Publications by authors named "Olaf B Paulson"

116 Publications

Neural Substrates of Psychotic Depression: Findings From the Global ECT-MRI Research Collaboration.

Schizophr Bull 2021 Oct 8. Epub 2021 Oct 8.

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.

Psychotic major depression (PMD) is hypothesized to be a distinct clinical entity from nonpsychotic major depression (NPMD). However, neurobiological evidence supporting this notion is scarce. The aim of this study is to identify gray matter volume (GMV) differences between PMD and NPMD and their longitudinal change following electroconvulsive therapy (ECT). Structural magnetic resonance imaging (MRI) data from 8 independent sites in the Global ECT-MRI Research Collaboration (GEMRIC) database (n = 108; 56 PMD and 52 NPMD; mean age 71.7 in PMD and 70.2 in NPMD) were analyzed. All participants underwent MRI before and after ECT. First, cross-sectional whole-brain voxel-wise GMV comparisons between PMD and NPMD were conducted at both time points. Second, in a flexible factorial model, a main effect of time and a group-by-time interaction were examined to identify longitudinal effects of ECT on GMV and longitudinal differential effects of ECT between PMD and NPMD, respectively. Compared with NPMD, PMD showed lower GMV in the prefrontal, temporal and parietal cortex before ECT; PMD showed lower GMV in the medial prefrontal cortex (MPFC) after ECT. Although there was a significant main effect of time on GMV in several brain regions in both PMD and NPMD, there was no significant group-by-time interaction. Lower GMV in the MPFC was consistently identified in PMD, suggesting this may be a trait-like neural substrate of PMD. Longitudinal effect of ECT on GMV may not explain superior ECT response in PMD, and further investigation is needed.
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http://dx.doi.org/10.1093/schbul/sbab122DOI Listing
October 2021

Interictal pontine metabolism in migraine without aura patients: A 3 Tesla proton magnetic resonance spectroscopy study.

Neuroimage Clin 2021 Sep 20;32:102824. Epub 2021 Sep 20.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address:

In the pons, glutamatergic mechanisms are involved in regulating inhibitory descending pain modulation, serotoninergic neurotransmission as well as modulating the sensory transmission of the trigeminovascular system. Migraine involves altered pontine activation and structural changes, while biochemical, genetic and clinical evidence suggests that altered interictal pontine glutamate levels may be an important pathophysiological feature of migraine abetting to attack initiation. Migraine without aura patients were scanned outside attacks using a proton magnetic resonance spectroscopy protocol optimized for the pons at 3 Tesla. The measurements were performed on two separate days to increase accuracy and compared to similar repeated measurements in healthy controls. We found that interictal glutamate (i.e. Glx) levels in the pons of migraine patients (n = 33) were not different from healthy controls (n = 16) (p = 0.098), while total creatine levels were markedly increased in patients (9%, p = 0.009). There was no correlation of glutamate or total creatine levels to migraine frequency, days since the last attack, usual pain intensity of attacks or disease duration. In conclusion, migraine is not associated with altered interictal pontine glutamate levels. However, the novel finding of increased total creatine levels suggests that disequilibrium in the pontine energy metabolism could be an important feature of migraine pathophysiology.
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http://dx.doi.org/10.1016/j.nicl.2021.102824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498457PMC
September 2021

Human Cerebral Perfusion, Oxygen Consumption, and Lactate Production in Response to Hypoxic Exposure.

Cereb Cortex 2021 Aug 27. Epub 2021 Aug 27.

Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine, and PET, Copenhagen University Hospital Rigshospitalet, Glostrup 2600, Denmark.

Exposure to moderate hypoxia in humans leads to cerebral lactate production, which occurs even when the cerebral metabolic rate of oxygen (CMRO2) is unaffected. We searched for the mechanism of this lactate production by testing the hypothesis of upregulation of cerebral glycolysis mediated by hypoxic sensing. Describing the pathways counteracting brain hypoxia could help us understand brain diseases associated with hypoxia. A total of 65 subjects participated in this study: 30 subjects were exposed to poikilocapnic hypoxia, 14 were exposed to isocapnic hypoxia, and 21 were exposed to carbon monoxide (CO). Using this setup, we examined whether lactate production reacts to an overall reduction in arterial oxygen concentration or solely to reduced arterial oxygen partial pressure. We measured cerebral blood flow (CBF), CMRO2, and lactate concentrations by magnetic resonance imaging and spectroscopy. CBF increased (P < 10-4), whereas the CMRO2 remained unaffected (P > 0.076) in all groups, as expected. Lactate increased in groups inhaling hypoxic air (poikilocapnic hypoxia: $0.0136\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P < 10-6; isocapnic hypoxia: $0.0142\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P = 0.003) but was unaffected by CO (P = 0.36). Lactate production was not associated with reduced CMRO2. These results point toward a mechanism of lactate production by upregulation of glycolysis mediated by sensing a reduced arterial oxygen pressure. The released lactate may act as a signaling molecule engaged in vasodilation.
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http://dx.doi.org/10.1093/cercor/bhab294DOI Listing
August 2021

Elevated body weight modulates subcortical volume change and associated clinical response following electroconvulsive therapy.

J Psychiatry Neurosci 2021 Jul 5;46(4):E418-E426. Epub 2021 Jul 5.

From the Institute for Translational Psychiatry, University of Münster, Münster, Germany (Opel, Repple, Dannlowski, Redlich); Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany (Kavakbasi, Baune); the Departments of Neurology, Psychiatry, and Biobehavioral Sciences, University of California, Los Angeles, CA (Narr); the Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque, NM (Abbott); the Institute of Behavioral Science, Feintein Institutes for Medical Research, Manhasset, NY (Argyelan); the Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, NY (Argyelan); the Department of Psychiatry, University of California, Los Angeles (Espinoza); the Department of Geriatric Psychiatry, University Psychiatric Center KU Leuven, KU Leuven, Leuven, Belgium (Emsell, Vandenbulcke); the KU Leuven, Leuven Brain Institute, Department of Neurosciences, Neuropsychiatry & Geriatric Psychiatry, University Psychiatric Center KU Leuven, Belgium (Bouckaert); the Academic Center for ECT and Neurostimulation (AcCENT), University Psychiatric Center (UPC)-KU Leuven, Kortenberg, Belgium (Sienaert); the Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden (Nordanskog); the Psychiatric Center Copenhagen (Rigshospitalet), Mental Health Services of the Capital Region of Denmark, Copenhagen, Denmark (Jorgensen); the Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Denmark (Paulson); the Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark (Hanson); the Center for Magnetic Resonance, Department of Health Technology, Technical University of Denmark, Kgs, Lyngby, Denmark (Hanson); the GGZ in Geest Specialized Mental Health Care, Amsterdam, the Netherlands (Dols, Van Exel, Oudega); the Amsterdam UMC, Vrije Universiteit Amsterdam, Psychiatry, Amsterdam Neuroscience, Amsterdam, the Netherlands (Dols, van Exel, Oudega); the Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (Takamiya, Kishimoto); the Department of Radiology, Haukeland University Hospital, Bergen, Norway (Ousdal); the Department of Biomedicine, University of Bergen, Bergen, Norway (Haavik); the Division of Psychiatry, Haukeland University Hospital, Bergen, Norway (Haavik, Hammar); the Department of Biological and Medical Psychology, University of Bergen, Norway (Hammar); the NORMENT, Department of Psychiatry, Haukeland University Hospital, Bergen, Norway (Oedegaard, Kessler); the Department of Clinical Medicine, University of Bergen, Bergen, Norway (Oedegaard, Kessler, Oltedal); the Department of Radiology, University of California, San Diego, La Jolla, California (Bartsch); the Mohn Medical Imaging and Visualization Centre, Department of Radiology, Haukeland University Hospital, Bergen, Norway (Bartsch, Oltedal); the Departments of Radiology, Neurosciences, and Psychiatry, University of California, San Diego (Dale); the Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, California (Dale); the Department of Psychiatry, University of Melbourne, Melbourne, Australia (Baune); the The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia (Baune); and the Department of Psychology, University of Halle, Halle, Germany (Redlich).

