Diffusion kurtosis imaging probes cortical alterations and white matter pathology following cuprizone induced demyelination and spontaneous remyelination.

Although MRI is the gold standard for the diagnosis and monitoring of multiple sclerosis (MS), current conventional MRI techniques often fail to detect cortical alterations and provide little information about gliosis, axonal damage and myelin status of lesioned areas. Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) provide sensitive and complementary measures of the neural tissue microstructure. Additionally, specific white matter tract integrity (WMTI) metrics modelling the diffusion in white matter were recently derived. In the current study we used the well-characterized cuprizone mouse model of central nervous system demyelination to assess the temporal evolution of diffusion tensor (DT), diffusion kurtosis tensor (DK) and WMTI-derived metrics following acute inflammatory demyelination and spontaneous remyelination. While DT-derived metrics were unable to detect cuprizone induced cortical alterations, the mean kurtosis (MK) and radial kurtosis (RK) were found decreased under cuprizone administration, as compared to age-matched controls, in both the motor and somatosensory cortices. The MK remained decreased in the motor cortices at the end of the recovery period, reflecting long lasting impairment of myelination. In white matter, DT, DK and WMTI-derived metrics enabled the detection of cuprizone induced changes differentially according to the stage and the severity of the lesion. More specifically, the MK, the RK and the axonal water fraction (AWF) were the most sensitive for the detection of cuprizone induced changes in the genu of the corpus callosum, a region less affected by cuprizone administration. Additionally, microgliosis was associated with an increase of MK and RK during the acute inflammatory demyelination phase. In regions undergoing severe demyelination, namely the body and splenium of the corpus callosum, DT-derived metrics, notably the mean diffusion (MD) and radial diffusion (RD), were among the best discriminators between cuprizone and control groups, hence highlighting their ability to detect both acute and long lasting changes. Interestingly, WMTI-derived metrics showed the aptitude to distinguish between the different stages of the disease. Both the intra-axonal diffusivity (Da) and the AWF were found to be decreased in the cuprizone treated group, Da specifically decreased during the acute inflammatory demyelinating phase whereas the AWF decrease was associated to the spontaneous remyelination and the recovery period. Altogether our results demonstrate that DKI is sensitive to alterations of cortical areas and provides, along with WMTI metrics, information that is complementary to DT-derived metrics for the characterization of demyelination in both white and grey matter and subsequent inflammatory processes associated with a demyelinating event.

Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI.

BACKGROUND: An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI. METHODS: Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented. RESULTS: Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra-structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs. CONCLUSION: Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra-structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease-modifying treatments for schizophrenia.

Neuroanatomical targets of reboxetine and bupropion as revealed by pharmacological magnetic resonance imaging.

RATIONALE: One of the key targets of psychopharmacology research is to determine the potential sites of action of antidepressants in order to characterise their underlying mechanism of action. OBJECTIVE: Using blood oxygenation level-dependent (BOLD) pharmacological magnetic resonance imaging (phMRI), the neuroanatomical target-sites of reboxetine (a selective noradrenaline reuptake inhibitor) and bupropion (an antidepressant with stimulatory effects on dopamine and potentially on noradrenaline) were mapped. METHODS: Separate groups of rats were challenged acutely or chronically (daily injections for 14 days) with saline or psychoactive compounds and scanned. Subsequent statistical parametric mapping of the main effects of the drug was performed by identifying changes in the BOLD signal. RESULTS: Acute reboxetine challenge at a low dose (10 mg/kg i.p.) produced positive BOLD responses specifically in the hypothalamus, whereas a larger dose (30 mg/kg i.p.) produced activations in the hypothalamus, anterior hippocampus and prefrontal cortex. Chronic reboxetine (30 mg/kg i.p.) treatment induced increased BOLD responses in the posterior hippocampus and prefrontal cortex, while no significant contrast changes were observed in the hypothalamus and a significant decrease was apparent in the amygdala. In contrast, acute bupropion (15 and 30 mg/kg i.p.) challenge in both doses produced no significant contrast changes in the regions of interest. However, chronic bupropion treatment (30 mg/kg i.p.) produced robust increases in BOLD responses in the hippocampus, amygdala and prefrontal cortex. CONCLUSION: In summary, this study demonstrates that reboxetine and bupropion evoke a significant increase in BOLD functional activity in specific regions of the brain, including the hypothalamus, hippocampus, prefrontal cortex and amygdala. Furthermore, the study illustrates the potential value of pharmacological MRI in rodents to delineate pharmacologically induced changes in regional brain function.

