Microstructural and mechanical insight into atherosclerotic plaques: an ex vivo DTI study to better assess plaque vulnerability.

Non-invasive microstructural characterisation has the potential to determine the stability, or lack thereof, of atherosclerotic plaques and ultimately aid in better assessing plaques' risk to rupture. If linked with mechanical characterisation using a clinically relevant imaging technique, mechanically sensitive rupture risk indicators could be possible. This study aims to provide this link-between a clinically relevant imaging technique and mechanical characterisation within human atherosclerotic plaques. Ex vivo diffusion tensor imaging, mechanical testing, and histological analysis were carried out on human carotid atherosclerotic plaques. DTI-derived tractography was found to yield significant mechanical insight into the mechanical properties of more stable and more vulnerable microstructures. Coupled with insights from digital image correlation and histology, specific failure characteristics of different microstructural arrangements furthered this finding. More circumferentially uniform microstructures failed at higher stresses and strains when compared to samples which had multiple microstructures, like those seen in a plaque cap. The novel findings in this study motivate diagnostic measures which use non-invasive characterisation of the underlying microstructure of plaques to determine their vulnerability to rupture.

Diffusion tensor imaging and arterial tissue: establishing the influence of arterial tissue microstructure on fractional anisotropy, mean diffusivity and tractography.

This study investigates diffusion tensor imaging (DTI) for providing microstructural insight into changes in arterial tissue by exploring how cell, collagen and elastin content effect fractional anisotropy (FA), mean diffusivity (MD) and tractography. Five ex vivo porcine carotid artery models (n = 6 each) were compared-native, fixed native, collagen degraded, elastin degraded and decellularised. Vessels were imaged at 7 T using a DTI protocol with b = 0 and 800 s/mm2 and 10 isotopically distributed directions. FA and MD were evaluated in the vessel media and compared across models. FA values measured in native (p < 0.0001), fixed native (p < 0.0001) and collagen degraded (p = 0.0018, p = 0.0016, respectively) were significantly higher than those in elastin degraded and decellularised arteries. Native and fixed native had significantly lower MD values than elastin degraded (p < 0.0001) and decellularised tissue (p = 0.0032, p = 0.0003, respectively). Significantly lower MD was measured in collagen degraded compared with the elastin degraded model (p = 0.0001). Tractography yielded helically arranged tracts for native and collagen degraded vessels only. FA, MD and tractography were found to be highly sensitive to changes in the microstructural composition of arterial tissue, specifically pointing to cell, not collagen, content as the dominant source of the measured anisotropy in the vessel wall.

Investigation of the mechanisms mediating MDMA "Ecstasy"-induced increases in cerebro-cortical perfusion determined by btASL MRI.

RATIONALE: Acute administration of the recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has previously been shown to increase cerebro-cortical perfusion as determined by bolus-tracking arterial spin labelling (btASL) MRI. OBJECTIVES: The purpose of the current study was to assess the mechanisms mediating these changes following systemic administration of MDMA to rats. METHODS: Pharmacological manipulation of serotonergic, dopaminergic and nitrergic transmission was carried out to determine the mechanism of action of MDMA-induced increases in cortical perfusion using btASL MRI. RESULTS: Fenfluramine (10 mg/kg), like MDMA (20 mg/kg), increased cortical perfusion. Increased cortical perfusion was not obtained with the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodophenyl-aminopropane hydrochloride (DOI) (1 mg/kg). Depletion of central 5-HT following systemic administration of the tryptophan hydroxylase inhibitor para-chlorophenylalanine (pCPA) produced effects similar to those observed with MDMA. Pre-treatment with the 5-HT receptor antagonist metergoline (4 mg/kg) or with the 5-HT reuptake inhibitor citalopram (30 mg/kg), however, failed to produce any effect alone or influence the response to MDMA. Pre-treatment with the dopamine D1 receptor antagonist SCH 23390 (1 mg/kg) failed to influence the changes in cortical perfusion obtained with MDMA. Treatment with the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole (7-NI) (25 mg/kg) provoked no change in cerebral perfusion alone yet attenuated the MDMA-related increase in cortical perfusion. CONCLUSIONS: Cortical 5-HT depletion is associated with increases in perfusion although this mechanism alone does not account for MDMA-related changes. A role for NO, a key regulator of cerebrovascular perfusion, is implicated in MDMA-induced increases in cortical perfusion.

MDMA 'ecstasy' increases cerebral cortical perfusion determined by bolus-tracking arterial spin labelling (btASL) MRI.