Background: Obesity is a frequent somatic comorbidity of major depression, and it has been associated with worse clinical outcomes and brain structural abnormalities. Converging evidence suggests that electroconvulsive therapy (ECT) induces both clinical improvements and increased subcortical grey matter volume in patients with depression. However, it remains unknown whether increased body weight modulates the clinical response and structural neuroplasticity that occur with ECT.

Methods: To address this question, we conducted a longitudinal investigation of structural MRI data from the Global ECT-MRI Research Collaboration (GEMRIC) in 223 patients who were experiencing a major depressive episode (10 scanning sites). Structural MRI data were acquired before and after ECT, and we assessed change in subcortical grey matter volume using FreeSurfer and Quarc.

Results: Higher body mass index (BMI) was associated with a significantly lower increase in subcortical grey matter volume following ECT. We observed significant negative associations between BMI and change in subcortical grey matter volume, with pronounced effects in the thalamus and putamen, where obese participants showed increases in grey matter volume that were 43.3% and 49.6%, respectively, of the increases found in participants with normal weight. As well, BMI significantly moderated the association between subcortical grey matter volume change and clinical response to ECT. We observed no significant association between BMI and clinical response to ECT.

Limitations: Because only baseline BMI values were available, we were unable to study BMI changes during ECT and their potential association with clinical and grey matter volume change.

Conclusion: Future studies should take into account the relevance of body weight as a modulator of structural neuroplasticity during ECT treatment and aim to further explore the functional relevance of this novel finding.
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http://dx.doi.org/10.1503/jpn.200176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410473PMC
July 2021

Glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with differences in uncinate fasciculus microstructure.

Pediatr Res 2021 Mar 31. Epub 2021 Mar 31.

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

Background: Evidence suggests that fronto-limbic brain regions and connecting white matter fibre tracts in the left hemisphere are more sensitive to glucocorticoids than in the right hemisphere. It is unknown whether treatment with glucocorticoids in childhood is associated with microstructural differences of the uncinate fasciculus and cingulum bundle, which connect fronto-limbic brain regions. Here, we tested the hypothesis that prior glucocorticoid treatment would be associated with differences in fractional anisotropy (FA) of the left relative to right uncinate fasciculus and cingulum bundle.

Methods: We performed diffusion-weighted imaging in 28 children and adolescents aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disease and 28 healthy controls.

Results: Patients displayed significantly different asymmetry in the microstructure of uncinate fasciculus with higher left but similar right uncinate fasciculus FA and axial diffusivity compared to controls. No apparent differences were observed for the cingulum. Notably, higher cumulative glucocorticoid doses were significantly associated with higher uncinate fasciculus FA and axial diffusivity bilaterally.

Conclusions: Our findings indicate that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in the microstructure of the uncinate fasciculi, and that higher cumulative glucocorticoid doses have a proportional impact on the microstructure.

Impact: It is unknown if treatment with glucocorticoids in childhood have long-term effects on fronto-limbic white matter microstructure. The study examined if children and adolescents previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder differed in fronto-limbic white matter microstructure compared to healthy controls. The nephrotic and rheumatic patients had higher left but similar right uncinate fasciculus FA and axial diffusivity. Higher bilateral uncinate fasciculus FA and axial diffusivity was associated with higher cumulative glucocorticoid doses. We revealed new evidence suggesting that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in uncinate fasciculi microstructure.
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http://dx.doi.org/10.1038/s41390-021-01394-wDOI Listing
March 2021

Feasibility of Glutamate and GABA Detection in Pons and Thalamus at 3T and 7T by Proton Magnetic Resonance Spectroscopy.

Front Neurosci 2020 23;14:559314. Epub 2020 Oct 23.

Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Glutamate detection in pons and thalamus using proton magnetic resonance spectroscopy (H-MRS) after an intervention is of interest for studying various brain disorders. However, H-MRS in these brain regions is challenging and time-consuming, especially in longitudinal study designs. H-MRS of more cortical structures at the ultrahigh magnetic field strength of 7T yields an improved spectral output, including separation of the glutamate signal from the glutamine signal, in a shorter and more feasible scan time, as compared to conventional clinical field strengths. For this purpose, we compared the feasibility of H-MRS at 3T and 7T in pons and thalamus by applying a longitudinal study design of repeated measures on same day and three separate days at both field strength in five healthy participants. Total H-MRS acquisition time was reduced by a factor 3.75 for pons and by a factor 3 for thalamus at 7T as compared to 3T. We found higher spectral signal-to-noise ratio (SNR) ( < 0.001), lower linewidth ( = 0.001) and lower Cramér-Rao lower bounds (CRLB) ( < 0.001) for the combined glutamate and glutamine signal (Glx) in thalamus at 7T as compared to 3T. In pons, CRLB of Glx and SNR were lower at 7T ( = 0.002 and = 0.006), with no differences in linewidth compared to 3T. Mean within-subject variability of Glx concentration estimates was lower at 7T compared to 3T for both pons and thalamus. At 7T, it was possible to assess glutamate and γ-aminobutyric acid (GABA) simultaneously in pons and thalamus. In conclusion, H-MRS at 7T resulted in improved spectral quality while allowing shorter scan times than at 3T as well as estimation of the pure glutamate signal in pons and thalamus. This opens up the opportunity for multimodal study designs and multiregional subcortical H-MRS research. Glutamate and GABA measurement at 7T in pons and thalamus is advantageous for future investigations of excitatory-inhibitory mechanisms in brain disorders.
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http://dx.doi.org/10.3389/fnins.2020.559314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645149PMC
October 2020

Blood pressure and brain injury in cardiac surgery: a secondary analysis of a randomized trial.