Neuroadaptive responses to citalopram in rats using pharmacological magnetic resonance imaging.

RATIONALE: The majority of psychoactive compounds, including antidepressants in clinical practice, were discovered largely by serendipity. The underlying neuropharmacological mechanisms of action of these compounds leading to resolution of depressive symptomatology are targets of the current research. Pharmacological magnetic resonance imaging (phMRI), a rapidly developing advancement of blood oxygenation level dependent (BOLD) contrast offers the potential to localize the regional sites of action in the CNS. OBJECTIVE: Acute and chronic effects of the clinically effective selective serotonin reuptake inhibitor (SSRI) citalopram were examined for changes in BOLD contrast using phMRI in rats. To pharmacologically characterize the specific involvement of the 5-HT(1A) receptors, citalopram was co-administered with a highly selective 5-HT(1A) receptor antagonist WAY100635. RESULTS: Acute citalopram treatment (10 and 20 mg/kg i.p.) produced a widespread and dose-dependent activation throughout the whole brain. Following 14 days of chronic daily administration of citalopram (20 mg/kg i.p.), localized effects were observed; regions integral in the therapeutic antidepressant effects included the hypothalamus, hippocampus, and cortical regions, suggesting desensitization of serotonergic receptors in the midbrain contributing to elevated levels of 5-HT. Co-administration with WAY100635 (0.3 mg/kg s.c.) increased BOLD activation in the frontal cortex and decreased BOLD contrast in the hypothalamus, hippocampus, and hindbrain structures. CONCLUSION: The present findings highlight the adaptive nature of responses to citalopram which exhibits regional and pharmacological specificity. These findings translate well to the clinical findings and suggest that this approach may offer the opportunity to develop more efficacious antidepressants with a faster clinical response.

Measuring brain hemodynamic changes in a songbird: responses to hypercapnia measured with functional MRI and near-infrared spectroscopy.

Songbirds have been evolved into models of choice for the study of the cerebral underpinnings of vocal communication. Nevertheless, there is still a need for in vivo methods allowing the real-time monitoring of brain activity. Functional Magnetic Resonance Imaging (fMRI) has been applied in anesthetized intact songbirds. It relies on blood oxygen level-dependent (BOLD) contrast revealing hemodynamic changes. Non-invasive near-infrared spectroscopy (NIRS) is based on the weak absorption of near-infrared light by biological tissues. Time-resolved femtosecond white laser NIRS is a new probing method using real-time spectral measurements which give access to the local variation of absorbing chromophores such as hemoglobins. In this study, we test the efficiency of our time-resolved NIRS device in monitoring physiological hemodynamic brain responses in a songbird, the zebra finch (Taeniopygia guttata), using a hypercapnia event (7% inhaled CO(2)). The results are compared to those obtained using BOLD fMRI. The NIRS measurements clearly demonstrate that during hypercapnia the blood oxygen saturation level increases (increase in local concentration of oxyhemoglobin, decrease in deoxyhemoglobin concentration and total hemoglobin concentration). Our results provide the first correlation in songbirds of the variations in total hemoglobin and oxygen saturation level obtained from NIRS with local BOLD signal variations.

Reduction of ECG and gradient related artifacts in simultaneously recorded human EEG/MRI data.

Nowadays, electroencephalography signals can be acquired from a patient lying in a magnetic resonance imaging system. It is even possible to acquire EEG signals during an MR imaging sequence. However, such EEG signals are severely distorted by artifacts originating from various effects (e.g., MR gradients, ECG). In this paper, a simple method is presented to reduce such artifacts. Thereby, special attention is focused on artifacts related to the patient's electrocardiogram. The method is shown to be effective, adaptive, and automatic.

Restoration of MR-induced artifacts in simultaneously recorded MR/EEG data.

