Magnetic resonance imaging of the middle and inner ear after intratympanic injection of a gadolinium-containing gel.

OBJECTIVE: To investigate the distribution and elimination of a gadolinium containing high viscosity formulation of sodium hyaluronan (HYA gel) after injection to the middle ear. MATERIALS AND METHODS: The T1 contrast agent gadolinium-diethylenetriamine pentaacetic acid-bis methylamine (Gd-DTPA-BMA) was added to HYA gel and delivered to the middle ear of 13 albino guinea pigs by 3 different ways of injection. Magnetic resonance imaging was performed with a 4.7 T MRI system using a T1-weighted 3-dimentional rapid acquisition with relaxation enhancement sequence. RESULTS: An injection technique where the Gd-DTPA-BMA-containing HYA gel was delivered to the middle ear through a percutaneous injection through the auditory bulla after a small incision had been made in the tympanic membrane gave the best filling of the middle ear, covering the cochlea and the region of the round window niche for 24 hours in a majority of the ears studied. Ears injected without an incision in the tympanic membrane showed an immediate uptake of Gd-DTPA-BMA in the inner ear as a sign of rupture of the round window membrane. CONCLUSION: A percutaneous injection of a HYA gel into the tympanic bulla is distributed in a predictable way and gives a good filling of the middle ear cavity. The HYA gel remains in close vicinity to the RWM for more than 24 hours. Injection should be performed after an incision of the tympanic membrane has been made to prevent rupture of the round window membrane.

MRI evidence of endolymphatic impermeability to the gadolinium molecule in the in vivo mouse inner ear at 9.4 tesla.

OBJECTIVE: Previous in vivo experimental magnetic resonance imaging (MRI) investigations of the mammalian inner ear at 4.7 Tesla have indicated that intravenously injected gadolinium (Gd) penetrates the perilymphatic labyrinth, but not the endolymphatic membranous labyrinth. In the present study, high field MRI at 9.4T was used to visualize the in vivo mouse vestibulo-cochlea system, and to determine whether the endolymphatic system is permeable to a Gd complex. METHODS: A 9.4 T Varian magnet equipped with a 12 cm inner diameter gradient system with maximum gradient strength of 600 mT/m, a millipede coil (Varian design) and a Gd contrast agent were used for image acquisition in the normal C57 BL-6 mouse. RESULTS: High-resolution 2D and 3D images of the mouse cochlea were acquired within 80 minutes following intravenous injection of Gd. Gd initially permeated the perilymphatic scala tympani and scala vestibuli, and permitted visualization of both cochlear turns from base to apex. The superior, inferior and lateral semicircular canals were subsequently visualized in 3 planes. The membranous endolymphatic labyrinth was impermeable to intravenously injected Gd, and thus showed no apparent uptake of Gd at 9.4T. CONCLUSION: The 9.4T field strength MRI permitted acquisition of high resolution images of anatomical and physiological features of the normal, wild type mouse perilymphatic inner ear in vivo, and provided further evidence that the endolymphatic system is impermeable to intravenously injected Gd.

Decreased axonal transport rates in the Tg2576 APP transgenic mouse: improvement with the gamma-secretase inhibitor MRK-560 as detected by manganese-enhanced MRI.

Neuropil deposition of beta-amyloid (Aß) peptides is believed to be a key event in the neurodegenerative process of Alzheimer's disease (AD). An early and consistent clinical finding in AD is olfactory dysfunction with associated pathology. Interestingly, transgenic amyloid precursor protein (Tg2576) mice also show early amyloid pathology in olfactory regions. Moreover, a recent study indicates that axonal transport is compromised in the olfactory system of Tg2576 mice, as measured by manganese-enhanced magnetic resonance imaging (MEMRI). Here we tested whether the putative axonal transport deficit in the Tg2576 mouse model improves in response to a selective gamma-secretase inhibitor, N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560). Tg2576 mice or wild-type (WT) littermates were treated daily with MRK-560 (30 µmol/kg) or vehicle for 4 (acute) or 29 days (chronic). The subsequent MEMRI analysis revealed a distinct axonal transport dysfunction in the Tg2576 mice compared with its littermate controls. Interestingly, the impairment of axonal transport could be fully reversed by chronic administration of MRK-560, in line with the significantly lowered levels of both soluble and insoluble forms of Aß found in the brain and olfactory bulbs (OBs) following treatment. However, no improvement of axonal transport was observed after acute treatment with MRK-560, where soluble but not insoluble forms of Aß were reduced in the brain and OBs. The present results show that axonal transport is impaired in Tg2576 mice compared with WT controls, as measured by MEMRI. Chronic treatment in vivo with a gamma-secretase inhibitor, MRK-560, significantly reduces soluble and insoluble forms of Aß, and fully reverses the axonal transport dysfunction.

Age related changes in brain metabolites observed by 1H MRS in APP/PS1 mice.

