Publications by authors named "Annette van der Toorn"

46 Publications

Remote Corticospinal Tract Degeneration After Cortical Stroke in Rats May Not Preclude Spontaneous Sensorimotor Recovery.

Neurorehabil Neural Repair 2021 Sep 21:15459683211041318. Epub 2021 Sep 21.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.

Recovery of motor function after stroke appears to be related to the integrity of axonal connections in the corticospinal tract (CST) and corpus callosum, which may both be affected after cortical stroke. In the present study, we aimed to elucidate the relationship of changes in measures of the CST and transcallosal tract integrity, with the interhemispheric functional connectivity and sensorimotor performance after experimental cortical stroke. We conducted in vivo diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and behavior testing in twenty-five male Sprague Dawley rats recovering from unilateral photothrombotic stroke in the sensorimotor cortex. Twenty-three healthy rats served as controls. A reduction in the number of reconstructed fibers, a lower fractional anisotropy, and higher radial diffusivity in the ipsilesional but intact CST, reflected remote white matter degeneration. In contrast, transcallosal tract integrity remained preserved. Functional connectivity between the ipsi- and contralesional forelimb regions of the primary somatosensory cortex significantly reduced at week 8 post-stroke. Comparably, usage of the stroke-affected forelimb was normal at week 28, following significant initial impairment between day 1 and week 8 post-stroke. Our study shows that post-stroke motor recovery is possible despite degeneration in the CST and may be supported by intact neuronal communication between hemispheres.
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http://dx.doi.org/10.1177/15459683211041318DOI Listing
September 2021

Activation response and functional connectivity change in rat cortex after bilateral transcranial direct current stimulation-An exploratory study.

J Neurosci Res 2021 May 28;99(5):1377-1389. Epub 2021 Jan 28.

Biomedical Magnetic Resonance Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique implicated as a promising adjunct therapy to improve motor function through the neuromodulation of brain networks. Particularly bilateral tDCS, which affects both hemispheres, may yield stronger effects on motor learning than unilateral stimulation. Therefore, the aim of this exploratory study was to develop an experimental model for simultaneous magnetic resonance imaging (MRI) and bilateral tDCS in rats, to measure instant and resultant effects of tDCS on network activity and connectivity. Naïve, male Sprague-Dawley rats were divided into a tDCS (n = 7) and sham stimulation group (n = 6). Functional MRI data were collected during concurrent bilateral tDCS over the sensorimotor cortex, while resting-state functional MRI and perfusion MRI were acquired directly before and after stimulation. Bilateral tDCS induced a hemodynamic activation response, reflected by a bilateral increase in blood oxygenation level-dependent signal in different cortical areas, including the sensorimotor regions. Resting-state functional connectivity within the cortical sensorimotor network decreased after a first stimulation session but increased after a second session, suggesting an interaction between multiple tDCS sessions. Perfusion MRI revealed no significant changes in cerebral blood flow after tDCS. Our exploratory study demonstrates successful application of an MRI-compatible bilateral tDCS setup in an animal model. Our results indicate that bilateral tDCS can locally modulate neuronal activity and connectivity, which may underlie its therapeutic potential.
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http://dx.doi.org/10.1002/jnr.24793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048424PMC
May 2021

Imaging Markers for the Characterization of Gray and White Matter Changes from Acute to Chronic Stages after Experimental Traumatic Brain Injury.

J Neurotrauma 2021 Jun 11;38(12):1642-1653. Epub 2021 Jan 11.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands. ORCID ID: 0000-0002-8185-9209; 0000-0002-4623-4078.

Despite clinical symptoms, a large majority of people with mild traumatic brain injury (TBI) have normal computed tomography (CT) and magnetic resonance imaging (MRI) scans. Therefore, present-day neuroimaging tools are insufficient to diagnose or classify low grades of TBI. Advanced neuroimaging techniques, such as diffusion-weighted and functional MRI, may yield novel biomarkers that may aid in the diagnosis of TBI. Therefore, the present study had two aims: first, to characterize the development of MRI-based measures of structural and functional changes in gray and white matter regions from acute to chronic stages after mild and moderate TBI; and second, to identify the imaging markers that can most accurately predict outcome after TBI. To these aims, 52 rats underwent serial functional (resting-state) and structural (T1-, T2-, and diffusion-weighted) MRI before and 1 h, 1 day, 1 week, 1 month and 3-4 months after mild or moderate experimental TBI. All rats underwent behavioral testing. Histology was performed in subgroups of rats at different time points. Early after moderate TBI, axial and radial diffusivities were increased, and fractional anisotropy was reduced in the corpus callosum and bilateral hippocampi, which normalized over time and was paralleled by recovery of sensorimotor function. Correspondingly, histology revealed decreased myelin staining early after TBI, which was not detected at chronic stages. No significant changes in individual outcome measures were detected after mild TBI. However, multivariate analysis showed a significant additive contribution of diffusion parameters in the distinction between control and different grades of TBI-affected brains. Therefore, combining multiple imaging markers may increase the sensitivity for TBI-related pathology.
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http://dx.doi.org/10.1089/neu.2020.7151DOI Listing
June 2021

Intranasal mesenchymal stem cell therapy to boost myelination after encephalopathy of prematurity.

Glia 2021 03 12;69(3):655-680. Epub 2020 Oct 12.

Department for Developmental Origins of Disease, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Encephalopathy of prematurity (EoP) is a common cause of long-term neurodevelopmental morbidity in extreme preterm infants. Diffuse white matter injury (dWMI) is currently the most commonly observed form of EoP. Impaired maturation of oligodendrocytes (OLs) is the main underlying pathophysiological mechanism. No therapies are currently available to combat dWMI. Intranasal application of mesenchymal stem cells (MSCs) is a promising therapeutic option to boost neuroregeneration after injury. Here, we developed a double-hit dWMI mouse model and investigated the therapeutic potential of intranasal MSC therapy. Postnatal systemic inflammation and hypoxia-ischemia led to transient deficits in cortical myelination and OL maturation, functional deficits and neuroinflammation. Intranasal MSCs migrated dispersedly into the injured brain and potently improved myelination and functional outcome, dampened cerebral inflammationand rescued OL maturation after dWMI. Cocultures of MSCs with primary microglia or OLs show that MSCs secrete factors that directly promote OL maturation and dampen neuroinflammation. We show that MSCs adapt their secretome after ex vivo exposure to dWMI milieu and identified several factors including IGF1, EGF, LIF, and IL11 that potently boost OL maturation. Additionally, we showed that MSC-treated dWMI brains express different levels of these beneficial secreted factors. In conclusion, the combination of postnatal systemic inflammation and hypoxia-ischemia leads to a pattern of developmental brain abnormalities that mimics the clinical situation. Intranasal delivery of MSCs, that secrete several beneficial factors in situ, is a promising strategy to restore myelination after dWMI and subsequently improve the neurodevelopmental outcome of extreme preterm infants in the future.
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http://dx.doi.org/10.1002/glia.23919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821154PMC
March 2021

Good taste or gut feeling? A new method in rats shows oro-sensory stimulation and gastric distention generate distinct and overlapping brain activation patterns.

