Biomedical subjects

Mathias Hoehn

Publications and source records attributed to Mathias Hoehn.

At least 19 recordsLinked to original sources

PubMed2006

Differential effects of NMDA and AMPA glutamate receptors on functional magnetic resonance imaging signals and evoked neuronal activity during forepaw stimulation of the rat.

Most of the currently used methods for functional brain imaging do not visualize neuronal activity directly but rather rely on the elicited hemodynamic and/or metabolic responses. Glutamate, the major excitatory neurotransmitter, plays an important role in the neurovascular/neurometabolic coupling, but the specific mechanisms are still poorly understood. To investigate the role of the two major ionotropic glutamate receptors [NMDA receptors (NMDA-Rs) and AMPA receptors (AMPA-Rs)] for the generation of functional magnetic resonance imaging (fMRI) signals, we used fMRI [measurements of blood oxygenation level-dependent (BOLD), perfusion-weighted imaging (PWI), and cerebral blood volume (CBV)] together with recordings of somatosensory evoked potentials (SEPs) during electrical forepaw stimulation in the alpha-chloralose anesthetized rat. Intravenous injection of the NMDA-R antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] (0.06 mg/kg plus 3.6 microg x kg(-1) x h(-1)) significantly decreased BOLD (-51 +/- 19%; n = 5) and PWI (-57 +/- 26%; n = 5) responses but reduced the SEPs only mildly (approximately -10%). Systemic application of the AMPA-R antagonist GYKI-53655 [1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine] significantly decreased both the hemodynamic response (BOLD, -49 +/- 13 and -65 +/- 15%; PWI, -22 +/- 48 and -68 +/- 4% for 5 and 7 mg/kg, i.v., respectively; CBV, -80 +/- 7% for 7 mg/kg; n = 4) and the SEPs (up to -60%). These data indicate that the interaction of glutamate with its postsynaptic and/or glial receptors is necessary for the generation of blood flow and BOLD responses and illustrate the differential role of NMDA-Rs and AMPA-Rs in the signaling chain leading from increased neuronal activity to the hemodynamic response in the somatosensory cortex.

Animals↗

PubMed2006

Functional uncoupling of hemodynamic from neuronal response by inhibition of neuronal nitric oxide synthase.

The cerebrovascular coupling under neuronal nitric oxide synthase (nNOS) inhibition was investigated in alpha-chloralose anesthetized rats. Cerebral blood flow (CBF), cerebral blood volume (CBV), and blood oxygenation level dependent (BOLD) responses to electrical stimulation of the forepaw were measured before and after an intraperitoneal bolus of 7-nitroindazole (7-NI), an in vivo inhibitor of the neuronal isoform of nitric oxide synthase. Neuronal activity was measured by recording somatosensory-evoked potentials (SEPs) via intracranial electrodes. 7-Nitroindazole produced a significant attenuation of the activation-elicited CBF (P<10(-6)), CBV (P<10(-6)), and BOLD responses (P<10(-6)), without affecting the baseline perfusion level. The average DeltaCBF was nulled, while DeltaBOLD and DeltaCBV decreased to approximately 30% of their respective amplitudes before 7-NI administration. The average SEP amplitude decreased (P<10(-5)) to approximately 60% of its pretreatment value. These data describe a pharmacologically induced uncoupling between neuronal and hemodynamic responses to functional activation, and provide further support for the critical role of neuronally produced NO in the cerebrovascular coupling.

Anesthesia↗

PubMed2006

Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice.

Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer's disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.

Alzheimer Disease↗

PubMed2006

Temporal profile of T2-weighted MRI distinguishes between pannecrosis and selective neuronal death after transient focal cerebral ischemia in the rat.

