Jun 9.

Department of Clinical Neurophysiology, The Neuroscience Centre, Rigshospitalet, University of Copenhagen, Valdemar Hansens Vej 1-23, Glostrup, Denmark. Electronic address:

Objective: In critical care, continuous EEG (cEEG) monitoring is useful for delirium diagnosis. Although visual cEEG analysis is most commonly used, automatic cEEG analysis has shown promising results in small samples. Here we aimed to compare visual versus automatic cEEG analysis for delirium diagnosis in septic patients.

Methods: We obtained cEEG recordings from 102 septic patients who were scored for delirium six times daily. A total of 1252 cEEG blocks were visually analyzed, of which 805 blocks were also automatically analyzed.

Results: Automatic cEEG analyses revealed that delirium was associated with 1) high mean global field power (p < 0.005), mainly driven by delta activity; 2) low average coherence across all electrode pairs and all frequencies (p < 0.01); 3) lack of intrahemispheric (fronto-temporal and temporo-occipital regions) and interhemispheric coherence (p < 0.05); and 4) lack of cEEG reactivity (p < 0.005). Classification accuracy was assessed by receiver operating characteristic (ROC) curve analysis, revealing a slightly higher area under the curve for visual analysis (0.88) than automatic analysis (0.74) (p < 0.05).

Conclusions: Automatic cEEG analysis is a useful supplement to visual analysis, and provides additional cEEG diagnostic classifiers.

Significance: Automatic cEEG analysis provides useful information in septic patients.
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http://dx.doi.org/10.1016/j.clinph.2021.05.013DOI Listing
September 2021

Associations between cognition and white matter microstructure in first-episode antipsychotic-naïve patients with schizophrenia and healthy controls: A multivariate pattern analysis.

Cortex 2021 06 18;139:282-297. Epub 2021 Mar 18.

Centre for Neuropsychiatric Schizophrenia Research, CNSR and Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark; Department of Psychology, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Cognitive functions have been associated with white matter (WM) microstructure in schizophrenia, but most studies are limited by examining only select cognitive measures and single WM tracts in chronic, medicated patients. It is unclear if the cognition-WM relationship differs between antipsychotic-naïve patients with schizophrenia and healthy controls, as differential associations have not been directly examined. Here we examine if there are differential patterns of associations between cognition and WM microstructure in first-episode antipsychotic-naïve patients with schizophrenia and healthy controls, and we characterize reliable contributors to the pattern of associations across multiple cognitive domains and WM regions, in order to elucidate white matter contribution to the neural underpinnings of cognitive deficits.

Methods: Thirty-six first-episode antipsychotic-naïve patients with schizophrenia and 52 matched healthy controls underwent cognitive tests and diffusion-weighted imaging on a 3T Magnetic Resonance Imaging scanner. Using a multivariate partial least squares correlation analysis, we included 14 cognitive variables and mean fractional anisotropy values of 48 WM regions.

Results: Initial analyses showed significant group differences in both measures of WM and cognition. There was no group interaction effect in the pattern of associations between cognition and WM microstructure. The combined analysis of patients and controls lead to a significant pattern of associations (omnibus test p = .015). Thirty-four regions and seven cognitive functions contributed reliably to the associations.

Conclusions: The lack of an interaction effect suggests similar associations in first-episode antipsychotic-naïve patients with schizophrenia and healthy controls. This, together with the differences in both WM and cognitive measurements, supports the involvement of WM in cognitive deficits in schizophrenia. Our findings add to the field by showing a coherent picture of the overall pattern of association between cognition and WM. These findings increase our understanding of the impact of WM on cognition, contributing to the search for neuromarkers of cognitive deficits in schizophrenia.
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http://dx.doi.org/10.1016/j.cortex.2021.03.003DOI Listing
June 2021

Regional and interindividual relationships between cerebral perfusion and oxygen metabolism.

J Appl Physiol (1985) 2021 06 8;130(6):1836-1847. Epub 2021 Apr 8.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark.

Quantitative measurements of resting cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO) show large between-subject and regional variability, but the relationships between CBF and CMRO measurements regionally and globally are not fully established. Here, we investigated the between-subject and regional associations between CBF and CMRO measures with independent and quantitative PET techniques. We included resting CBF and CMRO measurements from 50 healthy volunteers (aged 22-81 yr), and calculated the regional and global values of oxygen delivery (Do) and oxygen extraction fraction (OEF). Linear mixed-model analysis showed that CBF and CMRO measurements were closely associated regionally, but no significant between-subject association could be demonstrated, even when adjusting for arterial Pco and hemoglobin concentration. The analysis also showed regional differences of OEF, reflecting variable relationship between Do and CMRO, resulting in lower estimates of OEF in thalami, brainstem, and mesial temporal cortices and higher estimates of OEF in occipital cortex. In the present study, we demonstrated no between-subject association of quantitative measurements of CBF and CMRO in healthy subjects. Thus, quantitative measurements of CBF did not reflect the underlying between-subject variability of oxygen metabolism measures, mainly because of large interindividual OEF variability not accounted for by Pco and hemoglobin concentration. Using quantitative PET-measurements in healthy human subjects, we confirmed a regional association of CBF and CMRO, but did not find an association of these values across subjects. This suggests that subjects have an individual coupling between perfusion and metabolism and shows that absolute perfusion measurements does not serve as a surrogate measure of individual measures of oxygen metabolism. The analysis further showed smaller, but significant regional differences of oxygen extraction fraction at rest.
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http://dx.doi.org/10.1152/japplphysiol.00939.2020DOI Listing
June 2021

Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis: The OPTiMiSE Study.