Eur J Cardiothorac Surg 2020 11;58(5):1035-1044

D epartment of Cardiothoracic Anaesthesiology, Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Objectives: Brain dysfunction is a serious complication after cardiac surgery. In the Perfusion Pressure Cerebral Infarcts trial, we allocated cardiac surgery patients to a mean arterial pressure of either 70-80 or 40-50 mmHg during cardiopulmonary bypass (CPB). In this secondary analysis, we compared selected cerebral metabolites using magnetic resonance spectroscopy hypothesizing that a postoperative decrease in occipital grey matter (GM) N-acetylaspartate-to-total-creatine ratio, indicative of ischaemic injury, would be found in the high-target group.

Methods: Of the 197 patients randomized in the Perfusion Pressure Cerebral Infarcts trial, 55 and 42 patients had complete and useful data from GM and white matter (WM), respectively. Spectroscopies were done preoperatively and on postoperative days 3-6. Cognitive function was assessed prior to surgery, at discharge and at 3 months. We predefined the statistical significance level to be 0.01.

Results: A postoperative decrease was found in GM N-acetylaspartate-to-total-creatine ratio in the high-target group [mean difference -0.09 (95% confidence interval -0.14 to -0.04), P = 0.014]. No significant differences were found in other metabolite ratios investigated in GM or WM. No significant association was found between changes in metabolite ratios and new cerebral infarcts, WM lesion score or cognitive dysfunction.

Conclusions: A higher mean arterial pressure during CPB was associated with signs of impaired cerebral metabolism, though not at the predefined significance level of 0.01. No significant association was found between metabolite ratio changes and neuroradiological pathology or change in cognitive function.

Clinical Trial Registration Number: Clinicaltrials.gov: NCT02185885.
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http://dx.doi.org/10.1093/ejcts/ezaa216DOI Listing
November 2020

Intradural artery dilation during experimentally induced migraine attacks.

Pain 2021 01;162(1):176-183

Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence, vasoreactivity in the intradural arteries during migraine is unknown. Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 T MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined. Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (P = 0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4%-5.7%]. Middle cerebral artery dilated by 9.4% [95% CI: 7.1%-11.7%] and superficial temporal artery by 2.3% [95% CI: 0.2%-4.4%]. Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks.
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http://dx.doi.org/10.1097/j.pain.0000000000002008DOI Listing
January 2021

Transcranial low-frequency pulsating electromagnetic fields (T-PEMF) as post-concussion syndrome treatment.

Acta Neurol Scand 2020 Dec 16;142(6):597-604. Epub 2020 Jul 16.

Neurobiology Research Unit, Department of Neurology, Rigshospitalet, Copenhagen, Denmark.

Background: Treatment options for the subgroup of people who develop long-lasting symptoms following mild traumatic brain injury are limited. Transcranial pulsating low-frequency electromagnetic stimulation (T-PEMF) in other patient groups has shown promising results in several studies with proposed neuroprotective and anti-inflammatory effects.

Objective: The present pilot study was conducted to access feasibility and tolerability of T-PEMF in treating post-concussion syndrome.

Methods: Seven patients with post-concussion syndrome received 5 weeks of daily 30 minutes T-PEMF treatment with evaluation after 2 and 5 weeks and 3 months after ending treatment.

Results: Compliance was high as all subject completed the full treatment. Two patients however experienced a worsening of their concussion symptoms during the course of treatment. The remaining patients had some discomfort in relation to treatment, mainly headache, but passing and less for each treatment. The majority (n = 5) had a reduction in symptoms overall, up to 61% (2%-61%) based on the Rivermead Post-Concussion Symptoms Questionnaire.

Conclusion: Further studies on T-PEMF as a treatment option for post-concussion syndrome are warranted.
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http://dx.doi.org/10.1111/ane.13300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689717PMC
December 2020

Glutamate levels and perfusion in pons during migraine attacks: A 3T MRI study using proton spectroscopy and arterial spin labeling.

J Cereb Blood Flow Metab 2021 03 19;41(3):604-616. Epub 2020 May 19.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark.

Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.
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http://dx.doi.org/10.1177/0271678X20906902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922760PMC
March 2021

No effect of the angiotensin receptor blocker candesartan on cerebrovascular autoregulation in rats during very high and low sodium intake.

J Renin Angiotensin Aldosterone Syst 2019 Jul-Sep;20(3):1470320319874615

Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Denmark.

Autoregulation of cerebral blood flow (CBF) denotes that CBF is constant despite fluctuation of blood pressure within wide limits. Inhibition of the renin-angiotensin system (RAS) is known to decrease the lower and upper limits of CBF autoregulation. We have previously shown that this includes inhibition by the angiotensin receptor blocker (ARB) candesartan. In the present study we investigated the influence of the ARB candesartan on the lower limit of CBF autoregulation in two groups of Sprague-Dawley rats, on high (4.0% Na) and low (0.004% Na) sodium diet, respectively. Control animals were given the same diet, but no ARB. CBF was studied with the laser Doppler method. Blood pressure was lowered by controlled bleeding. Results revealed that both high and low sodium diet with low and high renin levels respectively block the influence of candesartan on CBF autoregulation. This was expected in rats on a high salt diet with a low renin level, but unexpected in rats with a low salt intake with a high renin level.
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http://dx.doi.org/10.1177/1470320319874615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732866PMC
June 2020

Cigarette smoking and cerebral blood flow in a cohort of middle-aged adults.

J Cereb Blood Flow Metab 2020 04 12;40(4):904-905. Epub 2020 Feb 12.

Department of Neurology, Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.

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http://dx.doi.org/10.1177/0271678X20905609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168786PMC
April 2020

Brain Changes Induced by Electroconvulsive Therapy Are Broadly Distributed.

Biol Psychiatry 2020 03 25;87(5):451-461. Epub 2019 Jul 25.

Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, California; Department of Radiology, University of California, San Diego, La Jolla, California.

Background: Electroconvulsive therapy (ECT) is associated with volumetric enlargements of corticolimbic brain regions. However, the pattern of whole-brain structural alterations following ECT remains unresolved. Here, we examined the longitudinal effects of ECT on global and local variations in gray matter, white matter, and ventricle volumes in patients with major depressive disorder as well as predictors of ECT-related clinical response.

Methods: Longitudinal magnetic resonance imaging and clinical data from the Global ECT-MRI Research Collaboration (GEMRIC) were used to investigate changes in white matter, gray matter, and ventricle volumes before and after ECT in 328 patients experiencing a major depressive episode. In addition, 95 nondepressed control subjects were scanned twice. We performed a mega-analysis of single subject data from 14 independent GEMRIC sites.