During a Magnetic Resonance sequence, simultaneously acquired ElectroEncephaloGraphy (EEG) data are compromised by severe pollution due to artifacts originating from the switching of the magnetic field gradients. In this work, it is shown how these artifacts can be strongly reduced or even removed through application of an adaptive artifact restoration scheme. The method has proved to be fully automatic and to retain high frequency EEG information, which is indispensable for many EEG applications.

Imaging birds in a bird cage: in-vivo FSE 3D MRI of bird brain.

An in-vivo magnetic resonance imaging (MRI) procedure is described that allows one to obtain three-dimensional high quality images of the entire brain of small birds such as the canary (20 g) and the starling (75 g) with an image resolution of 0.1 mm (58-113 microm, dependent on the size of the imaged bird). The entire imaging procedure took about 2 h after which the birds recovered from anaesthesia uneventfully and could be reused for subsequent additional imaging. This non invasive MRI technique enables to correlate brain measures with behavioural or physiological data that are dynamic in nature and could permit significant progress for bird neurological research.

Estimation of the noise in magnitude MR images.

Magnitude magnetic resonance data are Rician distributed. In this note a new method is proposed to estimate the image noise variance for this type of data distribution. The method is based on a double image acquisition, thereby exploiting the knowledge of the Rice distribution moments.

Water household of the common carp, Cyprinus carpio, when submitted to an osmotic challenge, as determined by diffusion-weighted magnetic resonance imaging at 7 T.

In vivo diffusion-weighted magnetic resonance imaging (MRI) was used to determine the effects of an osmotic challenge (1% NaCl) to a freshwater fish, the common carp (Cyprinus carpio). The imaged region covered organs such as the swimbladder, the liver, the kidney, the intestine, the spinal cord, and muscle tissue. A striking difference between salt-treated and control fish was found in the liver. The apparent diffusion coefficient value of livers from control fish was (0.39 +/- 0.16) 10(-9) m2/s and of salt-treated fish was (1.23 +/- 0.14) 10(-9) m2/s, which points to an increase in extracellular water content. These results were partially confirmed by a decrease in dry/wet weight ratio of the liver tissue. We also found increased levels of stress proteins in liver tissue. The Q factor of the applied radiofrequency coil dropped dramatically when we performed experiments with salt-exposed fish, indicating an increased conductivity resulting from the increased ion concentration and osmolarity of the fish. The data on plasma osmolarity of salt-exposed fish confirm a significant osmolarity increase upon salt exposure (from 334 to 430 mOsm/kg) and exceeded the osmolarity of the salt water (324 mOsm/kg), indicating that carp tend to cope with an increased salinity by increasing the internal osmolarity (hyperosmotic regulation). These data demonstrate that diffusion-weighted MRI might be a useful and noninvasive tool in the study of osmotic challenges of aquatic organisms.

High resolution magnetic resonance imaging application in anatomy: the extensor digitorum muscle insertion on the first phalanx.

Classical dissection may give unsatisfactory results because of the presence of artifacts due to both the embalming process and displacement of the anatomical structures. This spatial disturbance could explain the divergent descriptions found in the literature about the presence, or the absence, of an insertion of the extensor digitorum muscle (ED) at the first phalanx (P1). Preliminary experiments by Van Sint Jan et al. (1996) found the same contradiction: dissections did not show a real tendon attachment, whereas a functional experiment seemed to show that "something" should exist between ED and P1 to explain the results. This paper presents the results of an in vitro MRI study of this anatomical area. A 7-T NMR microscope was used to collect accurate, noninvasive data. Subsequently, surface rendering was performed to visualize the structures in a three-dimensional manner. The results of this MRI study, together with functional data obtained in an earlier study, showed that no real insertion of ED on P1 exists. However, some collagenic fibers were occasionally-observed running from the ventral aspect of ED to both P1 and the metacarpo-phalangeal joint capsule. Those few collagenic fibers would play a secondary role in the extension of P1.

The insertion of the extensor digitorum tendon on the proximal phalanx.