Schizophr Bull 2021 03;47(2):444-455

Center for Neuropsychiatric Schizophrenia Research, CNSR, and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Mental Health Centre Glostrup, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1093/schbul/sbaa115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965060PMC
March 2021

Tadalafil may improve cerebral perfusion in small-vessel occlusion stroke-a pilot study.

Brain Commun 2020 20;2(1):fcaa020. Epub 2020 Feb 20.

Department of Neurology, Neurovascular Research Unit, Herlev Gentofte Hospital, University of Copenhagen, Herlev 2730, Denmark.

New treatments for cerebral small-vessel disease are needed to reduce the risk of small-vessel occlusion stroke and vascular cognitive impairment. We investigated an approach targeted to the signalling molecule cyclic guanosine monophosphate, using the phosphodiesterase 5 inhibitor tadalafil, to explore if it improves cerebral blood flow and endothelial function in patients with cerebral small-vessel disease and stroke. In a randomized, double-blinded, placebo-controlled, cross-over pilot trial (NCT02801032), we included patients who had a previous (>6 months) small-vessel occlusion stroke. They received a single dose of either 20 mg tadalafil or placebo on 2 separate days at least 1 week apart. We measured the following: baseline MRI for lesion load, repeated measurements of blood flow velocity in the middle cerebral artery by transcranial Doppler, blood oxygen saturation in the cortical microvasculature by near-infrared spectroscopy, peripheral endothelial response by EndoPAT and endothelial-specific blood biomarkers. Twenty patients with cerebral small-vessel disease stroke (3 women, 17 men), mean age 67.1 ± 9.6, were included. The baseline mean values ± standard deviations were as follows: blood flow velocity in the middle cerebral artery, 57.4 ± 10.8 cm/s; blood oxygen saturation in the cortical microvasculature, 67.0 ± 8.2%; systolic blood pressure, 145.8 ± 19.5 mmHg; and diastolic blood pressure, 81.3 ± 9.1 mmHg. We found that tadalafil significantly increased blood oxygen saturation in the cortical microvasculature at 180 min post-administration with a mean difference of 1.57 ± 3.02%. However, we saw no significant differences in transcranial Doppler measurements over time. Tadalafil had no effects on peripheral endothelial function assessed by EndoPAT and endothelial biomarker results conflicted. Our findings suggest that tadalafil may improve vascular parameters in patients with cerebral small-vessel disease stroke, although the effect size was small. Increased oxygenation of cerebral microvasculature during tadalafil treatment indicated improved perfusion in the cerebral microvasculature, theoretically presenting an attractive new therapeutic target in cerebral small-vessel disease. Future studies of the effect of long-term tadalafil treatment on cerebrovascular reactivity and endothelial function are needed to evaluate general microvascular changes and effects in cerebral small-vessel disease and stroke.
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http://dx.doi.org/10.1093/braincomms/fcaa020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530832PMC
February 2020

Associations Between Cognitive Function and Levels of Glutamatergic Metabolites and Gamma-Aminobutyric Acid in Antipsychotic-Naïve Patients With Schizophrenia or Psychosis.

Biol Psychiatry 2021 02 10;89(3):278-287. Epub 2020 Jul 10.

Center for Neuropsychiatric Schizophrenia Research and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, University of Copenhagen, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Background: Abnormal glutamate and GABA (gamma-aminobutyric acid) levels have been found in the early phase of schizophrenia and may underlie cognitive deficits. However, the association between cognitive function and levels of glutamatergic metabolites and GABA has not been investigated in a large group of antipsychotic-naïve patients.

Methods: In total, 56 antipsychotic-naïve patients with schizophrenia or psychotic disorder and 51 healthy control subjects underwent magnetic resonance spectroscopy to measure glutamate, glutamate+glutamine (Glx), and GABA levels in dorsal anterior cingulate cortex (ACC) and glutamate and Glx levels in left thalamus. The cognitive domains of attention, working memory, and IQ were assessed.

Results: The whole group of antipsychotic-naïve patients had lower levels of GABA in dorsal ACC (p = .03), and the subgroup of patients with a schizophrenia diagnosis had higher glutamate levels in thalamus (p = .01), but Glx levels in dorsal ACC and thalamus did not differ between groups. Glx levels in dorsal ACC were positively associated with working memory (logarithmically transformed: b = -.016 [higher score indicates worse performance], p = .005) and attention (b = .056, p = .035) in both patients and healthy control subjects, although the association with attention did not survive adjustment for multiple comparisons.

Conclusions: The findings suggest a positive association between glutamatergic metabolites and cognitive function that do not differ between patients and healthy control subjects. Moreover, our data indicate that decreased GABAergic levels in dorsal ACC are involved in schizophrenia and psychotic disorder, whereas increased glutamate levels in thalamus seem to be implicated in schizophrenia pathophysiology. The findings imply that first-episode patients with cognitive deficits may gain from glutamate-modulating compounds.
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http://dx.doi.org/10.1016/j.biopsych.2020.06.027DOI Listing
February 2021

Discovering correlates of age-related decline in a healthy late-midlife male birth cohort.

Aging (Albany NY) 2020 Sep 10;12(17):16709-16743. Epub 2020 Sep 10.

Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Studies exploring age-related brain and cognitive change have identified substantial heterogeneity among individuals, but the underlying reasons for the differential trajectories remain largely unknown. We investigated cross-sectional and longitudinal associations between brain-imaging phenotypes (IDPs) and cognitive ability, and how these relations may be modified by common risk and protective factors. Participants were recruited from the 1953 Danish Male Birth Cohort (N=123), a longitudinal study of cognitive and brain ageing. Childhood IQ and socio-demographic factors are available for these participants who have been assessed regularly on multiple IDPs and behavioural factors in midlife. Using Pearson correlations and canonical correlation analysis (CCA), we explored the relation between 454 IDPs and 114 behavioural variables. CCA identified a single mode of population covariation coupling cross-subject longitudinal changes in brain structure to changes in cognitive performance and to a range of age-related covariates (r=0.92, P < 0.001). Specifically, this CCA-mode indicated that; decreases in IQ and speed assessed tasks, higher rates of familial myocardial infarct, less physical activity, and poorer mental health are associated with larger decreases in whole brain grey matter and white matter. We found no evidence supporting the role of baseline scores as predictors of impending brain and behavioural change in late-midlife.
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http://dx.doi.org/10.18632/aging.103345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521526PMC
September 2020

A machine-learning framework for robust and reliable prediction of short- and long-term treatment response in initially antipsychotic-naïve schizophrenia patients based on multimodal neuropsychiatric data.

Transl Psychiatry 2020 08 10;10(1):276. Epub 2020 Aug 10.

Center for Neuropsychiatric Schizophrenia Research and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, Copenhagen University Hospital, Glostrup, Denmark.

The reproducibility of machine-learning analyses in computational psychiatry is a growing concern. In a multimodal neuropsychiatric dataset of antipsychotic-naïve, first-episode schizophrenia patients, we discuss a workflow aimed at reducing bias and overfitting by invoking simulated data in the design process and analysis in two independent machine-learning approaches, one based on a single algorithm and the other incorporating an ensemble of algorithms. We aimed to (1) classify patients from controls to establish the framework, (2) predict short- and long-term treatment response, and (3) validate the methodological framework. We included 138 antipsychotic-naïve, first-episode schizophrenia patients with data on psychopathology, cognition, electrophysiology, and structural magnetic resonance imaging (MRI). Perinatal data and long-term outcome measures were obtained from Danish registers. Short-term treatment response was defined as change in Positive And Negative Syndrome Score (PANSS) after the initial antipsychotic treatment period. Baseline diagnostic classification algorithms also included data from 151 matched controls. Both approaches significantly classified patients from healthy controls with a balanced accuracy of 63.8% and 64.2%, respectively. Post-hoc analyses showed that the classification primarily was driven by the cognitive data. Neither approach predicted short- nor long-term treatment response. Validation of the framework showed that choice of algorithm and parameter settings in the real data was successfully guided by results from the simulated data. In conclusion, this novel approach holds promise as an important step to minimize bias and obtain reliable results with modest sample sizes when independent replication samples are not available.
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http://dx.doi.org/10.1038/s41398-020-00962-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417553PMC
August 2020

Volume of hippocampal subregions and clinical improvement following electroconvulsive therapy in patients with depression.

Prog Neuropsychopharmacol Biol Psychiatry 2021 01 28;104:110048. Epub 2020 Jul 28.

Center for Neuropsychiatric Depression Research, Mental Health Center Glostrup, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Science, The University of Copenhagen, Copenhagen, Denmark.

It is thought that the hippocampal neurogenesis is an important mediator of the antidepressant effect of electroconvulsive therapy (ECT). However, most previous studies failed to demonstrate the relationship between the increase in the hippocampal volume and the antidepressant effect. We reinvestigated this relationship by looking at distinct hippocampal subregions and applying repeated measures correlation. Using a 3 Tesla MRI-scanner, we scanned 22 severely depressed in-patients at three time points: before the ECT series, after the series, and at six-month follow-up. The depression severity was assessed by the 17-item Hamilton Rating Scale for Depression (HAMD-17). The hippocampus was segmented into subregions using Freesurfer software. The dentate gyrus (DG) was the primary region of interest (ROI), due to the role of this region in neurogenesis. The other major hippocampal subregions were the secondary ROIs (n = 20). The general linear mixed model and the repeated measures correlation were used for statistical analyses. Immediately after the ECT series, a significant volume increase was present in the right DG (Cohen's d = 1.7) and the left DG (Cohen's d = 1.5), as well as 15 out of 20 secondary ROIs. The clinical improvement, i.e., the decrease in HAMD-17 score, was correlated to the increase in the right DG volume (r = -0.77, df = 20, p < .001), and the left DG volume (r = -0.75, df = 20, p < .001). Similar correlations were observed in 14 out of 20 secondary ROIs. Thus, ECT induces an increase not only in the volume of the DG, but also in the volume of other major hippocampal subregions. The volumetric increases may reflect a neurobiological process that may be related to the ECT's antidepressant effect. Further investigation of the relationship between hippocampal subregions and the antidepressant effect is warranted. A statistical approach taking the repeated measurements into account should be preferred in the analyses.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110048DOI Listing
January 2021

Processing of Positive Visual Stimuli Before and After Symptoms Provocation in Posttraumatic Stress Disorder - A Functional Magnetic Resonance Imaging Study of Trauma-Affected Male Refugees.

Chronic Stress (Thousand Oaks) 2020 Jan-Dec;4:2470547020917623. Epub 2020 May 4.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark.

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.
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http://dx.doi.org/10.1177/2470547020917623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254584PMC
May 2020

Striatal Volume Increase After Six Weeks of Selective Dopamine D Receptor Blockade in First-Episode, Antipsychotic-Naïve Schizophrenia Patients.

Front Neurosci 2020 20;14:484. Epub 2020 May 20.

Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research and Center for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark.

Patients with chronic schizophrenia often display enlarged striatal volumes, and antipsychotic drugs may contribute via the dopamine D receptor (DR) 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 DR 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 ( = 0.01). This interaction was explained by a significant striatal volume increase of 2.1% in patients (Cohens = 0.45). Striatal increase was predicted by amisulpride dose, but not by either DR 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 DR 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.
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http://dx.doi.org/10.3389/fnins.2020.00484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251943PMC
May 2020

Associations of neural processing of reward with posttraumatic stress disorder and secondary psychotic symptoms in trauma-affected refugees.