Results: Volumetric increases occurred in 79 of 84 gray matter regions of interest. In total, the cortical volume increased by mean ± SD of 1.04 ± 1.03% (Cohen's d = 1.01, p < .001) and the subcortical gray matter volume increased by 1.47 ± 1.05% (d = 1.40, p < .001) in patients. The subcortical gray matter increase was negatively associated with total ventricle volume (Spearman's rank correlation ρ = -.44, p < .001), while total white matter volume remained unchanged (d = -0.05, p = .41). The changes were modulated by number of ECTs and mode of electrode placements. However, the gray matter volumetric enlargements were not associated with clinical outcome.

Conclusions: The findings suggest that ECT induces gray matter volumetric increases that are broadly distributed. However, gross volumetric increases of specific anatomically defined regions may not serve as feasible biomarkers of clinical response.
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http://dx.doi.org/10.1016/j.biopsych.2019.07.010DOI Listing
March 2020

Diagnostic yield of high-density versus low-density EEG: The effect of spatial sampling, timing and duration of recording.

Clin Neurophysiol 2019 11 22;130(11):2060-2064. Epub 2019 Aug 22.

Department of Clinical Neurophysiology, Danish Epilepsy Centre, Dianalund, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark. Electronic address:

Objective: To investigate the effect of spatial sampling and of recording duration on the diagnostic yield of EEG for identification of interictal epileptiform discharges (IEDs). Previous studies demonstrated that high-density (HD) recordings increased accuracy of localization compared to low-density (LD) recordings.

Methods: We have prospectively evaluated the effect of spatial sampling and of recording duration in patients who had short-term (ST) recordings with a HD array of 256 electrodes following long-term (LT) recordings with a LD array consisting of the standard IFCN array of 25 electrodes. IED clusters were identified in four datasets: LT-LD, ST-LD (spatially down-sampled to the standard IFCN array), ST-HD and a shortened (90 minutes) epoch of LT-LD.

Results: Sixty consecutive patients were recruited. We identified 89 IED clusters totally. Two clusters were found by increasing spatial sampling from 25 to 256 electrodes. This modest increase was not statistically significant. Eight clusters were missed by reducing the recording duration to 90 minutes, as compared with the LT recordings (p = 0.003).

Conclusions: Recording duration is more important for the diagnostic yield of EEGs than increasing spatial sampling beyond the standard IFCN electrode array.

Significance: The standard IFCN electrode array provides sufficient spatial sampling for identification of the IEDs.
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http://dx.doi.org/10.1016/j.clinph.2019.08.007DOI Listing
November 2019

Diagnostic added value of electrical source imaging in presurgical evaluation of patients with epilepsy: A prospective study.

Clin Neurophysiol 2020 01 16;131(1):324-329. Epub 2019 Aug 16.

Department of Clinical Neurophysiology, Danish Epilepsy Centre, Dianalund, Denmark; Department of Clinical Neurophysiology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address:

Objective: To investigate the diagnostic added value of electrical source imaging (ESI) in presurgical evaluation of patients with drug resistant focal epilepsy.

Methods: Eighty-two consecutive patients were included. We analyzed both low density (LD) and high density (HD) EEG recordings. LD ESI was done on interictal and ictal signals recorded during long-term video-EEG monitoring (LTM), with standard 25 electrodes and age-matched template head models. HD ESI was done on shorter recordings (90-120 min), with 256 electrodes, using individual head model. The multidisciplinary team made decisions first blinded to ESI (based on all other modalities) and then discussed the results of the ESI. We considered that ESI had diagnostic added value, when it provided non-redundant information that changed the patientś management plan.

Results: ESI had diagnostic added value in 28 patients (34%). In most cases (85.7%), these changes were related to planning of the invasive recordings. In nine out of 13 patients, invasive recordings confirmed the localization. Out of eight patients in whom the ESI source was resected, six became seizure-free.

Conclusions: ESI provides non-redundant information in one third of the patients undergoing presurgical evaluation.

Significance: This study provides evidence for the diagnostic added value of ESI in presurgical evaluation.
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http://dx.doi.org/10.1016/j.clinph.2019.07.031DOI Listing
January 2020

The association between postoperative cognitive dysfunction and cerebral oximetry during cardiac surgery: a secondary analysis of a randomised trial.

Br J Anaesth 2019 Aug 17;123(2):196-205. Epub 2019 May 17.

Department of Cardiothoracic Anesthesia, Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Postoperative cognitive dysfunction (POCD) occurs commonly after cardiac surgery. Near-infrared spectroscopy (NIRS) has been used to monitor regional cerebral oxygen saturation (rScO) in order to minimise the occurrence of POCD by applying dedicated interventions when rScO decreases. However, the association between rScO intraoperatively and POCD has not been clarified.

Methods: This is a secondary analysis of a randomised trial with physician-blinded NIRS monitoring and cognitive testing at discharge from hospital and at 3 months after surgery. The association between intraoperative rScO values and POCD at discharge from hospital and at 3 months after surgery was investigated. The prespecified candidate predictive variable of interest was cumulative time during surgery with rScO ≥10% below its preoperative value.

Results: One hundred and fifty-three patients had complete NIRS data and neurocognitive assessments at discharge, and 44 of these patients (29%) had POCD. At 3 months, 148 patients had complete data, and 12 (8%) of these patients had POCD. The median time with rScO >10% below preoperative values did not differ for patients with and without POCD at discharge (difference=0.0 min; Hodges-Lehmann 95% confidence interval, -3.11-1.47, P=0.88). Other rScO time thresholds that were assessed were also not significantly different between those with and without POCD at discharge. This applied both to absolute rScO values and relative changes from preoperative values. Similar results were found in relation to POCD at 3 months.

Conclusions: No significant association was found between intraoperative rScO values and POCD. These findings bring into question the rationale for attempting to avoid decreases in rScO if the goal is to prevent POCD.

Clinical Trial Registration: NCT02185885.
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http://dx.doi.org/10.1016/j.bja.2019.03.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676044PMC
August 2019

Previous glucocorticoid treatment in childhood and adolescence is associated with long-term differences in subcortical grey matter volume and microstructure.

Neuroimage Clin 2019 11;23:101825. Epub 2019 Apr 11.

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

Background: Glucocorticoids are widely used in the treatment of several pediatric diseases with undisputed disease-related benefits. Perinatal exposure to high levels of glucocorticoids can have long-term adverse cerebral effects. In adults, glucocorticoid treatment has been associated with smaller volumes of subcortical grey matter structures. Recently, we observed smaller total brain volumes in children and adolescents treated with glucocorticoid during childhood compared to healthy controls. The possible long-term effects of glucocorticoid treatment during childhood on subcortical brain volume and microstructure remain unknown.