Int J Eat Disord 2021 07 15;54(7):1116-1126. Epub 2020 Jul 15.

Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.

Satiation is influenced by a variety of signals including gastric distention and oro-sensory stimulation. Here we developed a high-field (9.4 T) functional magnetic resonance imaging (fMRI) protocol to test how oro-sensory stimulation and gastric distention, as induced with a block-design paradigm, affect brain activation under different states of energy balance in rats. Repeated tasting of sucrose induced positive and negative fMRI responses in the ventral tegmental area and septum, respectively, and gradual neural activation in the anterior insula and the brain stem nucleus of the solitary tract (NTS), as revealed using a two-level generalized linear model-based analysis. These unique findings align with comparable human experiments, and are now for the first time identified in rats, thereby allowing for comparison between species. Gastric distention induced more extensive brain activation, involving the insular cortex and NTS. Our findings are largely in line with human studies that have shown that the NTS is involved in processing both visceral information and taste, and anterior insula in processing sweet taste oro-sensory signals. Gastric distention and sucrose tasting induced responses in mesolimbic areas, to our knowledge not previously detected in humans, which may reflect the rewarding effects of a full stomach and sweet taste, thereby giving more insight into the processing of sensory signals leading to satiation. The similarities of these data to human neuroimaging data demonstrate the translational value of the approach and offer a new avenue to deepen our understanding of the process of satiation in healthy people and those with eating disorders.
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http://dx.doi.org/10.1002/eat.23354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359261PMC
July 2021

Structural and functional MRI of altered brain development in a novel adolescent rat model of quinpirole-induced compulsive checking behavior.

Eur Neuropsychopharmacol 2020 04 7;33:58-70. Epub 2020 Mar 7.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands.

Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole (n = 21) or saline (n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional volumes, functional connectivity and structural integrity in the brain, respectively. After consecutive quinpirole injections, adolescent rats demonstrated clear checking behavior and repeated travelling between two open-field zones. MRI measurements revealed an increase of regional volumes within the frontostriatal circuits and an increase in fractional anisotropy (FA) in white matter areas during maturation in both experimental groups. Quinpirole-injected rats showed a larger developmental increase in FA values in the internal capsule and forceps minor compared to control rats. Our study points toward a link between development of compulsive behavior and altered white matter maturation in quinpirole-injected adolescent rats, in line with observations in pediatric patients with compulsive phenotypes. This novel animal model provides opportunities to investigate novel treatments and underlying mechanisms for patients with early-onset OCD specifically.
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http://dx.doi.org/10.1016/j.euroneuro.2020.02.004DOI Listing
April 2020

Active Recharge Burst and Tonic Spinal Cord Stimulation Engage Different Supraspinal Mechanisms: A Functional Magnetic Resonance Imaging Study in Peripherally Injured Chronic Neuropathic Rats.

Pain Pract 2020 06 23;20(5):510-521. Epub 2020 Mar 23.

Department of Anesthesiology and Pain Management, Pain Management and Research Centre, MUMC+, Maastricht, The Netherlands.

Objectives: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS.

Methods: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner.

Results: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas.

Conclusions: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst.
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http://dx.doi.org/10.1111/papr.12879DOI Listing
June 2020

Distinct structure-function relationships across cortical regions and connectivity scales in the rat brain.

Sci Rep 2020 01 9;10(1):56. Epub 2020 Jan 9.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.

An improved understanding of the structure-function relationship in the brain is necessary to know to what degree structural connectivity underpins abnormal functional connectivity seen in disorders. We integrated high-field resting-state fMRI-based functional connectivity with high-resolution macro-scale diffusion-based and meso-scale neuronal tracer-based structural connectivity, to obtain an accurate depiction of the structure-function relationship in the rat brain. Our main goal was to identify to what extent structural and functional connectivity strengths are correlated, macro- and meso-scopically, across the cortex. Correlation analyses revealed a positive correspondence between functional and macro-scale diffusion-based structural connectivity, but no significant correlation between functional connectivity and meso-scale neuronal tracer-based structural connectivity. Zooming in on individual connections, we found strong functional connectivity in two well-known resting-state networks: the sensorimotor and default mode network. Strong functional connectivity within these networks coincided with strong short-range intrahemispheric structural connectivity, but with weak heterotopic interhemispheric and long-range intrahemispheric structural connectivity. Our study indicates the importance of combining measures of connectivity at distinct hierarchical levels to accurately determine connectivity across networks in the healthy and diseased brain. Although characteristics of the applied techniques may affect where structural and functional networks (dis)agree, distinct structure-function relationships across the brain could also have a biological basis.
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http://dx.doi.org/10.1038/s41598-019-56834-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952407PMC
January 2020

Diet as connecting factor: Functional brain connectivity in relation to food intake and sucrose tasting, assessed with resting-state functional MRI in rats.

J Neurosci Res 2019 Nov 26. Epub 2019 Nov 26.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands.