Eur J Psychotraumatol 2020 4;11(1):1730091. Epub 2020 Mar 4.

Center for Neuropsychiatric Schizophrenia Research (CNSR) & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, Glostrup, Denmark.

: Psychological traumatic experiences can lead to posttraumatic stress disorder (PTSD). Secondary psychotic symptoms are not common but may occur. : 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. : 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. : 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. : 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.
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http://dx.doi.org/10.1080/20008198.2020.1730091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067194PMC
March 2020

Differential effects of age at illness onset on verbal memory functions in antipsychotic-naïve schizophrenia patients aged 12-43 years.

Psychol Med 2021 07 11;51(9):1570-1580. Epub 2020 Mar 11.

Center for Neuropsychiatric Schizophrenia Research (CNSR) and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Center Glostrup, Glostrup, Denmark.

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.
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http://dx.doi.org/10.1017/S0033291720000409DOI Listing
July 2021

Cerebral Glutamate and Gamma-Aminobutyric Acid Levels in Individuals at Ultra-high Risk for Psychosis and the Association With Clinical Symptoms and Cognition.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 06 19;5(6):569-579. Epub 2019 Dec 19.

Center for Neuropsychiatric Schizophrenia Research and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Center, University of Copenhagen, Glostrup, Denmark.

Background: Studies examining glutamate or gamma-aminobutyric acid (GABA) in ultra-high risk for psychosis (UHR) and the association with pathophysiology and cognition have shown conflicting results. We aimed to determine whether perturbed glutamate and GABA levels in the anterior cingulate cortex and glutamate levels in the left thalamus were present in UHR individuals and to investigate associations between metabolite levels and clinical symptoms and cognition.

Methods: We included 122 UHR individuals and 60 healthy control subjects. Participants underwent proton magnetic resonance spectroscopy to estimate glutamate and GABA levels and undertook clinical and cognitive assessments.

Results: We found no differences in metabolite levels between UHR individuals and healthy control subjects. In UHR individuals, we found negative correlations in the anterior cingulate cortex between the composite of glutamate and glutamine (Glx) and the Comprehensive Assessment of At-Risk Mental States composite score (p = .04) and between GABA and alogia (p = .01); positive associations in the anterior cingulate cortex between glutamate (p = .01) and Glx (p = .01) and spatial working memory and between glutamate (p = .04), Glx (p = .04), and GABA (p = .02) and set-shifting; and a positive association in the thalamus between glutamate and attention (p = .04). No associations between metabolites and clinical or cognitive scores were found in the healthy control subjects.

Conclusions: An association between glutamate and GABA levels and clinical symptoms and cognition found only in UHR individuals suggests a loss of the normal relationship between metabolite levels and cognitive function. Longitudinal studies with investigation of clinical and cognitive outcome and the association with baseline levels of glutamate and GABA could illuminate whether glutamatergic and GABAergic dysfunction predicts clinical outcome.
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http://dx.doi.org/10.1016/j.bpsc.2019.12.005DOI Listing
June 2020

Multimodal assessment of white matter microstructure in antipsychotic-naïve schizophrenia patients and confounding effects of recreational drug use.

Brain Imaging Behav 2021 Feb;15(1):36-48

Centre for Neuropsychiatric Schizophrenia Research, CNSR and Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Copenhagen University Hospital, Mental Health Centre, Nordstjernevej 41, 2600, Glostrup, Denmark.

Cerebral white matter (WM) aberrations in schizophrenia have been linked to multiple neurobiological substrates but the underlying mechanisms remain unknown. Moreover, antipsychotic treatment and substance use constitute potential confounders. Multimodal studies using diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) may provide deeper insight into the whole brain WM pathophysiology in schizophrenia. We combined DTI and MTI to investigate WM integrity in 51 antipsychotic-naïve, first-episode schizophrenia patients and 55 matched healthy controls, using 3 T magnetic resonance imaging (MRI). Psychopathology was assessed with the positive and negative syndrome scale (PANSS). A whole brain partial least squares correlation (PLSC) method was used to conjointly analyze DTI-derived measures (fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), mode of anisotropy (MO)) and the magnetization transfer ratio (MTR) to identify group differences, and associations with psychopathology. In secondary analyses, we excluded recreational substance users from both groups resulting in 34 patients and 51 healthy controls. The primary PLSC group difference analysis identified a significant pattern of lower FA, AD, MO and higher RD in patients (p = 0.04). This pattern suggests disorganized WM microstructure in patients. The secondary PLSC group difference analysis without recreational substance users revealed a significant pattern of lower FA and higher AD, RD, MO, MTR in patients (p = 0.04). This pattern in the substance free patients is consistent with higher extracellular free-water concentrations, which may reflect neuroinflammation. No significant associations with psychopathology were observed. Recreational substance use appears to be a confounding issue, which calls for attention in future WM studies.
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http://dx.doi.org/10.1007/s11682-019-00230-4DOI Listing
February 2021

Supplementary data for a focused review and meta-analysis of H-MRS studies on cerebral glutamate and GABA levels in high-risk of psychosis states.

Data Brief 2020 Feb 4;28:104920. Epub 2019 Dec 4.

Copenhagen Research Center for Mental Health, CORE, Mental Health Center Copenhagen, Copenhagen University Hospital, Gentofte Hospitalsvej 15.4, 2900 Hellerup, Denmark.