Method: We examined 30 children and adolescents, who had previously been treated with glucocorticoids for nephrotic syndrome or rheumatic disease, and 30 healthy volunteers. Patients and healthy control groups were matched by age, gender, and level of parent education. Participants underwent 3 T magnetic resonance (MR) brain imaging. T1-weighted and diffusion-weighted images were acquired. Volume and mean diffusivity (MD) measures were extracted for hippocampus, amygdala, nucleus accumbens, caudate nucleus and putamen. Multiple linear regression analyses were used to assess differences between patients and controls, and to evaluate possible dose-response relationships. A priori, we expected patients to display lower hippocampal and amygdala volumes.

Results: While children previously treated with glucocorticoids displayed smaller right hippocampal volumes than controls, this difference did not survive correction for multiple comparisons. Furthermore, patients as compared to controls showed lower right hippocampal MD, which remained when correcting for global changes in MD. The longer the time between the glucocorticoid treatment termination and MR-scan, the more right hippocampal MD values resembled that of healthy controls. Patient and controls did not differ in amygdala volume or MD. Analyses of the nucleus accumbens, caudate nucleus and putamen only revealed smaller putamen volumes in patients compared to controls, which remained significant when controlling for total brain volume.

Conclusion: The results suggest that extra-cerebral diseases during childhood treated with glucocorticoids may be associated with reduced subcortical grey matter volumes and lower right hippocampal mean diffusivity later in life. Our findings warrant replication and elaboration in larger, preferably prospective and longitudinal studies. Such studies may also allow disentangling disease-specific effects from possible glucocorticoid treatment effects.
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http://dx.doi.org/10.1016/j.nicl.2019.101825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475768PMC
April 2020

Domain-specific cognitive dysfunction after cardiac surgery. A secondary analysis of a randomized trial.

Acta Anaesthesiol Scand 2019 07 19;63(6):730-738. Epub 2019 Mar 19.

Department of Anaesthesia, Centre of Head and Orthopedics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Brain injury and cognitive dysfunction are serious complications after cardiac surgery. In the perfusion pressure cerebral infarcts (PPCI) trial, we allocated cardiac surgery patients to a mean arterial pressure of either 70-80 mm Hg (high-target) or 40-50 mm Hg (low-target) during cardiopulmonary bypass. In this secondary analysis, we aimed to assess potential differences in domain-specific patterns of cognitive deterioration between allocation groups and to investigate any associations of postoperative cognitive dysfunction (POCD) with diffusion-weighted magnetic resonance imaging (DWI)-detected brain lesions.

Methods: Of the 197 patients randomized in the PPCI trial, 89 in the low-target group and 80 in the high-target group had complete DWI datasets, and 92 and 80 patients had complete data for an evaluation of cognitive function at discharge respectively. Cognitive function was assessed prior to surgery, at discharge and at 3 months. DWI was obtained at baseline and on postoperative days 3 to 6.

Results: We found no statistically significant differences between the two groups when comparing the proportion of patients with a domain-specific deterioration over the pre-defined critical level in seven individual test variables at discharge. Significant deterioration was most common in tests thought to assess cognitive flexibility and interference susceptibility and least common in the memory test. POCD at discharge was more frequent in patients with DWI-positive brain lesions (OR adjusted for age and group allocation: 2.24 [95% CI 1.48-3.00], P = 0.036).

Conclusions: Domain-specific patterns of POCD were comparable between groups. A significant association was seen between DWI-positive brain lesions and POCD.
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http://dx.doi.org/10.1111/aas.13343DOI Listing
July 2019

Neuroticism predicts the impact of serotonin challenges on fear processing in subgenual anterior cingulate cortex.

Sci Rep 2018 12 17;8(1):17889. Epub 2018 Dec 17.

Danish Research Centre for Magnetic Resonance (DRCMR), Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

The personality trait neuroticism is associated with increased vulnerability to anxiety and mood disorders, conditions linked with abnormal serotonin neurotransmission and emotional processing. The interaction between neuroticism and serotonin during emotional processing is however not understood. Here we investigate how individual neuroticism scores influence the neural response to negative emotional faces and their sensitivity to serotonergic tone. Twenty healthy participants performed an emotional face task under functional MRI on three occasions: increased serotonin tone following infusion of a selective serotonin reuptake inhibitor (SSRI), decreased serotonin tone following acute tryptophan depletion (ATD) protocol, and no serotonin challenge (control). During the task, participants performed a gender-discrimination task of neutral, fearful or angry facial expressions. Individual variations in neuroticism scores were associated with neural response of subgenual anterior cingulate cortex to fearful facial expressions. The association was however opposite under the two serotoninergic challenges. The fear-related response in this region and individual neuroticism scores correlated negatively during citalopram challenge and positively during ATD. Thus, neuroticism scores were associated with the relative impact of serotonin challenges on fear processing in subgenual anterior cingulate cortex. This finding may link to a neural mechanism for the variable therapeutic effect of SSRI treatment observed in clinical populations.
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http://dx.doi.org/10.1038/s41598-018-36350-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297157PMC
December 2018

Gamma-aminobutyric acid edited echo-planar spectroscopic imaging (EPSI) with MEGA-sLASER at 7T.

Magn Reson Med 2019 02 29;81(2):773-780. Epub 2018 Aug 29.

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

Purpose: For rapid spatial mapping of gamma-aminobutyric acid (GABA) at the increased sensitivity and spectral separation for ultra-high magnetic field strength (7 tesla [T]), an accelerated edited magnetic resonance spectroscopic imaging technique was developed and optimized for the human brain at 7 T.

Methods: A MEGA-sLASER sequence was used for GABA editing and volume selection to maximize editing efficiency and minimize chemical shift displacement errors. To accommodate the high bandwidth requirements at 7 T, a single-shot echo planar readout was used for rapid simultaneous encoding of the temporal dimension and 1 spatial. B and B field aspects specific for 7 T were studied together with correction procedures, and feasibility of the EPSI MEGA-sLASER technique was tested in vivo in 5 healthy subjects.

Results: Localized edited spectra could be measured in all subjects giving spatial GABA signal distributions over a central brain region, having 45- to 50-Hz spatial intervoxel B field variations and up to 30% B field deviations. MEGA editing was found unaffected by the B inhomogeneities for the optimized sequence. The correction procedures reduced effects of intervoxel B inhomogeneities, corrected for spatial editing efficiency variations, and compensated for GABA resonance phase and frequency shifts from subtle motion and acquisition instabilities. The optimized oscillating echo-planar gradient scheme permitted full spectral acquisition at 7 T and exhibited minimal spectral-spatial ghosting effects for the selected brain region.