Transient middle cerebral artery occlusion (MCAO) by an intraluminal thread leads to primarily subcortical infarctions with little sensorimotor impairment in the Wistar rat strain. We investigated the course of infarct development in this lesion type for 10 weeks using magnetic resonance imaging (MRI) along with histological characterization. MCAO was induced in male Wistar rats (260 to 300 g) for 60 mins. Animals received follow-up T1- and T2-weighted MRI from day 1 until week 10. Separate groups of animals were analyzed histologically after 2, 6, and 10 weeks. Histology included immunohistochemistry for neuronal and astrocytic markers as well as hematoxylin eosin and luxol fast blue-cresyl violet staining. In contrast to lesions involving the cortex, exclusively subcortical infarctions were characterized by a complete resolution of initially increased T1 and T2 relaxation times by 10 weeks. Between 2 and 10 weeks, neuronal death and gliosis as well as a dense inflammatory infiltrate were evident in these lesions, without damage to fiber tracts or development of cystic cavities. Exclusively subcortical lesions in Wistar rats are characterized by normalization of T1 and T2 relaxation times, which might, however, not be mistaken for tissue recovery. Despite this MRI normalization, selective neuronal death and gliosis develop. Although MRI at individual time points might therefore be ambiguous, the temporal profile of relaxation time changes over the chronic time period allows discrimination of the lesion development into selective neuronal death or pannecrosis.

Animals↗

PubMed2006

Present status of magnetic resonance imaging and spectroscopy in animal stroke models.

Magnetic resonance imaging (MRI) is based on a wide variety of physical parameters, which, in principle, can all influence the image contrast conditions. As these diverse variables are validated by independent physiological, metabolic, hemodynamic, and histological techniques, a physiological MRI evolves. This imaging modality has been successfully applied to experimental stroke studies, covering a broad range of raised questions. In the present review, we present an overview of possible physiological criteria to be studied by in vivo MRI and magnetic resonance spectroscopy, and critically analyze the present limits and future potential of the imaging technique for experimental stroke investigations. The documented applications cover the spectrum from morphological-structural details of the lesion to hemodynamic and metabolic alterations, inflammatory reaction, evaluation of thrombolytic treatment, studies on recovery of functional brain activation by functional MRI, and, finally, the most recent applications of exploring stem cells for regenerative therapy.

Animals↗

PubMed2006

Correlation between MR-spectroscopic rat hippocampal choline levels and phospholipase A2.

Hippocampal choline-containing compounds (Cho) determined with 1H MR spectroscopy (MRS) are decreased in major depression episodes and return to baseline levels after antidepressive electroconvulsive therapy (ECT). A rise in hippocampal Cho has been observed in rats upon electroconvulsive shocks (ECS), an analogue of human ECT. Choline production involves the activity of various phospholipases. In order to investigate whether the increase of Cho correlates with an enhanced expression of phosphoslipase A2 (PLA2) we took rectangular tissue samples from the region of the MRS voxel for immunoblotting. Our data show a significant inverse correlation (p = 0.018) between PLA2 protein levels and MRS Cho/NAA levels suggesting a possible downregulation of PLA2 in compensation for an upregulation of other phospholipases.

Animals↗

PubMed2005

A fully noninvasive and robust experimental protocol for longitudinal fMRI studies in the rat.

Functional magnetic resonance imaging (fMRI) is a unique tool to study brain activity and plasticity changes. Combination of blood-oxygen level-dependent (BOLD) fMRI and electrical forepaw stimulation has been used as a standard model to study the somatosensory pathway and brain rehabilitation in rats. The majority of fMRI studies have been performed in animals anesthetized with alpha-chloralose as functional-metabolic coupling is best preserved under this anesthesia. However, alpha-chloralose is not suitable for survival procedures due to side effects, limiting its use to single time point studies of the same animal. We therefore developed a new, totally noninvasive fMRI protocol, using sedation with the alpha2-adrenoreceptor agonist medetomidine in combination with transcutaneous monitoring of blood gases. The continuous subcutaneous administration of medetomidine resulted in stable physiological conditions over a long time and all animals tolerated the repetitive fMRI experiments well. A robust and reproducible, significant BOLD signal increase was observed upon forepaw stimulation in the contralateral primary somatosensory cortex in two consecutive medetomidine sessions in all rats, which was similar to the BOLD signal increase observed in the same animals under alpha-chloralose during a third independent session. Activation in the secondary somatosensory cortex was observed less frequently under both medetomidine and alpha-chloralose. No head motion artifacts or nonspecific brain activation was present. Sedation was quickly reversed by the administration of the antagonist atipamezole after the fMRI experiment. These results demonstrate that longitudinal fMRI studies can be performed safely under sedation with medetomidine to study functional recovery processes upon therapeutical treatment.