Eating disorders and obesity form a major health problem in Western Society. To be able to provide adequate treatment and prevention, it is necessary to understand the neural mechanisms underlying the development of eating disorders and obesity. Specific brain networks have been shown to be involved in feeding behavior. We therefore hypothesized that functional connectivity in neural networks involved in feeding behavior is dependent on the status of homeostatic energy balance, thus on being hungry or satiated. To test our hypothesis, we measured functional connectivity and amplitudes of neural signals within neural networks in relation to food intake and sucrose tasting in rats. Therefore, 16 male Wistar rats, of which eight were food-restricted and eight were satiated, underwent resting-state functional magnetic resonance imaging (rs-fMRI) at 9.4 T. Subsequently, half of these animals underwent a sucrose tasting procedure followed by a second rs-fMRI scan. Functional connectivity and amplitude of low-frequency signal fluctuations were statistically analyzed in a linear mixed model. Although we did not detect a significant effect of food intake on functional connectivity before sucrose tasting, there was a trend toward interaction between group (satiated vs. hungry) and treatment (sucrose tasting). Functional connectivity between feeding-related regions tended to decrease stronger upon sucrose tasting in satiated rats as compared to food-restricted rats. Furthermore, rs-fMRI signal amplitudes decreased stronger upon sucrose tasting in satiated rats, as compared to food-restricted rats. These findings indicate that food intake and sucrose tasting can affect functional network organization, which may explain the specific patterns in feeding behavior.
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http://dx.doi.org/10.1002/jnr.24563DOI Listing
November 2019

Ultrahigh-resolution MRI reveals structural brain differences in serotonin transporter knockout rats after sucrose and cocaine self-administration.

Addict Biol 2020 01 12;25(1):e12722. Epub 2019 Feb 12.

Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.

Excessive use of cocaine is known to induce changes in brain white and gray matter. It is unknown whether the extent of these changes is related to individual differences in vulnerability to cocaine addiction. One factor increasing vulnerability involves reduced expression of the serotonin transporter (5-HTT). Human studies have shown that inherited 5-HTT downregulation is associated with structural changes in the brain. These genotype-related structural changes may contribute to risk for cocaine addiction. Here, we tested this idea by using ultrahigh-resolution structural magnetic resonance imaging (MRI) on postmortem tissue of 5-HTT and wild-type (5-HTT ) rats with a history of long access to cocaine or sucrose (control) self-administration. We found that 5-HTT rats, compared with wild-type control animals, self-administered more cocaine, but not sucrose, under long-access conditions. Ultrahigh-resolution structural MRI subsequently revealed that, independent of sucrose or cocaine self-administration, 5-HTT rats had a smaller amygdala. Moreover, we found an interaction between genotype and type of reward for dorsal raphe nucleus volume. The data point to an important but differential role of the amygdala and dorsal raphe nucleus in 5-HTT genotype-dependent vulnerability to cocaine addiction.
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http://dx.doi.org/10.1111/adb.12722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916608PMC
January 2020

Branching Pattern of the Cerebral Arterial Tree.

Anat Rec (Hoboken) 2019 08 5;302(8):1434-1446. Epub 2018 Dec 5.

Department of Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands.

Quantitative data on branching patterns of the human cerebral arterial tree are lacking in the 1.0-0.1 mm radius range. We aimed to collect quantitative data in this range, and to study if the cerebral artery tree complies with the principle of minimal work (Law of Murray). To enable easy quantification of branching patterns a semi-automatic method was employed to measure 1,294 bifurcations and 2,031 segments on 7 T-MRI scans of two corrosion casts embedded in a gel. Additionally, to measure segments with a radius smaller than 0.1 mm, 9.4 T-MRI was used on a small cast section to characterize 1,147 bifurcations and 1,150 segments. Besides MRI, traditional methods were employed. Seven hundred thirty-three bifurcations were manually measured on a corrosion cast and 1,808 bifurcations and 1,799 segment lengths were manually measured on a fresh dissected cerebral arterial tree. Data showed a large variation in branching pattern parameters (asymmetry-ratio, area-ratio, length-radius-ratio, tapering). Part of the variation may be explained by the variation in measurement techniques, number of measurements and location of measurement in the vascular tree. This study confirms that the cerebral arterial tree complies with the principle of minimum work. These data are essential in the future development of more accurate mathematical blood flow models. Anat Rec, 302:1434-1446, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
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http://dx.doi.org/10.1002/ar.23994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767475PMC
August 2019

High resolution 7T and 9.4T-MRI of human cerebral arterial casts enables accurate estimations of the cerebrovascular morphometry.

Sci Rep 2018 09 24;8(1):14235. Epub 2018 Sep 24.

University Medical Center Utrecht, Department of Radiology, Utrecht, The Netherlands.

Quantitative data on the morphology of the cerebral arterial tree could aid in modelling and understanding cerebrovascular diseases, but is scarce in the range between 200 micrometres and 1 mm diameter arteries. Traditional manual measurements are difficult and time consuming. 7T-MRI and 9.4T-MRI of human cerebral arterial plastic casts could proof feasible for acquiring detailed morphological data of the cerebral arterial tree in a time efficient method. One cast of the complete human cerebral arterial circulation embedded in gadolinium-containing gelatine gel was scanned at 7T-MRI (0.1 mm isotropic resolution). A small section of another cast was scanned at 9.4T-MRI (30 µm isotropic resolution). Subsequent 3D-reconstruction was performed using a semi-automatic approach. Validation of 7T-MRI was performed by comparing the radius calculated using MRI to manual measurements on the same cast. As manual measurement of the small section was not feasible, 9.4T-MRI was validated by scanning the small section both at 7T-MRI and 9.4T MRI and comparing the diameters of arterial segments. Linear regression slopes were 0.97 (R-squared 0.94) and 1.0 (R-squared 0.90) for 7T-MRI and 9.4T-MRI. This data shows that 7T-MRI and 9.4T-MRI and subsequent 3D reconstruction of plastic casts is feasible, and allows for characterization of human cerebral arterial tree morphology.
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http://dx.doi.org/10.1038/s41598-018-32427-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155186PMC
September 2018

Differences in structural and functional networks between young adult and aged rat brains before and after stroke lesion simulations.

Neurobiol Dis 2019 06 4;126:23-35. Epub 2018 Aug 4.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands.