Conclusion: The EPSI MEGA-sLASER technique was shown to provide time-efficient mapping of regional variations in cerebral GABA in a central volume of interest with spatial B and B field variations typical for 7 T.
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http://dx.doi.org/10.1002/mrm.27450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646902PMC
February 2019

Imaging Regional Metabolic Changes in the Ischemic Rat Heart In Vivo Using Hyperpolarized [1-C]Pyruvate.

Tomography 2017 Sep;3(3):123-130

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

We evaluated the use of hyperpolarized C magnetic resonance imaging (MRI) in an open-chest rat model of myocardial infarction to image regional changes in myocardial metabolism. In total, 10 rats were examined before and after 30 minutes of occlusion of the left anterior descending coronary artery using hyperpolarized [1-C]pyruvate. Cardiac metabolic images of [1-C]pyruvate and its metabolites [1-C]lactate, [1-C]alanine, and [C]bicarbonate were obtained before and after ischemia. Significant reduction in the [1-C]alanine and [1-C]lactate signals were observed in the ischemic region post ischemia. The severity of the ischemic insult was verified by increased blood levels of troponin I and by using late contrast-enhanced MRI that showed enhanced signal in the ischemic region. This study shows that hyperpolarized MRI can be used to image regional metabolic changes in the in vivo rat heart in an open-chest model of ischemia reperfusion. Hyperpolarized MRI enables new possibilities for evaluating changes in cardiac metabolism noninvasively and in real time, which potentially could be used for research to evaluate new treatments and metabolic interventions for myocardial ischemia and to apply knowledge to future application of the technique in humans.
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http://dx.doi.org/10.18383/j.tom.2017.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024437PMC
September 2017

Volume of the Human Hippocampus and Clinical Response Following Electroconvulsive Therapy.

Biol Psychiatry 2018 10 29;84(8):574-581. Epub 2018 May 29.

Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, California; Department of Radiology, University of California, San Diego, La Jolla, California; Department of Neurosciences, University of California, San Diego, La Jolla, California.

Background: Hippocampal enlargements are commonly reported after electroconvulsive therapy (ECT). To clarify mechanisms, we examined if ECT-induced hippocampal volume change relates to dose (number of ECT sessions and electrode placement) and acts as a biomarker of clinical outcome.

Methods: Longitudinal neuroimaging and clinical data from 10 independent sites participating in the Global ECT-Magnetic Resonance Imaging Research Collaboration (GEMRIC) were obtained for mega-analysis. Hippocampal volumes were extracted from structural magnetic resonance images, acquired before and after patients (n = 281) experiencing a major depressive episode completed an ECT treatment series using right unilateral and bilateral stimulation. Untreated nondepressed control subjects (n = 95) were scanned twice.

Results: The linear component of hippocampal volume change was 0.28% (SE 0.08) per ECT session (p < .001). Volume change varied by electrode placement in the left hippocampus (bilateral, 3.3 ± 2.2%, d = 1.5; right unilateral, 1.6 ± 2.1%, d = 0.8; p < .0001) but not the right hippocampus (bilateral, 3.0 ± 1.7%, d = 1.8; right unilateral, 2.7 ± 2.0%, d = 1.4; p = .36). Volume change for electrode placement per ECT session varied similarly by hemisphere. Individuals with greater treatment-related volume increases had poorer outcomes (Montgomery-Åsberg Depression Rating Scale change -1.0 [SE 0.35], per 1% volume increase, p = .005), although the effects were not significant after controlling for ECT number (slope -0.69 [SE 0.38], p = .069).

Conclusions: The number of ECT sessions and electrode placement impacts the extent and laterality of hippocampal enlargement, but volume change is not positively associated with clinical outcome. The results suggest that the high efficacy of ECT is not explained by hippocampal enlargement, which alone might not serve as a viable biomarker for treatment outcome.
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http://dx.doi.org/10.1016/j.biopsych.2018.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697556PMC
October 2018

Neural Response After a Single ECT Session During Retrieval of Emotional Self-Referent Words in Depression: A Randomized, Sham-Controlled fMRI Study.

Int J Neuropsychopharmacol 2018 03;21(3):226-235

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

Background: Negative neurocognitive bias is a core feature of depression that is reversed by antidepressant drug treatment. However, it is unclear whether modulation of neurocognitive bias is a common mechanism of distinct biological treatments. This randomized controlled functional magnetic resonance imaging study explored the effects of a single electroconvulsive therapy session on self-referent emotional processing.

Methods: Twenty-nine patients with treatment-resistant major depressive disorder were randomized to one active or sham electroconvulsive therapy session at the beginning of their electroconvulsive therapy course in a double-blind, between-groups design. The following day, patients were given a self-referential emotional word categorization test and a free recall test. This was followed by an incidental word recognition task during whole-brain functional magnetic resonance imaging at 3T. Mood was assessed at baseline, on the functional magnetic resonance imaging day, and after 6 electroconvulsive therapy sessions. Data were complete and analyzed for 25 patients (electroconvulsive therapy: n = 14, sham: n = 11). The functional magnetic resonance imaging data were analyzed using the FMRIB Software Library randomize algorithm, and the Threshold-Free Cluster Enhancement method was used to identify significant clusters (corrected at P < .05).

Results: A single electroconvulsive therapy session had no effect on hippocampal activity during retrieval of emotional words. However, electroconvulsive therapy reduced the retrieval-specific neural response for positive words in the left frontopolar cortex. This effect occurred in the absence of differences between groups in behavioral performance or mood symptoms.

Conclusions: The observed effect of electroconvulsive therapy on prefrontal response may reflect early facilitation of memory for positive self-referent information, which could contribute to improvements in depressive symptoms including feelings of self-worth with repeated treatments.
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http://dx.doi.org/10.1093/ijnp/pyx091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838818PMC
March 2018

High-Target Versus Low-Target Blood Pressure Management During Cardiopulmonary Bypass to Prevent Cerebral Injury in Cardiac Surgery Patients: A Randomized Controlled Trial.

Circulation 2018 04 16;137(17):1770-1780. Epub 2018 Jan 16.

Department of Cardiothoracic Anesthesia, The Heart Center (A.G.V., F.H., H.B.R., J.C.N.).

Background: Cerebral injury is an important complication after cardiac surgery with the use of cardiopulmonary bypass. The rate of overt stroke after cardiac surgery is 1% to 2%, whereas silent strokes, detected by diffusion-weighted magnetic resonance imaging, are found in up to 50% of patients. It is unclear whether a higher versus a lower blood pressure during cardiopulmonary bypass reduces cerebral infarction in these patients.