Adrenergic alpha-Agonists↗

PubMed2005

Subcortical lesions after transient thread occlusion in the rat: T2-weighted magnetic resonance imaging findings without corresponding sensorimotor deficits.

PURPOSE: To investigate infarct evolution and functional consequences of exclusive subcortical or cortico-subcortical strokes, transient middle cerebral artery occlusion (MCAO) was conducted in Wistar rats. MATERIALS AND METHODS: MCAO was induced in male Wistar rats (260-300 g) for 60 minutes. Lesion volumes and absolute T2 times on magnetic resonance imaging (MRI) were assessed 1 and 14 days after MCAO using a 4.7-T MRI animal scanner in conjunction with functional testing (adhesive tape removal, cylinder test, and ledged beam walking). RESULTS: Functional test scores were not distinguishable between sham-operated animals (N = 5) and those with exclusive caudoputaminal infarct (N = 8; group cp), but showed significant deficits in animals with cortico-subcortical infarction (N = 10; group cp+). The cp group had lower absolute T2 times and a more pronounced reduction in T2 lesion volume over time than the subcortical component in the cp+ group. There was no correlation of T2 lesion size or absolute T2 times and functional impairment in either group. CONCLUSION: When judged from functional tests alone, subcortical ischemic lesions may not be diagnosed reliably. Furthermore, T2-weighted (T2-w) MRI does not well anticipate functional deficits in primarily striatal lesions.

Animals↗

PubMed2005

MRI detection of macrophage activity after experimental stroke in rats: new indicators for late appearance of vascular degradation?

Focal cerebral ischemia was induced in rats and followed with high-resolution MRI methods for a chronic period of 10 weeks. Two weeks after stroke induction and at the end of the observation period, conventional histological analysis was combined with immunohistochemical staining for macrophages and with Prussian blue staining for the detection of ferric iron. In the late chronic phase, a patchy hypointensity was observed in the ischemic caudoputamen exclusively on T2*-weighted (T2*W) images, with no change in quantitative T(1) and T(2) relaxation time maps. This characteristic MRI pattern is different from hemorrhagic transformations (HTs) at earlier time points (2 weeks post stroke induction), which became apparent on images of all three imaging sequences. The exclusive T2*-sensitive hypointensity colocalized with iron-positive macrophages in the lesion territory at this time. These iron-containing macrophages were found predominantly around blood vessels in the ischemic tissue, and interpreted as the result of a phagocytotic incorporation of red blood cells leaking from slowly degrading vessels. The present investigation demonstrates the sensitivity of heavily T2*W 3D MRI for observing the inflammatory response in the chronic phase after stroke, without prior systemic labeling of the blood-borne macrophages by iron oxide nanoparticles.

Animals↗

PubMed2005

Stem cell implantation in ischemic mouse heart: a high-resolution magnetic resonance imaging investigation.