Neural network changes during aging may contribute to vulnerability and resilience to brain lesions in age-related neurological disorders, such as stroke. However, the relationship between age-related neural network features and stroke outcome is unknown. Therefore, we assessed structural and functional network status in young adult and aged rat brain, and measured the effects of simulated stroke lesions. Eleven rats underwent diffusion-weighted MRI and resting-state functional MRI at young adult age (post-natal day 88) and old age (between post-natal day 760 and 880). Structural and functional brain network features were calculated from graph-based network analysis. We performed three lesion simulations based on the brain injury pattern in frequently applied rodent stroke models, i.e. a small cortical lesion, a subcortical lesion, or a large cortical plus subcortical lesion, for which we computationally removed the involved network regions. Global network characteristics, i.e. integration and segregation, were not significantly different between the two age groups. However, we detected local differences in structural and functional networks between young adult and old rats, mainly reflected by shifts of hub regions. Stroke lesion simulations induced significant global and local network changes, characterized by lower efficiency and shifts of hub regions in structural and functional networks, which was most evident after a large cortical plus subcortical lesion. Functional and structural hub region shifts after lesion simulations differed between young adult and aged rats. Our lesion simulation study demonstrates that age-dependent brain network status affects structural and functional network reorganization after stroke, particularly involving hub shifts, which may influence functional outcome. Computational lesion studies offer a cheap and simple alternative to empirical studies and can complement or guide more complicated experimental studies in animal models and patients.
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http://dx.doi.org/10.1016/j.nbd.2018.08.003DOI Listing
June 2019

The Use of Magnetic Resonance Imaging for Non-Invasive Assessment of Venofer® Biodistribution in Rats.

Pharm Res 2018 Mar 8;35(4):88. Epub 2018 Mar 8.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.

Purpose: The aim of this study was to determine the potential of magnetic resonance imaging to evaluate the biodistribution of exogenous iron within 24 h after one single injection of Venofer® (iron sucrose).

Methods: Venofer® was evaluated in vitro for its ability to generate contrast in MR images. Subsequently, iron disposition was assessed in rats with MRI, in vivo up to 3 h and post mortem at 24 h after injection of Venofer®, at doses of 10- and 40 mg/kg body weight (n = 2 × 4), or saline (n = 4).

Results: Within 10-20 min after injection of Venofer®, transverse relaxation rates (R) clearly increased, representative of a local increase in iron concentration, in liver, spleen and kidney, including the kidney medulla and cortex. In liver and spleen R values remained elevated up to 3 h post injection, while the initial R increase in the kidney was followed by gradual decrease towards baseline levels. Bone marrow and muscle tissue did not show significant increases in R values. Whole-body post mortem MRI showed most prominent iron accumulation in the liver and spleen at 24 h post injection, which corroborated the in vivo results.

Conclusions: MR imaging is a powerful imaging modality for non-invasive assessment of iron distribution in organs. It is recommended to use this whole-body imaging approach complementary to other techniques that allow quantification of iron disposition at a (sub)cellular level.
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http://dx.doi.org/10.1007/s11095-018-2348-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843693PMC
March 2018

Diffusion MRI-based cortical connectome reconstruction: dependency on tractography procedures and neuroanatomical characteristics.

Brain Struct Funct 2018 Jun 20;223(5):2269-2285. Epub 2018 Feb 20.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht/Utrecht University, Yalelaan 2, 3584 CM, Utrecht, The Netherlands.

Diffusion MRI (dMRI)-based tractography offers unique abilities to map whole-brain structural connections in human and animal brains. However, dMRI-based tractography indirectly measures white matter tracts, with suboptimal accuracy and reliability. Recently, sophisticated methods including constrained spherical deconvolution (CSD) and global tractography have been developed to improve tract reconstructions through modeling of more complex fiber orientations. Our study aimed to determine the accuracy of connectome reconstruction for three dMRI-based tractography approaches: diffusion tensor (DT)-based, CSD-based and global tractography. Therefore, we validated whole brain structural connectome reconstructions based on ten ultrahigh-resolution dMRI rat brain scans and 106 cortical regions, from which varying tractography parameters were compared against standardized neuronal tracer data. All tested tractography methods generated considerable numbers of false positive and false negative connections. There was a parameter range trade-off between sensitivity: 0.06-0.63 interhemispherically and 0.22-0.86 intrahemispherically; and specificity: 0.99-0.60 interhemispherically and 0.99-0.23 intrahemispherically. Furthermore, performance of all tractography methods decreased with increasing spatial distance between connected regions. Similar patterns and trade-offs were found, when we applied spherical deconvolution informed filtering of tractograms, streamline thresholding and group-based average network thresholding. Despite the potential of CSD-based and global tractography to handle complex fiber orientations at voxel level, reconstruction accuracy, especially for long-distance connections, remains a challenge. Hence, connectome reconstruction benefits from varying parameter settings and combination of tractography methods to account for anatomical variation of neuronal pathways.
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http://dx.doi.org/10.1007/s00429-018-1628-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968063PMC
June 2018

Fast quantitative MRI as a nonlinear tomography problem.

Magn Reson Imaging 2018 02 9;46:56-63. Epub 2017 Nov 9.

Center for Image Sciences, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Quantitative Magnetic Resonance Imaging (MRI) is based on a two-steps approach: estimation of the magnetic moments distribution inside the body, followed by a voxel-by-voxel quantification of the human tissue properties. This splitting simplifies the computations but poses several constraints on the measurement process, limiting its efficiency. Here, we perform quantitative MRI as a one step process; signal localization and parameter quantification are simultaneously obtained by the solution of a large scale nonlinear inversion problem based on first-principles. As a consequence, the constraints on the measurement process can be relaxed and acquisition schemes that are time efficient and widely available in clinical MRI scanners can be employed. We show that the nonlinear tomography approach is applicable to MRI and returns human tissue maps from very short experiments.
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http://dx.doi.org/10.1016/j.mri.2017.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080622PMC
February 2018

Early life stress-induced alterations in rat brain structures measured with high resolution MRI.

PLoS One 2017 25;12(9):e0185061. Epub 2017 Sep 25.

Biomedical MR Imaging and Spectroscopy Group, Center for Images Sciences, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Adverse experiences early in life impair cognitive function both in rodents and humans. In humans this increases the vulnerability to develop mental illnesses while in the rodent brain early life stress (ELS) abnormalities are associated with changes in synaptic plasticity, excitability and microstructure. Detailed information on the effects of ELS on rodent brain structural integrity at large and connectivity within the brain is currently lacking; this information is highly relevant for understanding the mechanism by which early life stress predisposes to mental illnesses. Here, we exposed rats to 24 hours of maternal deprivation (MD) at postnatal day 3, a paradigm known to increase corticosterone levels and thereby activate glucocorticoid receptors in the brain. Using structural magnetic resonance imaging we examined: i) volumetric changes and white/grey matter properties of the whole cerebrum and of specific brain areas; and ii) whether potential alterations could be normalized by blocking glucocorticoid receptors with mifepristone during the critical developmental window of early adolescence, i.e. between postnatal days 26 and 28. The results show that MD caused a volumetric reduction of the prefrontal cortex, particularly the ventromedial part, and the orbitofrontal cortex. Within the whole cerebrum, white (relative to grey) matter volume was decreased and region-specifically in prefrontal cortex and dorsomedial striatum following MD. A trend was found for the hippocampus. Grey matter fractions were not affected. Treatment with mifepristone did not normalize these changes. This study indicates that early life stress in rodents has long lasting consequences for the volume and structural integrity of the brain. However, changes were relatively modest and-unlike behavior- not mitigated by blockade of glucocorticoid receptors during a critical developmental period.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185061PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612645PMC
October 2017

Combined fetal inflammation and postnatal hypoxia causes myelin deficits and autism-like behavior in a rat model of diffuse white matter injury.