Methods: In a patient- and assessor-blinded randomized trial, we allocated patients to a higher (70-80 mm Hg) or lower (40-50 mm Hg) target for mean arterial pressure by the titration of norepinephrine during cardiopulmonary bypass. Pump flow was fixed at 2.4 L·min·m. The primary outcome was the total volume of new ischemic cerebral lesions (summed in millimeters cubed), expressed as the difference between diffusion-weighted imaging conducted preoperatively and again postoperatively between days 3 and 6. Secondary outcomes included diffusion-weighted imaging-evaluated total number of new ischemic lesions.

Results: Among the 197 enrolled patients, mean (SD) age was 65.0 (10.7) years in the low-target group (n=99) and 69.4 (8.9) years in the high-target group (n=98). Procedural risk scores were comparable between groups. Overall, diffusion-weighted imaging revealed new cerebral lesions in 52.8% of patients in the low-target group versus 55.7% in the high-target group (=0.76). The primary outcome of volume of new cerebral lesions was comparable between groups, 25 mm (interquartile range, 0-118 mm; range, 0-25 261 mm) in the low-target group versus 29 mm (interquartile range, 0-143 mm; range, 0-22 116 mm) in the high-target group (median difference estimate, 0; 95% confidence interval, -25 to 0.028; =0.99), as was the secondary outcome of number of new lesions (1 [interquartile range, 0-2; range, 0-24] versus 1 [interquartile range, 0-2; range, 0-29] respectively; median difference estimate, 0; 95% confidence interval, 0-0; =0.71). No significant difference was observed in frequency of severe adverse events.

Conclusions: Among patients undergoing on-pump cardiac surgery, targeting a higher versus a lower mean arterial pressure during cardiopulmonary bypass did not seem to affect the volume or number of new cerebral infarcts.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02185885.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.030308DOI Listing
April 2018

Verbal learning and memory outcome in selective amygdalohippocampectomy versus temporal lobe resection in patients with hippocampal sclerosis.

Epilepsy Behav 2018 02 4;79:180-187. Epub 2018 Jan 4.

Neurobiology Research Unit, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, 28 Juliane Maries Vej, 3rd Floor, Building 6931, DK-2100 Copenhagen, Denmark; Epilepsy Clinic, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, 8 Ester Møllers Vej, 1.th Floor, Entrance 85, DK-2100 Copenhagen, Denmark. Electronic address:

Purpose: With the advent of new very selective techniques like thermal laser ablation to treat drug-resistant focal epilepsy, the controversy of resection size in relation to seizure outcome versus cognitive deficits has gained new relevance. The purpose of this study was to test the influence of the selective amygdalohippocampectomy (SAH) versus nonselective temporal lobe resection (TLR) on seizure outcome and cognition in patients with mesial temporal lobe epilepsy (MTLE) and histopathological verified hippocampal sclerosis (HS).

Methods: We identified 108 adults (>16years) with HS, operated between 1995 and 2009 in Denmark. Exclusion criteria are the following: Intelligence below normal range, right hemisphere dominance, other native languages than Danish, dual pathology, and missing follow-up data. Thus, 56 patients were analyzed. The patients were allocated to SAH (n=22) or TLR (n=34) based on intraoperative electrocorticography. Verbal learning and verbal memory were tested pre- and postsurgery.

Results: Seizure outcome did not differ between patients operated using the SAH versus the TLR at 1year (p=0.951) nor at 7years (p=0.177). Verbal learning was more affected in patients resected in the left hemisphere than in the right (p=0.002). In patients with left-sided TLR, a worsening in verbal memory performance was found (p=0.011). Altogether, 73% were seizure-free for 1year and 64% for 7years after surgery.

Conclusion: In patients with drug-resistant focal MTLE, HS and no magnetic resonance imaging (MRI) signs of dual pathology, selective amygdalohippocampectomy results in sustained seizure freedom and better memory function compared with patients operated with nonselective temporal lobe resection.
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http://dx.doi.org/10.1016/j.yebeh.2017.12.007DOI Listing
February 2018

Total brain, cortical, and white matter volumes in children previously treated with glucocorticoids.

Pediatr Res 2018 04 10;83(4):804-812. Epub 2018 Jan 10.

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

BackgroundPerinatal exposure to glucocorticoids and elevated endogenous glucocorticoid levels during childhood can have detrimental effects on the developing brain. Here, we examined the impact of glucocorticoid treatment during childhood on brain volumes.MethodsA total of 30 children and adolescents with rheumatic or nephrotic disease previously treated with glucocorticoids and 30 controls matched on age, sex, and parent education underwent magnetic resonance imaging (MRI) of the brain. Total cortical gray and white matter, brain, intracranial volume, and total cortical thickness and surface area were derived from MRI scans.ResultsPatients had significantly smaller gray and white matter and total brain volumes relative to healthy controls. Brain volume differences disappeared when accounting for intracranial volume, as patients had relatively smaller intracranial volumes. Group differences were mainly driven by the children with rheumatic disease. Total cortical thickness and cortical surface area did not significantly differ between groups. We found no significant associations between glucocorticoid-treatment variables and volumetric measures.ConclusionObserved smaller total brain, cortical gray, and white matter volumes in children and adolescents previously treated with glucocorticoids compared with that in healthy controls may reflect both developmental and degenerative processes. Prospective longitudinal studies are warranted to clarify whether findings are related to treatment or disease.
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http://dx.doi.org/10.1038/pr.2017.312DOI Listing
April 2018

Glucocorticoid treatment earlier in childhood and adolescence show dose-response associations with diurnal cortisol levels.

Dev Psychobiol 2017 12 9;59(8):1010-1020. Epub 2017 Sep 9.

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

Heightened levels of glucocorticoids in children and adolescents have previously been linked to prolonged changes in the diurnal regulation of the stress-hormone cortisol, a glucocorticoid regulated by the hypothalamic-pituitary-adrenal-axis (HPA-axis). To address this question, we examined the salivary cortisol awakening response (CAR) and daily cortisol output in 36 children and adolescents (25 girls/11 boys) aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder and 36 healthy controls. Patients and controls did not significantly differ in the CAR or diurnal cortisol output; however, sex-dependent group differences were observed. Specifically, female patients had a higher CAR relative to female controls, while male patients had higher daily cortisol levels compared to male controls. Notably, CAR in female patients and daily cortisol levels in male patients showed a positive linear relationship with the mean daily glucocorticoid doses administered during treatment. The observed dose-response associations suggest that glucocorticoid therapy during childhood and adolescence might trigger long-term changes in HPA-axis regulation, which may differ for males and females.
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http://dx.doi.org/10.1002/dev.21559DOI Listing
December 2017

Safety and EEG data quality of concurrent high-density EEG and high-speed fMRI at 3 Tesla.

PLoS One 2017 26;12(5):e0178409. Epub 2017 May 26.