Data (attached) for a focused review and meta-analysis of cerebral levels of glutamate, Glx, and GABA levels assessed with H-MRS in high-risk of psychosis states was collected and stored at covidence.org and extracted to The Cochrane Collaboration Review Manager software package (RevMan Version 5.3) for meta-analytical purposes. Meta-analyses were performed with a random-effects, inverse-variance weighted model to calculate the pooled effect size. Heterogeneity was measured using the I value. Significance was assessed using two-sided 95% confidence intervals. Potential publication bias was assessed by visual inspection of funnel plots. Supplementary to the co-submitted article are comprehensive meta-analyses of glutamate, Glx, and GABA, as well as the PRISMA flow diagram of included studies and a list of studies included in the review along with available measures and methodological variables. The attached data offers an insight into the included studies and the specified metabolite values for each study and offers possible further investigation for other researchers, as well as an insight into the review and meta-analyses performed. The supplementary material also serves to support findings and interpretations in the main article.
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http://dx.doi.org/10.1016/j.dib.2019.104920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920491PMC
February 2020

Cerebral glutamate and GABA levels in high-risk of psychosis states: A focused review and meta-analysis of H-MRS studies.

Schizophr Res 2020 01 26;215:38-48. Epub 2019 Nov 26.

Copenhagen Research Center for Mental Health, CORE, Mental Health Center Copenhagen, Copenhagen University Hospital, Gentofte Hospitalsvej 15.4, 2900, Hellerup, Denmark. Electronic address:

Disturbances in the brain glutamate and GABA (γ-aminobutyric acid) homeostasis may be markers of transition to psychosis in individuals at high-risk (HR). Knowledge of GABA and glutamate levels in HR stages could give an insight into changes in the neurochemistry underlying psychosis. Studies on glutamate in HR have provided conflicting data, and GABA studies have only recently been initialized. In this meta-analysis, we compared cerebral levels of glutamate and GABA in HR individuals with healthy controls (HC). We searched Medline and Embase for articles published on H-MRS studies on glutamate and GABA in HR states until April 9th, 2019. We identified a total of 28 eligible studies, of which eight reported GABA (243 HR, 356 HC) and 26 reported glutamate (299 HR, 279 HC) or Glx (glutamate + glutamine) (584 HR, 632 HC) levels. Sample sizes varied from 6 to 75 for HR and 10 to 184 for HC. Our meta-analysis of H-MRS studies on glutamate and GABA in HR states displayed significantly lower (P = 0.0003) levels of thalamic glutamate in HR individuals than in HC and significantly higher (P = 0.001) Glx in the frontal lobe of genetic HR individuals (1st-degree relatives) than in HC. No other significant differences in glutamate and GABA levels were found. Subject numbers in the studies on glutamate as well as GABA levels were generally small and the data conflicting. Our meta-analytical findings highlight the need for larger and more homogeneous studies of glutamate and GABA in high-risk states.
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http://dx.doi.org/10.1016/j.schres.2019.10.050DOI Listing
January 2020

Treatment response after 6 and 26 weeks is related to baseline glutamate and GABA levels in antipsychotic-naïve patients with psychosis.

Psychol Med 2020 10 16;50(13):2182-2193. Epub 2019 Sep 16.

Center for Neuropsychiatric Schizophrenia Research (CNSR) & Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark.

Background: Poor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs).

Methods: Thirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response.

Results: Before treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ.

Conclusion: Glutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.
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http://dx.doi.org/10.1017/S0033291719002277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557159PMC
October 2020

Comparison of simultaneous arterial spin labeling MRI and O-HO PET measurements of regional cerebral blood flow in rest and altered perfusion states.

J Cereb Blood Flow Metab 2020 08 9;40(8):1621-1633. Epub 2019 Sep 9.

Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark.

Arterial spin labelling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that may provide fully quantitative regional cerebral blood flow (rCBF) images. However, before its application in clinical routine, ASL needs to be validated against the clinical gold standard, O-HO positron emission tomography (PET). We aimed to compare the two techniques by performing simultaneous quantitative ASL-MRI and O-HO-PET examinations in a hybrid PET/MRI scanner. Duplicate rCBF measurements were performed in healthy young subjects ( = 14) in rest, during hyperventilation, and after acetazolamide (post-ACZ), yielding 63 combined PET/MRI datasets in total. Average global CBF by ASL-MRI and O-HO-PET was not significantly different in any state (40.0 ± 6.5 and 40.6 ± 4.1 mL/100 g/min, respectively in rest, 24.5 ± 5.1 and 23.4 ± 4.8 mL/100 g/min, respectively, during hyperventilation, and 59.1 ± 10.4 and 64.7 ± 10.0 mL/100 g/min, respectively, post-ACZ). Overall, strong correlation between the two methods was found across all states (slope = 1.01, R= 0.82), while the correlations within individual states and of reactivity measures were weaker, in particular in rest (R= 0.05,  = 0.03). Regional distribution was similar, although ASL yielded higher perfusion and absolute reactivity in highly vascularized areas. In conclusion, ASL-MRI and O-HO-PET measurements of rCBF are highly correlated across different perfusion states, but with variable correlation within and between hemodynamic states, and systematic differences in regional distribution.
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http://dx.doi.org/10.1177/0271678X19874643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370368PMC
August 2020

Discovering markers of healthy aging: a prospective study in a Danish male birth cohort.

Aging (Albany NY) 2019 08 26;11(16):5943-5974. Epub 2019 Aug 26.

Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

There is a pressing need to identify markers of cognitive and neural decline in healthy late-midlife participants. We explored the relationship between cross-sectional structural brain-imaging derived phenotypes (IDPs) and cognitive ability, demographic, health and lifestyle factors (non-IDPs). Participants were recruited from the 1953 Danish Male Birth Cohort (N=193). Applying an extreme group design, members were selected in 2 groups based on cognitive change between IQ at age ~20y (IQ-20) and age ~57y (IQ-57). Subjects showing the highest (n=95) and lowest (n=98) change were selected (at age ~57) for assessments on multiple IDPs and non-IDPs. We investigated the relationship between 453 IDPs and 70 non-IDPs through pairwise correlation and multivariate canonical correlation analysis (CCA) models. Significant pairwise associations included positive associations between IQ-20 and gray-matter volume of the temporal pole. CCA identified a richer pattern - a single "positive-negative" mode of population co-variation coupling individual cross-subject variations in IDPs to an extensive range of non-IDP measures ( = 0.75, P < 0.01). Specifically, this mode linked higher cognitive performance, positive early-life social factors, and mental health to a larger brain volume of several brain structures, overall volume, and microstructural properties of some white matter tracts. Interestingly, both statistical models identified IQ-20 and gray-matter volume of the temporal pole as important contributors to the inter-individual variation observed. The converging patterns provide novel insight into the importance of early adulthood intelligence as a significant marker of late-midlife neural decline and motivates additional study.
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http://dx.doi.org/10.18632/aging.102151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738442PMC
August 2019

Brain Responses to Passive Sensory Stimulation Correlate With Intelligence.

Front Aging Neurosci 2019 14;11:201. Epub 2019 Aug 14.

Department of Clinical Neurophysiology, Rigshospitalet Glostrup, Glostrup, Denmark.

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.
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http://dx.doi.org/10.3389/fnagi.2019.00201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702683PMC
August 2019

Effect of Home-Based High-Intensity Interval Training in Patients With Lacunar Stroke: A Randomized Controlled Trial.

Front Neurol 2019 28;10:664. Epub 2019 Jun 28.

Neurovascular Research Unit, Department of Neurology, Herlev Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

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. 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. 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 ( = 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 ( = 0.045). There were no significant differences between groups in the remaining secondary outcomes. 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. https://clinicaltrials.gov, identifier NCT02731235.
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http://dx.doi.org/10.3389/fneur.2019.00664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611174PMC
June 2019

Neurostereologic Lesion Volumes and Spreading Depolarizations in Severe Traumatic Brain Injury Patients: A Pilot Study.

Neurocrit Care 2019 06;30(3):557-568

Department of Neurosurgery, University of Cincinnati (UC) College of Medicine, and UC Gardner Neuroscience Institute, Cincinnati, OH, USA.

Background: Spreading depolarizations (SDs) occur in 50-60% of patients after surgical treatment of severe traumatic brain injury (TBI) and are independently associated with unfavorable outcomes. Here we performed a pilot study to examine the relationship between SDs and various types of intracranial lesions, progression of parenchymal damage, and outcomes.

Methods: In a multicenter study, fifty patients (76% male; median age 40) were monitored for SD by continuous electrocorticography (ECoG; median duration 79 h) following surgical treatment of severe TBI. Volumes of hemorrhage and parenchymal damage were estimated using unbiased stereologic assessment of preoperative, postoperative, and post-ECoG serial computed tomography (CT) studies. Neurologic outcomes were assessed at 6 months by the Glasgow Outcome Scale-Extended.

Results: Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P's < 0.05). Parenchymal damage increased significantly (median 34 ml [Interquartile range (IQR) - 2, 74]) over 7 (5, 8) days from preoperative to post-ECoG CT studies. Patients with and without SDs did not differ in extent of parenchymal damage increase [47 ml (3, 101) vs. 30 ml (- 2, 50), P = 0.27], but those exhibiting the isoelectric subtype of SDs had greater initial parenchymal damage and greater increases than other patients (P's < 0.05). Patients with temporal clusters of SDs (≥ 3 in 2 h; n = 10 patients), which included those with isoelectric SDs, had worse outcomes than those without clusters (P = 0.03), and parenchymal damage expansion also correlated with worse outcomes (P = 0.01). In multivariate regression with imputation, both clusters and lesion expansion were significant outcome predictors.

Conclusions: These results suggest that subarachnoid and subdural blood are important primary injury factors in provoking SDs and that clustered SDs and parenchymal lesion expansion contribute independently to worse patient outcomes. These results warrant future prospective studies using detailed quantification of TBI lesion types to better understand the relationship between anatomic and physiologic measures of secondary injury.
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http://dx.doi.org/10.1007/s12028-019-00692-wDOI Listing
June 2019

Home-based aerobic exercise in patients with lacunar stroke: Design of the HITPALS randomized controlled trial.

Contemp Clin Trials Commun 2019 Jun 2;14:100332. Epub 2019 Feb 2.

Department of Neurology, Neurovascular Research Unit, Herlev GentofteHospital, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1016/j.conctc.2019.100332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378897PMC
June 2019

Heritability of Cerebral Blood Flow and the Correlation to Schizophrenia Spectrum Disorders: A Pseudo-continuous Arterial Spin Labeling Twin Study.

Schizophr Bull 2019 10;45(6):1231-1241

Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Mental Health Centre Glostrup, University of Copenhagen, Copenhagen, Denmark.