Glia 2018 01 19;66(1):78-93. Epub 2017 Sep 19.

Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, 3584EA, The Netherlands.

Diffuse white matter injury (WMI) is a serious problem in extremely preterm infants, and is associated with adverse neurodevelopmental outcome, including cognitive impairments and an increased risk of autism-spectrum disorders. Important risk factors include fetal or perinatal inflammatory insults and fluctuating cerebral oxygenation. However, the exact mechanisms underlying diffuse WMI are not fully understood and no treatment options are currently available. The use of clinically relevant animal models is crucial to advance knowledge on the pathophysiology of diffuse WMI, allowing the definition of novel therapeutic targets. In the present study, we developed a multiple-hit animal model of diffuse WMI by combining fetal inflammation and postnatal hypoxia in rats. We characterized the effects on white matter development and functional outcome by immunohistochemistry, MRI and behavioral paradigms. Combined fetal inflammation and postnatal hypoxia resulted in delayed cortical myelination, microglia activation and astrogliosis at P18, together with long-term changes in oligodendrocyte maturation as observed in 10 week old animals. Furthermore, rats with WMI showed impaired motor performance, increased anxiety and signs of autism-like behavior, i.e. reduced social play behavior and increased repetitive grooming. In conclusion, the combination of fetal inflammation and postnatal hypoxia in rats induces a pattern of brain injury and functional impairments that closely resembles the clinical situation of diffuse WMI. This animal model provides the opportunity to elucidate pathophysiological mechanisms underlying WMI, and can be used to develop novel treatment options for diffuse WMI in preterm infants.
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http://dx.doi.org/10.1002/glia.23216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724703PMC
January 2018

Modified structural network backbone in the contralesional hemisphere chronically after stroke in rat brain.

J Cereb Blood Flow Metab 2018 09 12;38(9):1642-1653. Epub 2017 Jun 12.

1 Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands.

Functional outcome after stroke depends on the local site of ischemic injury and on remote effects within connected networks, frequently extending into the contralesional hemisphere. However, the pattern of large-scale contralesional network remodeling remains largely unresolved. In this study, we applied diffusion-based tractography and graph-based network analysis to measure structural connectivity in the contralesional hemisphere chronically after experimental stroke in rats. We used the minimum spanning tree method, which accounts for variations in network density, for unbiased characterization of network backbones that form the strongest connections in a network. Ultrahigh-resolution diffusion MRI scans of eight post-mortem rat brains collected 70 days after right-sided stroke were compared against scans from 10 control brains. Structural network backbones of the left (contralesional) hemisphere, derived from 42 atlas-based anatomical regions, were found to be relatively stable across stroke and control animals. However, several sensorimotor regions showed increased connection strength after stroke. Sensorimotor function correlated with specific contralesional sensorimotor network backbone measures of global integration and efficiency. Our findings point toward post-stroke adaptive reorganization of the contralesional sensorimotor network with recruitment of distinct sensorimotor regions, possibly through strengthening of connections, which may contribute to functional recovery.
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http://dx.doi.org/10.1177/0271678X17713901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120129PMC
September 2018

In Vivo Molecular MRI of ICAM-1 Expression on Endothelium and Leukocytes from Subacute to Chronic Stages After Experimental Stroke.

Transl Stroke Res 2017 May 16. Epub 2017 May 16.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands.

Molecular MRI allows in vivo detection of vascular cell adhesion molecules expressed on inflamed endothelium, which enables detection of specific targets for anti-neuroinflammatory treatment. We explored to what extent MR contrast agent targeted to intercellular adhesion molecule-1 (ICAM-1) could detect endothelial- and leukocyte-associated ICAM-1 expression at different stages after experimental stroke. Furthermore, we assessed potential interfering effects of ICAM-1-targeted contrast agent on post-stroke lesion growth. Micron-sized particles of iron oxide (MPIO) functionalized with control IgG (IgG-MPIO) or anti-ICAM-1 antibody (αICAM-1-MPIO) were administrated at 1, 2, 3, 7, and 21 days after unilateral transient middle cerebral artery occlusion in mice, followed by in vivo MRI and postmortem immunohistochemistry. αICAM-1-MPIO induced significant contrast effects in the lesion core on post-stroke days 1, 2, and 3, and in the lesion borderzone and contralesional tissue on post-stroke day 2. αICAM-1-MPIO were confined to ICAM-1-positive vessels and occasionally co-localized with leukocytes. On post-stroke day 21, abundant leukocyte-associated αICAM-1-MPIO was immunohistochemically detected in the lesion core. However, MRI-based detection of αICAM-1-MPIO-labeled leukocytes was confounded by pre-contrast MRI hypointensities, presumably caused by phagocytosed blood remains. IgG-MPIO did not induce significant MRI contrast effects at 1 h after injection. Lesion development was not affected by injection of αICAM-1-MPIO or IgG-MPIO. αICAM-1-MPIO are suitable for in vivo MRI of ICAM-1 expression on vascular endothelium and leukocytes at different stages after stroke. Development of clinically applicable MPIO may offer unique opportunities for MRI-based diagnosis of neuroinflammation and identification of anti-inflammatory targets in acute stroke patients.
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http://dx.doi.org/10.1007/s12975-017-0536-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590030PMC
May 2017

A novel approach to map induced activation of neuronal networks using chemogenetics and functional neuroimaging in rats: A proof-of-concept study on the mesocorticolimbic system.