BACKGROUND AND PURPOSE: The purpose of this study was to assess cerebral perfusion changes following systemic administration of the recreational drug 3,4-methylendioxymethamphetamine (MDMA 'ecstasy') to rats. EXPERIMENTAL APPROACH: Cerebral perfusion was quantified using bolus-tracking arterial spin labelling (btASL) MRI. Rats received MDMA (20 mg·kg(-1); i.p.) and were assessed 1, 3 or 24 h later. Rats received MDMA (5 or 20 mg·kg(-1); i.p.) and were assessed 3 h later. In addition, rats received MDMA (5 or 10 mg·kg(-1); i.p.) or saline four times daily over 2 consecutive days and were assessed 8 weeks later. Perfusion-weighted images were generated in a 7 tesla (7T) MRI scanner and experimental data was fitted to a quantitative model of cerebral perfusion to generate mean transit time (MTT), capillary transit time (CTT) and signal amplitude. KEY RESULTS: MDMA reduces MTT and CTT and increases amplitude in somatosensory and motor cortex 1 and 3 h following administration, indicative of an increase in perfusion. Prior exposure to MDMA provoked a long-term reduction in cortical 5-HT concentration, but did not produce a sustained effect on cerebral cortical perfusion. The response to acute MDMA challenge (20 mg·kg(-1); i.p.) was attenuated in these animals indicating adaptation in response to prior MDMA exposure. CONCLUSIONS AND IMPLICATIONS: MDMA provokes changes in cortical perfusion, which are quantifiable by btASL MRI, a neuroimaging tool with translational potential. Future studies are directed towards elucidation of the mechanisms involved and correlating changes in cerebrovascular function with potential behavioural deficits associated with drug use.

Schizophrenia-related endophenotypes in heterozygous neuregulin-1 'knockout' mice.

Neuregulin-1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N-methyl-D-aspartate receptor antagonists MK-801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK-801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N-acetylaspartate and GABA were determined using high-performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor-activating effects of acute PCP. Subchronic MK-801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance-related behaviours observed in vehicle-treated mutants. No phenotypic differences were demonstrated in N-acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia-relevant processes including the effects of psychotomimetic N-methyl-D-aspartate receptor antagonists.

Bolus-tracking arterial spin labelling: theoretical and experimental results.

Arterial spin labelling (ASL) is a magnetic resonance imaging (MRI) technique that can be used to provide a quantitative assessment of cerebral perfusion. Despite the development of a number of theoretical models to facilitate quantitative ASL, some key challenges still remain. The purpose of this study is to develop a novel quantitative ASL method based on a macroscopic model that reduces the number of variables required to describe the physiological processes involved. To this end, a novel Fokker-Planck equation consisting of stochastically varying macroscopic variables was derived from a general Langevin equation. ASL data from the rat brain was acquired using a bolus-tracking ASL protocol where a bolus of labelled spins flowing from an inversion plane in the neck into an imaging plane in the brain can be observed. Bolus durations of 1.5 s, 2.0 s and 3.0 s were used and the solution to the Fokker-Planck equation for the boundary conditions of bolus-tracking ASL was fitted to the experimental data using a least-squares fit. The mean transit time (MTT) and capillary transit time (CTT) were calculated from the first and second moments of the resultant curve respectively and the arterial transit time (ATT) was calculated by subtracting the CTT from the MTT. The average MTT, CTT and ATT values were 1.75 +/- 0.22 s, 1.43 +/- 0.12 s and 0.32 +/- 0.04 s respectively. In conclusion, a new ASL protocol has been developed by combining the theoretical model with ASL experiments. The technique has the unique ability to provide solutions for varying bolus volumes and the generality of the new model is demonstrated by the derivation of additional solutions for the continuous and pulsed ASL (CASL and PASL) techniques.

Perfusion and diffusion magnetic resonance imaging in human cerebral venous thrombosis.

BACKGROUND: Diagnosis of cerebral venous thrombosis (CVT) is usually achieved by digital subtraction angiography or magnetic resonance angiography, while structural brain tissue damage can be assessed by computed tomography or magnetic resonance imaging (MRI). Using perfusion and diffusion weighted imaging (PWI, DWI) we aimed in this study to identify pathophysiological patterns corresponding to only functional and hence reversible tissue involvement. METHODS: PWI, DWI, and conventional MRI were performed in six CVT patients acutely and after 16-26 days when their clinical condition had improved. All patients were treated with partial thromboplastin time-effective intravenous heparin. After intravenous administration of a paramagnetic contrast agent, bolus track PWI allows pixel based determination of mean transit time (MTT) and cerebral blood volume (CBV). DWI was performed with two different b values (0, 1000 s/mm2) for calculation of apparent diffusion coefficient (ADC) maps. RESULTS: In five of six cases increased MTT values were observed initially, whereas the CBV was normal, indicating a reduction of cerebral blood flow. ADC values were normal. On follow up after clinical recovery MTT prolongations had resolved. Areas with prolonged MTT did not evolve into structural lesions. CONCLUSION: In patients with CVT, prolongations of MTT in the absence of changes in CBV and ADC seem to indicate reversible involvement of brain tissue, a situation corresponding to the ischaemic penumbra.

MRI of small human stroke shows reversible diffusion changes in subcortical gray matter.

Six patients who had suffered small cerebral ischemia affecting subcortical gray matter were examined with diffusion weighted imaging (DWI) and T2-weighted imaging within the first 8 h, during the next 2 days and after 5-16 days. Areas of apparent diffusion coefficient (ADC) decreases were observed acutely and reached the maximum size during the subsequent 2 days. Noticeably, in all subjects, a large portion of the ADC lesion was reversible as judged from the lesion size on final T2 image. The regular reversibility of the ADC decreases in this setting may indicate a hitherto not understood pathophysiological process occurring in small ischemic stroke.