Advances in the biology of stem cells have evoked great interest in cell replacement therapies for the regeneration of heart tissue after myocardial infarction. However, results from human trials are controversial, since the destination of the injected cells, their engraftment and their long-term fate have remained unclear. Here we investigate whether transplanted cells can be identified in the intact and lesioned murine myocardium employing high-resolution MRI. Cardiac progenitor cells, expressing the enhanced green fluorescent protein (EGFP), were labeled with ultra-small paramagnetic iron-oxide (USPIO) nanoparticles and transplanted into the intact or injured myocardium of mice. Their precise location was determined with high-resolution MRI and compared with histological tissue sections, stained with Prussian blue for iron content. These experiments showed that iron nanoparticle-loaded cells could be identified at high resolution in the mouse heart. However, ischemic myocardium (after cryoinjury or left coronary artery ligation) was characterized by a signal attenuation similar to that induced by USPIO-labeled cells in T2*-weighted MR images, making detection of labeled stem cells in this area by T2*-sensitive contrast rather difficult. In animals with myocardial injury only, the signal attenuated areas were of the same size in proton density- and T2*-weighted MR images. In injured animals also receiving labeled cells the lesioned area appeared larger in T2*--than in proton density-weighted MR images. This sequence-dependent lesion size change is due to the increased signal loss caused by the iron oxide nanoparticles, most sensitively detectable in the T2*-sensitive images. Thus, using the novel combination of these two parameter weightings, USPIO-labeled cells can be detected at high resolution in ischemic myocardium.

Animals↗

PubMed2005

Metabolic differences between primary and recurrent human brain tumors: a 1H NMR spectroscopic investigation.

High-resolution proton magnetic resonance spectroscopy was performed on tissue specimens from 33 patients with astrocytic tumors (22 astrocytomas, 11 glioblastomas) and 13 patients with meningiomas. For all patients, samples of primary tumors and their first recurrences were examined. Increased anaplasia, with respect to malignant transformation, resulting in a higher malignancy grade, was present in 11 recurrences of 22 astrocytoma patients. Spectroscopic features of tumor types, as determined on samples of the primary occurrences, were in good agreement with previous studies. Compared with the respective primary astrocytomas, characteristic features of glioblastomas were significantly increased concentrations of alanine (Ala) (p = 0.005), increased metabolite ratios of glycine (Gly)/total creatine (tCr) (p = 0.0001) and glutamate (Glu)/glutamine (Gln) (p = 0.004). Meningiomas showed increased Ala (p = 0.02) and metabolite ratios [Gly, total choline (tCho), Ala] over tCr (p = 0.001) relative to astrocytomas, and N-acetylaspartate and myo-inositol were absent. Metabolic changes of an evolving tumor were observed in recurrent astrocytomas: owing to their consecutive assessments, more indicators of malignant degeneration were detected in astrocytoma recurrences (e.g. Gly, p = 0.029; tCho, p = 0.034; Glu, p = 0.015; tCho/tCr, p = 0.001) in contrast to the comparison of primary astrocytomas with primary glioblastomas. The present investigation demonstrated a correlation of the tCho-signal with tumor progression. Significantly elevated concentrations of Ala (p = 0.037) and Glu (p = 0.003) and metabolite ratio tCho/tCr (p = 0.005) were even found in recurrent low-grade astrocytomas with unchanged histopathological grading (n = 11). This may be related to an early stage of malignant transformation, not yet detectable morphologically, and emphasizes the high sensitivity of 1H NMR spectroscopy in elucidating characteristics of brain tumor metabolism.

Adult↗

PubMed2005

Continuous noninvasive monitoring of transcutaneous blood gases for a stable and persistent BOLD contrast in fMRI studies in the rat.

The physiological status of anesthetized rats greatly influences blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI). Monitoring of physiological parameters, particularly partial pressure of carbon dioxide (pCO(2)) levels in the blood, is therefore an important part in the design and performance of reliable fMRI experiments. In this paper, the use of a transcutaneous blood gas analyzing system in rats as a completely noninvasive and MR-compatible method is demonstrated. It was successfully used to monitor continuously pCO(2) values, as an effective alternative to more invasive methods, such as analysis of repetitive arterial blood samples or endtidal capnography. In addition, the transcutaneous pCO(2) of rats anesthetized for long periods was studied using different anesthetic substances and experimental protocols. On-line monitoring of pCO(2) values permitted experimental conditions to be established in which the animals remained normocapnic and during which a robust and consistent BOLD contrast could be observed upon somatosensory forepaw stimulation. A transcutaneous pCO(2) threshold level was defined for the reliable detection of a stimulus-dependent BOLD response.