Neuroimage 2017 08 11;156:109-118. Epub 2017 May 11.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Bolognalaan 50, 3584 CJ Utrecht, The Netherlands. Electronic address:

Linking neural circuit activation at whole-brain level to neuronal activity at cellular level remains one of the major challenges in neuroscience research. We set up a novel functional neuroimaging approach to map global effects of locally induced activation of specific midbrain projection neurons using chemogenetics (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-technology) combined with pharmacological magnetic resonance imaging (phMRI) in the rat mesocorticolimbic system. Chemogenetic activation of DREADD-targeted mesolimbic or mesocortical pathways, i.e. projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) or medial prefrontal cortex (mPFC), respectively, induced significant blood oxygenation level-dependent (BOLD) responses in areas with DREADD expression, but also in remote defined neural circuitry without DREADD expression. The time-course of brain activation corresponded with the behavioral output measure, i.e. locomotor (hyper)activity, in the mesolimbic pathway-targeted group. Chemogenetic activation specifically increased neuronal activity, whereas functional connectivity assessed with resting state functional MRI (rs-fMRI) remained stable. Positive and negative BOLD responses distinctively reflected simultaneous ventral pallidum activation and substantia nigra pars reticulata deactivation, respectively, demonstrating the concept of mesocorticolimbic network activity with concurrent activation of the direct and indirect pathways following stimulation of specific midbrain projection neurons. The presented methodology provides straightforward and widely applicable opportunities to elucidate relationships between local neuronal activity and global network activity in a controllable manner, which will increase our understanding of the functioning and dysfunctioning of large-scale neuronal networks in health and disease.
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http://dx.doi.org/10.1016/j.neuroimage.2017.05.021DOI Listing
August 2017

Prediction of hemorrhagic transformation after experimental ischemic stroke using MRI-based algorithms.

J Cereb Blood Flow Metab 2017 Aug 1;37(8):3065-3076. Epub 2016 Jan 1.

1 Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands.

Estimation of hemorrhagic transformation (HT) risk is crucial for treatment decision-making after acute ischemic stroke. We aimed to determine the accuracy of multiparametric MRI-based predictive algorithms in calculating probability of HT after stroke. Spontaneously, hypertensive rats were subjected to embolic stroke and, after 3 h treated with tissue plasminogen activator (Group I: n = 6) or vehicle (Group II: n = 7). Brain MRI measurements of T, T*, diffusion, perfusion, and blood-brain barrier permeability were obtained at 2, 24, and 168 h post-stroke. Generalized linear model and random forest (RF) predictive algorithms were developed to calculate the probability of HT and infarction from acute MRI data. Validation against seven-day outcome on MRI and histology revealed that highest accuracy of hemorrhage prediction was achieved with a RF-based model that included spatial brain features (Group I: area under the receiver-operating characteristic curve (AUC) = 0.85 ± 0.14; Group II: AUC = 0.89 ± 0.09), with significant improvement over perfusion- or permeability-based thresholding methods. However, overlap between predicted and actual tissue outcome was significantly lower for hemorrhage prediction models (maximum Dice's Similarity Index (DSI) = 0.20 ± 0.06) than for infarct prediction models (maximum DSI = 0.81 ± 0.06). Multiparametric MRI-based predictive algorithms enable early identification of post-ischemic tissue at risk of HT and may contribute to improved treatment decision-making after acute ischemic stroke.
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http://dx.doi.org/10.1177/0271678X16683692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536810PMC
August 2017

Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage.

Stroke 2017 02 27;48(2):452-458. Epub 2016 Dec 27.

From the Departments of Neurology (A.M.H., H.J.A.v.O., M.D.F., A.M.J.M.v.d.M., M.J.H.W.), Human Genetics (A.M.J.M.v.d.M.), Medical Statistics (E.v.Z.), Leiden University Medical Center, Leiden, The Netherlands; Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands (A.M.H., A.v.d.T., U.S.R., R.M.D.); and Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Centre, Dallas (L.M., K.P., A.M.S.).

Background And Purpose: Spreading depolarizations (SDs) may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). We tested whether SD-inhibitor valproate reduces brain injury in an SAH rat model with and without experimental SD induction.

Methods: Rats were randomized in a 2×2 design and pretreated with valproate (200 mg/kg) or vehicle for 4 weeks. SAH was induced by endovascular puncture of the right internal carotid bifurcation. One day post-SAH, brain tissue damage was measured with T-weighted magnetic resonance imaging, followed by cortical application of 1 mol/L KCl (to induce SDs) or NaCl (no SDs). Magnetic resonance imaging was repeated on day 3 followed by histology to confirm neuronal death. Neurological function was measured with an inclined slope test.

Results: In the groups with KCl application, lesion growth between days 1 and 3 was 57±73 mm3 in the valproate-treated versus 237±232 mm3 in the vehicle-treated group. In the groups without SD induction, lesion growth in the valproate- and vehicle-treated groups was 8±20 mm3 versus 27±52 mm3. On fitting a 2-way analysis of variance model, we found a significant interaction effect between treatment and KCl/NaCl application of 161 mm3 (P=0.04). Number and duration of SDs, mortality, and neurological function were not statistically significantly different between groups. Lesion growth on magnetic resonance imaging correlated to histological infarct volume (Spearman's rho =0.83; P=0.0004), with areas of lesion growth exhibiting reduced neuronal death compared with primary lesions.

Conclusions: In our rat SAH model, valproate treatment significantly reduced brain lesion growth after KCl application. Future studies are needed to confirm that this protective effect is based on SD inhibition.
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http://dx.doi.org/10.1161/STROKEAHA.116.014738DOI Listing
February 2017

Magnetic resonance imaging of local and remote vascular remodelling after experimental stroke.

J Cereb Blood Flow Metab 2017 Aug 1;37(8):2768-2779. Epub 2016 Jan 1.