Whether aberrant cerebral blood flow (CBF) in schizophrenia is affected by genetic influences, and consequently a potential marker for genetic susceptibility, is unknown. Our aims were to determine the heritability of CBF in thalamic, frontal, and striatal areas, and to ascertain if associations with disease were under genetic influence. Monozygotic (MZ) twin pairs concordant (n = 2) or discordant (n = 20) for schizophrenia spectrum disorders (ICD-10 F2x.x), matched on sex and age with dizygotic (DZ; n = 20) and healthy control pairs (MZ: n = 27; DZ: n = 18; total: n = 181 individuals), were recruited via the National Danish Twin Register. CBF in thalamus, frontal lobes, and putamen was measured with pseudo-continuous arterial spin labeling on a 3 T magnetic resonance scanner. Twin statistics were performed with structural equation modeling. CBF in the frontal lobes was heritable (h2 = 0.44, 95% CI [0.22-0.60]) but not correlated to disease. CBF correlated to schizophrenia spectrum disorders in the left thalamus (r = 0.17, [0.03-0.31]; P = 0.02), as well as in the left putamen (r = 0.19, [0.05-0.32]; P = 0.007) and the right putamen (r = 0.18, [0.03-0.32]; P = 0.02). When restricting the sample to schizophrenia (F20.x) only, shared genetic influences between CBF in the left putamen and schizophrenia liability (phenotypic correlation = 0.44, [0.28-0.58], P < 0.001) were found. Our results provide heritability estimates of CBF in the frontal lobes, and we find CBF in thalamus and putamen to be altered in schizophrenia spectrum disorders. Furthermore, shared genetic factors influence schizophrenia liability and striatal perfusion. Specifically, higher perfusion in the left putamen may constitute a marker of genetic susceptibility for schizophrenia.
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http://dx.doi.org/10.1093/schbul/sbz007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811820PMC
October 2019

The relation between dopamine D receptor blockade and the brain reward system: a longitudinal study of first-episode schizophrenia patients.

Psychol Med 2020 01 15;50(2):220-228. Epub 2019 Jan 15.

Center for Neuropsychiatric Schizophrenia Research and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark.

Background: Psychotic symptoms have been linked to salience abnormalities in the brain reward system, perhaps caused by a dysfunction of the dopamine neurotransmission in striatal regions. Blocking dopamine D2 receptors dampens psychotic symptoms and normalises reward disturbances, but a direct relationship between D2 receptor blockade, normalisation of reward processing and symptom improvement has not yet been demonstrated. The current study examined the association between blockade of D2 receptors in the caudate nucleus, alterations in reward processing and the psychopathology in a longitudinal study of antipsychotic-naïve first-episode schizophrenia patients.

Methods: Twenty-two antipsychotic-naïve first-episode schizophrenia patients (10 males, mean age 23.3) and 23 healthy controls (12 males, mean age 23.5) were examined with single-photon emission computed tomography using 123I-labelled iodobenzamide. Reward disturbances were measured with functional magnetic resonance imaging (fMRI) using a modified version of the monetary-incentive-delay task. Patients were assessed before and after 6 weeks of treatment with amisulpride.

Results: In line with previous results, patients had a lower fMRI response at baseline (0.2 ± 0.5 v. 0.7 ± 0.6; p = 0.008), but not at follow-up (0.5 ± 0.6 v. 0.6 ± 0.7), and a change in the fMRI signal correlated with improvement in Positive and Negative Syndrome Scale positive symptoms (ρ = -0.435, p = 0.049). In patients responding to treatment, a correlation between improvement in the fMRI signal and receptor occupancy was found (ρ = 0.588; p = 0.035).

Conclusion: The results indicate that salience abnormalities play a role in the reward system in schizophrenia. In patients responding to a treatment-induced blockade of dopamine D2 receptors, the psychotic symptoms may be ameliorated by normalising salience abnormalities in the reward system.
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http://dx.doi.org/10.1017/S0033291718004099DOI Listing
January 2020

Sleep deprivation disrupts striatal anti-apoptotic responses in 6-hydroxy dopamine-lesioned parkinsonian rats.

Iran J Basic Med Sci 2018 Dec;21(12):1289-1296

Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Objectives: 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.
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http://dx.doi.org/10.22038/ijbms.2018.28546.6919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312672PMC
December 2018

Early focal brain injury after subarachnoid hemorrhage correlates with spreading depolarizations.

Neurology 2019 01 28;92(4):e326-e341. Epub 2018 Dec 28.

From the Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital (N.E., B.P.), University of Copenhagen; Departments of Clinical Physiology and Nuclear Medicine (E.R.) and Clinical Neurophysiology (M.F., M.L.), Rigshospitalet, University of Copenhagen, Denmark; Department of Neuroradiology (M.S., G.B.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Center for Stroke Research Berlin (S.M., M.K.L.W., V.K., C.R., P.V., J.W., J.P.D.) and Departments of Experimental Neurology (S.M., C.R., J.P.D.), Neurology (S.M., J.P.D.), and Neurosurgery (P.V., J.W.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Department of Neurosurgery (E.S., O.W.S.), University Hospital Heidelberg, Ruprecht Karls University Heidelberg; Neurosurgery Center Ludwigsburg-Heilbronn (O.W.S.), RKH Klinikum Ludwigsburg, Germany; UC Gardner Neuroscience Institute (J.A.H.) and Department of Neurosurgery (J.A.H.), University of Cincinnati (UC) College of Medicine, OH; Institute for Clinical Epidemiology and Applied Biostatistics (P.M.), University of Tübingen, Germany; Department of Neuroscience and Center for Healthy Aging, Panum Institute (M.L.), and Faculty of Health and Medical Sciences (B.P.), University of Copenhagen, Denmark; Bernstein Center for Computational Neuroscience Berlin (J.P.D.), Berlin; and Einstein Center for Neurosciences Berlin (J.P.D.), Germany.

Objective: To investigate whether spreading depolarization (SD)-related variables at 2 different time windows (days 1-4 and 5-8) after aneurysmal subarachnoid hemorrhage (aSAH) correlate with the stereologically determined volume of early focal brain injury on the preinterventional CT scan.