Adult↗

PubMed2004

Histochemical detection of ultrasmall superparamagnetic iron oxide (USPIO) contrast medium uptake in experimental brain ischemia.

Recently, macrophage infiltration in different central nervous system (CNS) pathologies has been visualized with ultrasmall particles of iron oxide (USPIO) as a new cell-specific contrast medium for MRI. However, validation of these findings at the histological level has been hampered by the fact that the in situ detection of iron uptake by conventional Prussian blue staining is not sensitive enough to detect low amounts of iron in the brain. Here, an improved method for the histochemical detection of USPIO uptake in ischemic brain lesions is reported. The procedure relies on the sequential enhancement of Prussian blue staining by diaminobenzidine and silver/gold impregnation. After photothrombotic cortical brain infarction, this method allowed sensitive in situ detection of iron-laden macrophages which matched both macrophage immunostaining and USPIO-induced signal alterations in high-resolution 7 T MRI. This staining method provides a basis for correlative histological assessment of USPIO-enhanced MRI in a broad spectrum of CNS pathologies.

Animals↗

PubMed2004

Central nervous system inflammatory response after cerebral infarction as detected by magnetic resonance imaging.

Brain inflammation contributes to the tissue injury caused by ischemic stroke. Macrophages as the most abundant inflammatory cell population in stroke lesions can be visualized using ultrasmall superparamagnetic iron oxide (USPIO) as a cell-specific contrast agent for magnetic resonance imaging (MRI). The aim of our present study was to delineate the inflammatory response during experimental cerebral infarction by means of USPIO-enhanced MRI and to correlate the spatial distribution of USPIO-induced MR signal alterations with cellular infiltration and iron deposition. To this end USPIOs were administered to Wistar rats 5 days after photothrombotic cerebral infarction. MR imaging at 7 T performed 24 h later displayed a rim-like signal loss around the infarction in the USPIO treated animals. On histological brain sections obtained from the same animals after MRI the distribution of iron and ED1+ phagocytes was in full spatial agreement with the signal loss seen on T2*-weighted images. Our study validates USPIO-enhanced MRI as an important tool for the noninvasive visualization of brain inflammation in stroke and other CNS pathologies.

Animals↗

PubMed2004

Characterization of a novel chronic photothrombotic ring stroke model in rats by magnetic resonance imaging, biochemical imaging, and histology.

A novel photothrombotic ring stroke model was characterized by multiparametric magnetic resonance imaging, imaging of cerebral blood flow (CBF), adenosine triphosphate (ATP), pH, and histology. Ischemia was initiated by transosseous irradiation of a predefined brain area intravenously perfused by the photosensitive dye erythrosin B in male Wistar rats. In the region of the primary ring-lesion, the phototoxic reaction caused necrosis reflected by low relative ATP levels (28 +/- 15%), alkalosis (pH: 7.35 +/- 0.50), and histologic evidence at 14 days after lesion induction. In the ring-encircled interior region (region-at-risk), spontaneous tissue reperfusion (relative CBF: 93 +/- 3%) enabled partial tissue preservation. This was demonstrated by a less impaired energy metabolism (ATP: 65 +/- 23%), normal pH (7.01 +/- 0.50), and still normal cellular structures shown by histologic staining. Analysis of the temporal characteristics within the region-at-risk revealed a slow continuous increase of the apparent diffusion coefficient of water (ADC) to 144 +/- 16% of control (14d) and an early vasogenic edema, reflected by an increase of the T2 relaxation time to 143 +/- 17% of control (2d). Both final ADC and T2 correlated well with the tissue pH within the region-at-risk, thus emphasizing the usefulness of this multiparametric noninvasive imaging approach.

Adenosine Triphosphate↗

PubMed2004

Functional magnetic resonance imaging and somatosensory evoked potentials in rats with a neonatally induced freeze lesion of the somatosensory cortex.