1 Biomedical MR Imaging and Spectroscopy Group, University Medical Center Utrecht, Utrecht, The Netherlands.

The pattern of vascular remodelling in relation to recovery after stroke remains largely unclear. We used steady-state contrast-enhanced magnetic resonance imaging to assess the development of cerebral blood volume and microvascular density in perilesional and exofocal areas from (sub)acutely to chronically after transient stroke in rats. Microvascular density was verified histologically after infusion with Evans Blue dye. At day 1, microvascular cerebral blood volume and microvascular density were reduced in and around the ischemic lesion (intralesional borderzone: microvascular cerebral blood volume = 72 ± 8%; microvascular density = 76 ± 8%) (P < 0.05), while total cerebral blood volume remained relatively unchanged. Perilesional microvascular cerebral blood volume and microvascular density subsequently normalized (day 7) and remained relatively stable (day 70). In remote ipsilateral areas in the thalamus and substantia nigra - not part of the ischemic lesion - microvascular density gradually increased between days 1 and 70 (thalamic ventral posterior nucleus: microvascular density = 119 ± 9%; substantia nigra: microvascular density = 122 ± 8% (P < 0.05)), which was confirmed histologically. Our data indicate that initial microvascular collapse, with maintained collateral flow in larger vessels, is followed by dynamic revascularization in perilesional tissue. Furthermore, progressive neovascularization in non-ischemic connected areas may offset secondary neuronal degeneration and/or contribute to non-neuronal tissue remodelling. The complex spatiotemporal pattern of vascular remodelling, involving regions outside the lesion territory, may be a critical endogenous process to promote post-stroke brain reorganization.
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http://dx.doi.org/10.1177/0271678X16674737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536787PMC
August 2017

Spreading depolarizations increase delayed brain injury in a rat model of subarachnoid hemorrhage.

J Cereb Blood Flow Metab 2016 07 30;36(7):1224-31. Epub 2015 Nov 30.

Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Centre Utrecht, Utrecht, The Netherlands

Spreading depolarizations may contribute to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage, but the effect of spreading depolarizations on brain lesion progression after subarachnoid hemorrhage has not yet been assessed directly. Therefore, we tested the hypothesis that artificially induced spreading depolarizations increase brain tissue damage in a rat model of subarachnoid hemorrhage. Subarachnoid hemorrhage was induced by endovascular puncture of the right internal carotid bifurcation. After one day, brain tissue damage was measured with T2-weighted MRI, followed by application of 1 M KCl (SD group, N = 16) or saline (no-SD group, N = 16) to the right cortex. Cortical laser-Doppler flowmetry was performed to record spreading depolarizations. MRI was repeated on day 3, after which brains were extracted for assessment of subarachnoid hemorrhage severity and histological damage. 5.0 ± 2.7 spreading depolarizations were recorded in the SD group. Subarachnoid hemorrhage severity and mortality were similar between the SD and no-SD groups. Subarachnoid hemorrhage-induced brain lesions expanded between days 1 and 3. This lesion growth was larger in the SD group (241 ± 233 mm(3)) than in the no-SD group (29 ± 54 mm(3)) (p = 0.001). We conclude that induction of spreading depolarizations significantly advances lesion growth after experimental subarachnoid hemorrhage. Our study underscores the pathophysiological consequence of spreading depolarizations in the development of delayed cerebral tissue injury after subarachnoid hemorrhage.
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http://dx.doi.org/10.1177/0271678X15619189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929702PMC
July 2016

Measurement of distinctive features of cortical spreading depolarizations with different MRI contrasts.

NMR Biomed 2015 May 27;28(5):591-600. Epub 2015 Mar 27.

Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.

Growing clinical evidence suggests critical involvement of spreading depolarizations (SDs) in the pathophysiology of neurological disorders such as migraine and stroke. MRI provides powerful tools to detect and assess co-occurring cerebral hemodynamic and cellular changes during SDs. This study reports the feasibility and advantages of two MRI scans, based on balanced steady-state free precession (b-SSFP) and diffusion-weighted multi-spin-echo (DT2), heretofore unexplored for monitoring SDs. These were compared with gradient-echo MRI. SDs were induced by KCl application in rat brain. Known for high SNR, the T2- and T1-based b-SSFP contrast was hypothesized to provide higher spatiotemporal specificity than T2*-based gradient-echo scanning. DT2 scanning was designed to provide simultaneous T2 and apparent diffusion coefficient (ADC) measurements, thus enabling combined quantitative assessment of hemodynamic and cellular changes during SDs. Procedures were developed to automate identification of SD-induced responses in all the scans. These responses were analyzed to determine detection sensitivity and temporal characteristics of signals from each scanning method. Cluster analysis was performed to elucidate unique temporal patterns for each contrast. All scans allowed detection of SD-induced responses. b-SSFP scans showed significantly larger relative intensity changes, narrower peak widths and greater spatial specificity compared with gradient-echo MRI. SD-induced effects on ADC, calculated from DT2 scans, showed the most pronounced signal changes, displaying about 20% decrease, as against 10-15% signal increases observed with b-SSFP and gradient-echo scanning. Cluster analysis revealed additional temporal sub-patterns, such as an initial dip on gradient-echo scans and temporally shifted T2 and proton density changes in DT2 data. To summarize, b-SSFP and DT2 scanning provide distinct information on SDs compared with gradient-echo MRI. DT2 scanning, with its potential to simultaneously provide cellular and hemodynamic information, can offer unique information on the inter-relationship between these processes in pathologic brain, which may improve monitoring of spreading depolarizations in (pre)clinical settings.
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http://dx.doi.org/10.1002/nbm.3288DOI Listing
May 2015

Stress-induced alterations in large-scale functional networks of the rodent brain.

Neuroimage 2015 Jan 22;105:312-22. Epub 2014 Oct 22.

Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.

Stress-related psychopathology is associated with altered functioning of large-scale brain networks. Animal research into chronic stress, one of the most prominent environmental risk factors for development of psychopathology, has revealed molecular and cellular mechanisms potentially contributing to human mental disease. However, so far, these studies have not addressed the system-level changes in extended brain networks, thought to critically contribute to mental disorders. We here tested the effects of chronic stress exposure (10 days immobilization) on the structural integrity and functional connectivity patterns in the brain, using high-resolution structural MRI, diffusion kurtosis imaging, and resting-state functional MRI, while confirming the expected changes in neuronal dendritic morphology using Golgi-staining. Stress effectiveness was confirmed by a significantly lower body weight and increased adrenal weight. In line with previous research, stressed animals displayed neuronal dendritic hypertrophy in the amygdala and hypotrophy in the hippocampal and medial prefrontal cortex. Using independent component analysis of resting-state fMRI data, we identified ten functional connectivity networks in the rodent brain. Chronic stress appeared to increase connectivity within the somatosensory, visual, and default mode networks. Moreover, chronic stress exposure was associated with an increased volume and diffusivity of the lateral ventricles, whereas no other volumetric changes were observed. This study shows that chronic stress exposure in rodents induces alterations in functional network connectivity strength which partly resemble those observed in stress-related psychopathology. Moreover, these functional consequences of stress seem to be more prominent than the effects on gross volumetric change, indicating their significance for future research.
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http://dx.doi.org/10.1016/j.neuroimage.2014.10.037DOI Listing
January 2015

Axial osteitis of the proximal sesamoid bones and desmitis of the intersesamoidean ligament in the hindlimb of Friesian horses: review of 12 cases (2002-2012) and post-mortem analysis of the bone-ligament interface.