Methods: In this observational multicenter study of 54 patients, volumes of unaffected brain tissue, ventricles, cerebellum, aSAH, intracerebral hemorrhage, and focal parenchymal hypodensity were stereologically estimated. Patients were electrocorticographically monitored using subdural electrodes for 81.8 hours (median) (interquartile range: 70.6-90.5) during days 1-4 (n = 54) and for 75.9 (59.5-88.7) hours during days 5-8 (n = 51). Peak total SD-induced depression duration of a recording day (PTDDD) and peak numbers of (1) SDs, (2) isoelectric SDs, and (3) spreading depressions of a recording day were determined following the recommendations of the Co-Operative Studies on Brain Injury Depolarizations.

Results: Thirty-three of 37 patients with early focal brain injury (intracerebral hemorrhage and/or hypodensity) in contrast to 7 of 17 without displayed SDs during days 1-4 (sensitivity: 89% [95% confidence interval, CI: 75%-97%], specificity: 59% [CI: 33%-82%], positive predictive value: 83% [CI: 67%-93%], negative predictive value: 71% [CI: 42%-92%], Fisher exact test, < 0.001). All 4 SD-related variables during days 1-4 significantly correlated with the volume of early focal brain injury (Spearman rank order correlations). A multiple ordinal regression analysis identified the PTDDD as the most important predictor.

Conclusions: Our findings suggest that early focal brain injury after aSAH is associated with early SDs and further support the notion that SDs are a biomarker of focal brain lesions.
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http://dx.doi.org/10.1212/WNL.0000000000006814DOI Listing
January 2019

Accuracy of diagnostic classification algorithms using cognitive-, electrophysiological-, and neuroanatomical data in antipsychotic-naïve schizophrenia patients.

Psychol Med 2019 12 18;49(16):2754-2763. Epub 2018 Dec 18.

Centre for Neuropsychiatric Schizophrenia Research & Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, University of Copenhagen, Copenhagen, Denmark.

Background: A wealth of clinical studies have identified objective biomarkers, which separate schizophrenia patients from healthy controls on a group level, but current diagnostic systems solely include clinical symptoms. In this study, we investigate if machine learning algorithms on multimodal data can serve as a framework for clinical translation.

Methods: Forty-six antipsychotic-naïve, first-episode schizophrenia patients and 58 controls underwent neurocognitive tests, electrophysiology, and magnetic resonance imaging (MRI). Patients underwent clinical assessments before and after 6 weeks of antipsychotic monotherapy with amisulpride. Nine configurations of different supervised machine learning algorithms were applied to first estimate the unimodal diagnostic accuracy, and next to estimate the multimodal diagnostic accuracy. Finally, we explored the predictability of symptom remission.

Results: Cognitive data significantly classified patients from controls (accuracies = 60-69%; p values = 0.0001-0.009). Accuracies of electrophysiology, structural MRI, and diffusion tensor imaging did not exceed chance level. Multimodal analyses with cognition plus any combination of one or more of the remaining three modalities did not outperform cognition alone. None of the modalities predicted symptom remission.

Conclusions: In this multivariate and multimodal study in antipsychotic-naïve patients, only cognition significantly discriminated patients from controls, and no modality appeared to predict short-term symptom remission. Overall, these findings add to the increasing call for cognition to be included in the definition of schizophrenia. To bring about the full potential of machine learning algorithms in first-episode, antipsychotic-naïve schizophrenia patients, careful a priori variable selection based on independent data as well as inclusion of other modalities may be required.
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http://dx.doi.org/10.1017/S0033291718003781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877469PMC
December 2019

Patterns of Cortical Structures and Cognition in Antipsychotic-Naïve Patients With First-Episode Schizophrenia: A Partial Least Squares Correlation Analysis.

Biol Psychiatry Cogn Neurosci Neuroimaging 2019 05 25;4(5):444-453. Epub 2018 Sep 25.

Center for Neuropsychiatric Schizophrenia Research and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Schizophrenia is associated with alterations in cortical structures and cognitive impairments, but antipsychotic medication may affect these measures. We investigated patterns of relationships between cortical structures and cognitive domains in antipsychotic-naïve patients with first-episode schizophrenia.

Methods: T1-weighted 3T magnetic resonance imaging was performed in 105 patients and 136 healthy control subjects. Using FreeSurfer, we obtained measurements of cortical thickness, surface area, and mean curvature. Using an extensive neurocognitive battery including the Danish Adult Reading Test and subtests from the Cambridge Neuropsychological Test Automated Battery, we obtained estimates of premorbid intelligence, spatial working memory, spatial planning, intra-extradimensional set shifting, and reaction and movement times. With univariate analyses, we tested group differences between cortical structures and cognition. With partial least squares correlation analyses, we investigated patterns of associations between cortical structures and cognition.

Results: Patients had significantly higher mean curvature and were impaired on 7 of 11 cognitive parameters. The between-group partial least squares correlation analysis revealed two cortical thickness/cognition patterns that differentiated patients and healthy control subjects (omnibus test, p = .011). Most cortical regions contributed reliably to these patterns. In patients, spatial working memory, spatial planning, reaction and movement times, and premorbid intelligence contributed reliably to the pattern; in healthy control subjects, spatial planning and intra-extradimensional set shifting contributed reliably.

Conclusions: Antipsychotic-naïve patients with first-episode schizophrenia displayed a higher mean curvature, but no significant difference in other gray matter indices was found. Nevertheless, the pattern of associations between global cortical thickness and cognitive functions was markedly different between groups. These multivariate analyses reveal a novel linkage between regional cortical brain structure and cognitive deficits at the earliest, never-medicated illness stage.
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http://dx.doi.org/10.1016/j.bpsc.2018.09.006DOI Listing
May 2019
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