Brain plasticity is an important mechanism for functional recovery from a cerebral lesion. The authors aimed to visualize plasticity in adult rats with a neonatal freeze lesion in the somatosensory cortex using functional magnetic resonance imaging (fMRI), and hypothesized activation outside the primary projection area. A freeze lesion was induced in the right somatosensory cortex of newborn Wistar rats (n = 12). Sham-operated animals (n = 7) served as controls. After 6 or 7 months, a neurologic examination was followed by recording of somatosensory evoked potentials (SSEPs) and magnetic resonance experiments (anatomical images, fMRI with blood oxygen level-dependent contrast and perfusion-weighted imaging) with electrical forepaw stimulation under alpha-chloralose anesthesia. Lesioned animals had no obvious neurologic deficits. Anatomical magnetic resonance images showed a malformed cortex or hyperintense areas (cysts) in the lesioned hemisphere. SSEPs were distorted and smaller in amplitude, and fMRI activation was significantly weaker in the lesioned hemisphere. Only in a few animals were cortical areas outside the primary sensory cortex activated. The results are discussed in respect to an apparent absence of plasticity, loss of excitable tissue, the excitability of the lesioned hemisphere, altered connectivity, and a disturbed coupling of increased neuronal activity to the hemodynamic response.

Animals↗

PubMed2003

Specific creatine rise in learned helplessness induced by electroconvulsive shock treatment.

Metabolic changes in the hippocampus formation can be investigated with in vivo magnetic resonance spectroscopy (MRS). Learned helplessness (LH) is a well validated animal model of depression which we established in Sprague-Dawley rats defining some as "learned helpless" (LH) or not "learned helpless" (NLH). Helpless and non-helpless rats received a course of daily administered electroconvulsive shocks (ECS) for 6 days. MRS measurements were performed on a 4.7 T animal scanner with an average voxel size within the rat hippocampus of 10 microl. In LH rats hippocampal creatine/NAA rose significantly (14%) whereas creatine/NAA of NLH rats showed no increase at all. A possible connection between hippocampal creatine levels and major depressive disorders as a reflection of changes in energy metabolism is discussed.

Animals↗

PubMed2003

Differences in clot preparation determine outcome of recombinant tissue plasminogen activator treatment in experimental thromboembolic stroke.

BACKGROUND AND PURPOSE: Thrombin-induced clots used in experimental thromboembolic stroke differ from clots forming spontaneously under clinical conditions. We investigated whether this difference influences the efficacy and outcome of thrombolytic treatment. METHODS: In rats, the middle cerebral artery was occluded by intracarotid injection of fibrin-rich clots, prepared either according to established methods by adding thrombin to freshly drawn arterial blood or by spontaneous coagulation. The mechanical properties of clots were determined in vitro by elasticity and plasticity tests. One hour after embolism, thrombolysis was started by intra-arterial application of recombinant tissue plasminogen activator (rtPA) (10 mg/kg). Treatment efficacy was monitored by MR measurements of blood perfusion, apparent diffusion coefficient (ADC), T2 relaxation time and blood-brain barrier permeability, and by pictorial measurements of ATP and pH. RESULTS: Thrombin-induced clots were classified as elastic, and spontaneously forming clots were classified as plastic. Middle cerebral artery embolism with thrombin-induced or spontaneously forming clots led to similar reduction of perfusion and ADC, but rtPA treatment efficacy differed greatly. In the spontaneously forming clot group, blood perfusion returned to or above control within 2 hours, ADC and ATP normalized, tissue pH exhibited alkalosis, and T2 and blood-brain barrier permeability did not change. In the thrombin-induced clot group, in contrast, blood reperfusion was delayed, ADC and ATP remained reduced, tissue pH was acidic, and edema developed, as reflected by increased T2 and blood-brain barrier permeability. CONCLUSIONS: rtPA-induced thrombolysis promotes rapid reperfusion and tissue recovery in animals embolized with spontaneously forming clots but not in those embolized with thrombin-induced clots. This difference is explained by the different mechanical and possibly molecular consequences of clot preparation and must be considered for the interpretation of thrombolysis experiments.

Adenosine Triphosphate↗