Department of Neurology, University of New Mexico, Albuquerque, NM, United States of America.

Purpose: Concurrent EEG and fMRI is increasingly used to characterize the spatial-temporal dynamics of brain activity. However, most studies to date have been limited to conventional echo-planar imaging (EPI). There is considerable interest in integrating recently developed high-speed fMRI methods with high-density EEG to increase temporal resolution and sensitivity for task-based and resting state fMRI, and for detecting interictal spikes in epilepsy. In the present study using concurrent high-density EEG and recently developed high-speed fMRI methods, we investigate safety of radiofrequency (RF) related heating, the effect of EEG on cortical signal-to-noise ratio (SNR) in fMRI, and assess EEG data quality.

Materials And Methods: The study compared EPI, multi-echo EPI, multi-band EPI and multi-slab echo-volumar imaging pulse sequences, using clinical 3 Tesla MR scanners from two different vendors that were equipped with 64- and 256-channel MR-compatible EEG systems, respectively, and receive only array head coils. Data were collected in 11 healthy controls (3 males, age range 18-70 years) and 13 patients with epilepsy (8 males, age range 21-67 years). Three of the healthy controls were scanned with the 256-channel EEG system, the other subjects were scanned with the 64-channel EEG system. Scalp surface temperature, SNR in occipital cortex and head movement were measured with and without the EEG cap. The degree of artifacts and the ability to identify background activity was assessed by visual analysis by a trained expert in the 64 channel EEG data (7 healthy controls, 13 patients).

Results: RF induced heating at the surface of the EEG electrodes during a 30-minute scan period with stable temperature prior to scanning did not exceed 1.0° C with either EEG system and any of the pulse sequences used in this study. There was no significant decrease in cortical SNR due to the presence of the EEG cap (p > 0.05). No significant differences in the visually analyzed EEG data quality were found between EEG recorded during high-speed fMRI and during conventional EPI (p = 0.78). Residual ballistocardiographic artifacts resulted in 58% of EEG data being rated as poor quality.

Conclusion: This study demonstrates that high-density EEG can be safely implemented in conjunction with high-speed fMRI and that high-speed fMRI does not adversely affect EEG data quality. However, the deterioration of the EEG quality due to residual ballistocardiographic artifacts remains a significant constraint for routine clinical applications of concurrent EEG-fMRI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178409PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446172PMC
September 2017

Does a single session of electroconvulsive therapy alter the neural response to emotional faces in depression? A randomised sham-controlled functional magnetic resonance imaging study.

J Psychopharmacol 2017 09 29;31(9):1215-1224. Epub 2017 Mar 29.

1 Psychiatric Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.

Negative neurocognitive bias is a core feature of major depressive disorder that is reversed by pharmacological and psychological treatments. This double-blind functional magnetic resonance imaging study investigated for the first time whether electroconvulsive therapy modulates negative neurocognitive bias in major depressive disorder. Patients with major depressive disorder were randomised to one active ( n=15) or sham electroconvulsive therapy ( n=12). The following day they underwent whole-brain functional magnetic resonance imaging at 3T while viewing emotional faces and performed facial expression recognition and dot-probe tasks. A single electroconvulsive therapy session had no effect on amygdala response to emotional faces. Whole-brain analysis revealed no effects of electroconvulsive therapy versus sham therapy after family-wise error correction at the cluster level, using a cluster-forming threshold of Z>3.1 ( p<0.001) to secure family-wise error <5%. Groups showed no differences in behavioural measures, mood and medication. Exploratory cluster-corrected whole-brain analysis ( Z>2.3; p<0.01) revealed electroconvulsive therapy-induced changes in parahippocampal and superior frontal responses to fearful versus happy faces as well as in fear-specific functional connectivity between amygdala and occipito-temporal regions. Across all patients, greater fear-specific amygdala - occipital coupling correlated with lower fear vigilance. Despite no statistically significant shift in neural response to faces after a single electroconvulsive therapy session, the observed trend changes after a single electroconvulsive therapy session point to an early shift in emotional processing that may contribute to antidepressant effects of electroconvulsive therapy.
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http://dx.doi.org/10.1177/0269881117699615DOI Listing
September 2017

Perfusion Pressure Cerebral Infarct (PPCI) trial - the importance of mean arterial pressure during cardiopulmonary bypass to prevent cerebral complications after cardiac surgery: study protocol for a randomised controlled trial.

Trials 2016 May 17;17(1):247. Epub 2016 May 17.

Department of Cardiothoracic Anaesthesiology, Heart Centre, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.

Background: Debilitating brain injury occurs in 1.6-5 % of patients undergoing cardiac surgery with cardiopulmonary bypass. Diffusion-weighted magnetic resonance imaging studies have reported stroke-like lesions in up to 51 % of patients after cardiac surgery. The majority of the lesions seem to be caused by emboli, but inadequate blood flow caused by other mechanisms may increase ischaemia in the penumbra or cause watershed infarcts. During cardiopulmonary bypass, blood pressure can be below the lower limit of cerebral autoregulation. Although much debated, the constant blood flow provided by the cardiopulmonary bypass system is still considered by many as appropriate to avoid cerebral ischaemia despite the low blood pressure.

Methods/design: The Perfusion Pressure Cerebral Infarct trial is a single-centre superiority trial with a blinded outcome assessment. The trial is randomising 210 patients with coronary vessel and/or valve disease and who are undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients are stratified by age and surgical procedure and are randomised 1:1 to either an increased mean arterial pressure (70-80 mmHg) or 'usual practice' (40-50 mmHg) during cardiopulmonary bypass. The cardiopulmonary bypass pump flow is fixed and set at 2.4 L/minute/m(2) body surface area plus 10-20 % in both groups. The primary outcome measure is the volume of the new ischaemic cerebral lesions (in mL), expressed as the difference between a baseline, diffusion-weighted, magnetic resonance imaging scan and an equal scan conducted 3-6 days postoperatively. Secondary endpoints are the total number of new ischaemic cerebral lesions, postoperative cognitive dysfunction at discharge and 3 months postoperatively, diffuse cerebral injury evaluated by magnetic resonance spectroscopy and selected biochemical markers of cerebral injury. The sample size will enable us to detect a 50 % reduction in the primary outcome measure in the intervention compared to the control group at a significance level of 0.05 and with a power of 0.80.

Discussion: This is the first clinical randomised study to evaluate whether the mean arterial pressure level during cardiopulmonary bypass influences the development of brain injuries that are detected by diffusion-weighted magnetic resonance imaging.

Trial Registration: ClinicalTrials.gov, NCT02185885 . Registered on 7 July 2014.
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http://dx.doi.org/10.1186/s13063-016-1373-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869311PMC
May 2016
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