Review of the literature reveals that the relationship between the extensor digitorum muscle tendon to the proximal phalanx and the metacarpophalangeal joint capsule remains unclear. The present study presents data about these relationships and consists of three parts: dissection of the region, high-gradient magnetic resonance imaging, and functional study. A total of 50 hands were used. Dissection was performed on 30, magnetic resonance studies were performed on 10, and the remaining 10 hands were used for the functional analysis. Dissection did not reveal an insertion of the extensor digitorum tendon on the base of the proximal phalanx. An extension of the dorsal part of the metacarpophalangeal joint capsule running proximally toward the palmar side of the extensor tendon was observed in eight hands. In the remaining 22 hands, only loose connective tissue was found between the articular capsule and the tendon. The development of this tissue was variable. These observations were correlated using a 7T magnetic resonance installation. The results of the functional study showed that hyperextension of the proximal phalanx increased after resection of the metacarpophalangeal structures lying under the extensor tendon. In conclusion, no real tendinous insertion of the extensor digitorum tendon on the base of the proximal phalanx could be found. Loose connective tissue was observed between the metacarpophalangeal joint capsule and the palmar aspect of the tendon, which seemed to play a secondary role in the extension of the proximal phalanx.

Complementary use of T2-weighted and postcontrast T1- and T2*-weighted imaging to distinguish sites of reversible and irreversible brain damage in focal ischemic lesions in the rat brain.

The evolution of a photochemically induced cortical infarct was monitored using T2-, postcontrast (GdDOTA) T1-, and postcontrast (DyDTPA-BMA) T2*-weighted NMR imaging techniques. Data acquired with these different NMR imaging types were compared, both qualitatively and quantitatively. The T2*-weighted NMR images after spordiamide injection (DyDTPA-BMA) were perfusion-weighted images that allowed the differentiation between several infarct-related areas in terms of different degrees of perfusion deficiency. No quantitative information on cerebral blood flow (CBF) was obtained. A clear distinction was made between areas with a complete lack of CBF located in the core of the lesion and temporary CBF insufficiencies in the rim surrounding this core. Concomitant observations on T2-weighted and postcontrast T1-weighted images revealed the same temporary rim characterized by an increased water content, and an intact blood-brain barrier (BBB), as well as by reduced perfusion. This rim appeared within the first hours after infarct induction, reached a maximum 24 h later, and lasted between 3-5 days, when its size gradually decreased until complete disappearance. These observations suggest the existence of an area at risk. Only on postcontrast T1-weighted images, the core of the lesion remained visible during the whole experimental period (10 days) and reflected in all likelihood the irreversibly damaged ischemic central core. The combined application of different NMR imaging techniques when studying focal cerebral infarctions in the rat brain allowed us to distinguish, in terms of NMR characteristics, zones of reversible from irreversible brain damage and to estimate the severity of the damage. This might offer an appropriate experimental setup for the screening of cerebroprotective compounds.

Complementary use of T2- and postcontrast T1-weighted NMR images for the sequential monitoring of focal ischemic lesions in the rat brain.

The noninvasive nature of NMR imaging enables serial studies on a single animal. In 12 male Wistar rats, the dynamic progression of a photochemically induced (Rose Bengal) infarct was studied starting immediately after induction and up to 10 days. The results demonstrated that both T2- and postcontrast T1-weighted NMR images are required to discern the time dependent dynamics of the ischemic process. The ischemic lesion was already visible on T2-weighted images within 30 min after the induction. Twenty-four hours after the insult, both area and intensity reached maximum values. Hereafter and up to day 10, both parameters decreased. Postcontrast T1- weighted images revealed a blood-brain barrier (BBB) rupture immediately after the induction which persisted until 10 days after the insult. The application of contrast agents such as Gd-DOTA or Gd-HP-DO3A also allowed the detection of 10-day-old lesions which were not always discernable on T2-weighted images. The penetration of both contrast agents in the affected area proceeded slower the first 5 days after the insult while at day 10, maximum contrast enhancement was reached almost immediately after administration of the contrast agent. At 24 hr after the insult, the discrepancy between the lesion area as determined on T2-weighted images and on postcontrast T1-weighted images was maximal. At this stage, the lesion was characterized by central core with a leaky BBB surrounded by a reversible zone which appeared enhanced on T2-weighted images.