BMC Vet Res 2014 Nov 19;10:272. Epub 2014 Nov 19.

Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, P,O, Box 80,163, Utrecht, 3584 CM, The Netherlands.

Background: Axial osteitis of the proximal sesamoid bones and desmitis of the intersesamoidean ligament has been described in Friesian horses as well as in other breeds. The objectives of this study were to review the outcome of clinical cases of this disease in Friesian horses and analyse the pathology of the bone-ligament interface. Case records of Friesian horses diagnosed with axial osteitis of the proximal sesamoid bones and desmitis of the intersesamoidean ligament in the period 2002-2012 were retrospectively evaluated. Post-mortem examination was performed on horses that were euthanized (n = 3) and included macroscopic necropsy (n = 3), high-field (9.4 Tesla) magnetic resonance imaging (n = 1) and histopathology (n = 2).

Results: Twelve horses were included, aged 6.8 ± 2.7 years. The hindlimb was involved in all cases. Lameness was acute in onset and severe, with a mean duration of 1.9 ± 1.0 months. Three horses were euthanized after diagnosis; 9 horses underwent treatment. Two horses (22%) became sound for light riding purposes, 2 horses (22%) became pasture sound (comfortable at pasture, but not suitable for riding), 5 horses (56%) remained lame. In addition to bone resorption at the proximo-axial margin of the proximal sesamoid bones, magnetic resonance imaging and histopathology showed osteoporosis of the peripheral compact bone and spongious bone of the proximal sesamoid bones and chronic inflammation of the intersesamoidean ligament.

Conclusions: Axial osteitis of the proximal sesamoid bones and desmitis of the intersesamoidean ligament in the hindlimb of Friesian horses carries a poor prognosis. Pathological characterization (inflammation, proximo-axial bone resorption and remodelling of the peripheral compact bone and spongious bone of the proximal sesamoid bones) may help in unravelling the aetiology of this disease.
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http://dx.doi.org/10.1186/s12917-014-0272-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239326PMC
November 2014

Can diffusion kurtosis imaging improve the sensitivity and specificity of detecting microstructural alterations in brain tissue chronically after experimental stroke? Comparisons with diffusion tensor imaging and histology.

Neuroimage 2014 Aug 15;97:363-73. Epub 2014 Apr 15.

Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Electronic address:

Imaging techniques that provide detailed insights into structural tissue changes after stroke can vitalize development of treatment strategies and diagnosis of disease. Diffusion-weighted MRI has been playing an important role in this regard. Diffusion kurtosis imaging (DKI), a recent addition to this repertoire, has opened up further possibilities in extending our knowledge about structural tissue changes related to injury as well as plasticity. In this study we sought to discern the microstructural alterations characterized by changes in diffusion tensor imaging (DTI) and DKI parameters at a chronic time point after experimental stroke. Of particular interest was the question of whether DKI parameters provide additional information in comparison to DTI parameters in understanding structural tissue changes, and if so, what their histological origins could be. Region-of-interest analysis and a data-driven approach to identify tissue abnormality were adopted to compare DTI- and DKI-based parameters in post mortem rat brain tissue, which were compared against immunohistochemistry of various cellular characteristics. The unilateral infarcted area encompassed the ventrolateral cortex and the lateral striatum. Results from region-of-interest analysis in the lesion borderzone and contralateral tissue revealed significant differences in DTI and DKI parameters between ipsi- and contralateral sensorimotor cortex, corpus callosum, internal capsule and striatum. This was reflected by a significant reduction in ipsilateral mean diffusivity (MD) and fractional anisotropy (FA) values, accompanied by significant increases in kurtosis parameters in these regions. Data-driven analysis to identify tissue abnormality revealed that the use of kurtosis-based parameters improved the detection of tissue changes in comparison with FA and MD, both in terms of dynamic range and in being able to detect changes to which DTI parameters were insensitive. This was observed in gray as well as white matter. Comparison against immunohistochemical stainings divulged no straightforward correlation between diffusion-based parameters and individual neuronal, glial or inflammatory tissue features. Our study demonstrates that DKI allows sensitive detection of structural tissue changes that reflect post-stroke tissue remodeling. However, our data also highlights the generic difficulty in unambiguously asserting specific causal relationships between tissue status and MR diffusion parameters.
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http://dx.doi.org/10.1016/j.neuroimage.2014.04.013DOI Listing
August 2014

Lesion development and reperfusion benefit in relation to vascular occlusion patterns after embolic stroke in rats.

J Cereb Blood Flow Metab 2014 Feb 4;34(2):332-8. Epub 2013 Dec 4.

Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.

Vascular occlusion sites largely determine the pattern of cerebral tissue damage and likelihood of subsequent reperfusion after acute ischemic stroke. We aimed to elucidate relationships between flow obstruction in segments of the internal carotid artery (ICA) and middle cerebral artery (MCA), and (1) profiles of acute ischemic lesions and (2) probability of subsequent beneficial reperfusion. Embolic stroke was induced by unilateral intracarotid blood clot injection in normotensive (n=53) or spontaneously hypertensive (n=20) rats, followed within 2  hours by magnetic resonance (MR) angiography (MRA), diffusion- (DWI) and perfusion-weighted magnetic resonance imaging (MRI) (PWI). In a subset of animals (n=9), MRI was repeated after 24 and 168  hours to determine the predictive value of the occlusion pattern on benefit of reperfusion. The extent of cerebral perfusion and diffusion abnormality was related to the pattern of flow obstruction in ICA and MCA segments. Hypertensive animals displayed significantly larger cortical perfusion lesions. Acute perfusion-diffusion lesion mismatches were detected in all animals that subsequently benefitted from reperfusion. Yet, the presence of an angiography-diffusion mismatch was more specific in predicting reperfusion benefit. Combination of DWI, PWI, and MRA exclusively informs on the impact of arterial occlusion profiles after acute ischemic stroke, which may improve prognostication and subsequent treatment decisions.
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http://dx.doi.org/10.1038/jcbfm.2013.202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915211PMC
February 2014
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