Recovery of the rodent brain after cardiac arrest: a functional MRI study.

Recovery of the cerebral cortex after 10 min of cardiac arrest was studied in rat using noninvasive MRI techniques. The apparent diffusion coefficient (ADC) of brain water was imaged to document reversal of the metabolic impairment. Perfusion-weighted imaging and blood oxygen level dependent (BOLD) imaging were performed to assess functional recovery. To this purpose, rats were anesthetized with alpha-chloralose, and somatosensory cortex was activated by electrical stimulation of the contralateral forepaw. In sham-operated controls, cortical ADC was 862 +/- 10 microm2/s, and stimulation of forepaw led to a focal increase of signal intensity in somatosensory cortex by 71 +/- 22% in perfusion-weighted images and by 6 +/- 1% in BOLD images. One hour after successful resuscitation following 10 min of cardiac arrest, ADC did not differ from control but functional activation was completely suppressed. After 3 hours of reperfusion, functional activity began to reappear but the recovery of the BOLD signal progressed faster than that of the perfusion-weighted signal. The differences in the recovery of ADC, BOLD, and perfusion imaging are related to differences between metabolic and functional recovery on one hand and between blood flow and oxygen extraction on the other. The combination of these MRI methods thus provides detailed qualitative information about the progression of brain recovery after transient circulatory arrest.

Reperfusion after thrombolytic therapy of embolic stroke in the rat: magnetic resonance and biochemical imaging.

The effect of thrombolytic therapy was studied in rats submitted to thromboembolic stroke by intracarotid injection of autologous blood clots. Thrombolysis was initiated after 15 minutes with an intracarotid infusion of recombinant tissue-type activator (10 mg/kg body weight). Reperfusion was monitored for 3 hours using serial perfusion- and diffusion magnetic resonance imaging, and the outcome of treatment was quantified by pictorial measurements of ATP, tissue pH, and blood flow. In untreated animals, clot embolism resulted in an immediate decrease in blood flow and a sharp decrease in the apparent diffusion coefficient (ADC) that persisted throughout the observation period. Thrombolysis successfully recanalized the embolized middle cerebral artery origin and led to gradual improvement of blood flow and a slowly progressing reversal of ADC changes in the periphery of the ischemic territory, but only to transient and partial improvement in the center. Three hours after initiation of thrombolysis, the tissue volume with ADC values less than 80% of control was 39 +/- 22% as compared to 61 +/- 20% of ipsilateral hemisphere in untreated animals (means +/- SD, P = .03) and the volume of ATP-depleted brain tissue was 25 +/- 31% as compared to 46 +/- 29% in untreated animals. Recovery of ischemic brain injury after thromboembolism is incomplete even when therapy is started as early as 15 minutes after clot embolism. Possible explanations for our findings include downstream displacement of clot material, microembolism of the vascular periphery, and events associated with reperfusion injury.

Functional MRI of somatosensory activation in rat: effect of hypercapnic up-regulation on perfusion- and BOLD-imaging.

Functional activation of somatosensory cortex was studied in alpha-chloralose anesthetized rats by functional magnetic resonance imaging (fMRI), using both perfusion-weighted and T2*-weighted (blood oxygenation level dependent, BOLD) imaging. The sensitivity of functional activation was altered by ventilating animals for 3 minutes with 6% CO2. Before hypercapnic conditioning, electrical stimulation of the left forepaw at a frequency of 3 Hz led to an increase of signal intensity (relative to the unstimulated baseline condition) in the right somatosensory cortex by 6+/-2% (means+/-SD) in T2*-weighted images and by 45%+/-48% in perfusion-weighted images. After hypercapnic conditioning the signal intensity increase in perfusion-weighted images doubled to 91%+/-62% (P=0.034), whereas that of T2*-weighted images only marginally increased to 7+/-4% (not significant). This different behavior in both imaging modalities is interpreted as evidence for an increased flow response in combination with a higher oxygen extraction. Thus, the fMRI data reflect hypercapnia-induced resetting of the functional-metabolic coupling of the tissue during activation.

Ultrafast perfusion-weighted MRI of functional brain activation in rats during forepaw stimulation: comparison with T2 -weighted MRI.

A fast version of the arterial spin tagging technique for the detection of cerebral perfusion is presented. Based on adiabatic spin inversion in combination with snapshot FLASH imaging, our technique allows the recording of perfusion changes with a temporal resolution of about 3 s. Differences of cerebral perfusion dependent on the choice of anesthesia were observed in rat brain. Furthermore, with this arterial spin tagging method we demonstrated perfusion increases in the somatosensory cortex of anaesthetized rats during forepaw stimulation. Comparison of the activated areas in the T2 -weighted BOLD images and the perfusion-weighted images showed good spatial correspondence, but the sensitivity to the functional activation was more than ten times higher in the perfusion technique.