Translational biomarkers in Alzheimer's disease based on non-invasive in vivo methods are highly warranted. (1)H magnetic resonance spectroscopy (MRS) is non-invasive and applicable in vivo in both humans and experimental animals. In vivo(1)H MRS and 3D MRI were performed on brains of double transgenic (tg) mice expressing a double mutant human beta-amyloid precursor protein APP(K670N,M671L) and human mutated presenilin gene PS1M146L, and wild-type (wt) littermates at 2.5, 6.5 and 9 months of age using a 9.4T magnet. For quantification, LCModel was used, and the data were analyzed using multivariate data analysis (MVDA). MVDA evidenced a significant separation, which became more pronounced with age, between tg and wt mice at all time points. While myo-inositol and guanidoacetate were important for group separation in young mice, N-acetylaspartate, glutamate and macrolipids were important for separation of aged tg and wt mice. Volume segmentation revealed that brain and hippocampus were readily smaller in tg as compared to wt mice at the age of 2.5 months. Amyloid plaques were seen in 6.5 and 9 months, but not in 2.5 months old animals. In conclusion, differences in brain metabolites could be accurately depicted in tg and wt mice in vivo by combining MRS with MVDA. First differences in metabolite content were readily seen at 2.5 months, when volume defects in tg mice were present, but no amyloid plaques.

Carbamazepine protects against megencephaly and abnormal expression of BDNF and Nogo signaling components in the mceph/mceph mouse.

Carbamazepine (CBZ) is a commonly used antiepileptic drug known to block voltage-gated sodium channels. Infants exposed to CBZ in utero show reduced head circumference, for reasons unknown. We investigated CBZ's effect on neural growth in megencephaly (mceph/mceph) mice lacking functional Kv1.1. Mice fed with CBZ were assessed for brain structure size, seizure behavior and expression of markers for neuronal plasticity and rescue in brain. CBZ counteracted brain overgrowth and the increased size of neurons in the mceph/mceph mouse. These effects of CBZ occurred at doses that did not fully suppress epileptic behavior. Furthermore, CBZ normalized Bdnf mRNA levels and mRNA species encoding Nogo signaling pathway proteins. In conclusion, CBZ protects efficiently against abnormal growth and abnormal expression patterns of nerve growth signaling systems in the mceph/mceph brain. These observations and the effect of CBZ in utero suggest that CBZ treatment might be advantageous in some types of human idiopathic megalencephaly.

Proton magnetic resonance spectroscopy in neuroblastoma: current status, prospects and limitations.

Non-invasive biological information about residual neuroblastoma tumour tissue could allow treatment monitoring without the need for repeated biopsies. Magnetic resonance spectroscopy (MRS) can be performed with standard MR-scanners, providing specific biochemical information from selected tumour regions. By proton 1H-MRS, lipids, certain amino acids and lactate can be detected and their relative concentrations estimated in vivo. Using experimental models of neuroblastoma, we have described the potential of 1H-MRS for the prediction of tumour tissue viability and treatment response. Whereas viable neuroblastoma tissue is dominated by the choline 1H-MRS resonance, cell death as a consequence of spontaneous necrosis or successful treatment with chemotherapy, angiogenesis inhibitors, or NSAIDs is associated with decreased choline content. Therapy-induced neuroblastoma cell death is also associated with enhanced 1H-MRS resonances from mobile lipids and polyunsaturated fatty acids. The mobile lipid/choline ratio correlates significantly with cell death and based on the dynamics of this ratio tumour regression or continued growth (drug resistance) after chemotherapy can be predicted in vivo. The implications of these findings are discussed with focus on the potentials and limitations of introducing 1H-MRS for clinical assessment of treatment response in children with neuroblastoma. Biochemical monitoring of neuroblastoma with 1H-MRS could enable tailoring of individual therapy as well as provide early pharmacodynamic evaluation of novel therapeutic modalities.

Imaging of the guinea pig cochlea following round window gadolinium application.

Precise, non-invasive determination of the aetiology and site of pathology of inner ear disorders is difficult. The aim of this study was to describe an alternative method for inner ear visualization, based on local application of the paramagnetic contrast agent gadolinium. Using a 4.7 T MRI scanner, high contrast images of all four cochlear turns were obtained 3.5 h after placing gadolinium on the round window membrane. Gadolinium cleared from the cochlea within 96 h. Auditory brainstem response measurements performed on a separate group of animals showed no significant threshold shifts after the application, indicating that gadolinium is non-toxic to the guinea pig cochlea.

Numb rats walk - a behavioural and fMRI comparison of mild and moderate spinal cord injury.

Assessment of sensory function serves as a sensitive measure for predicting the functional outcome following spinal cord injury in patients. However, little is known about loss and recovery of sensory function in rodent spinal cord injury models as most tests of sensory functions rely on behaviour and thus motor function. We used functional magnetic resonance imaging (fMRI) to investigate cortical and thalamic BOLD-signal changes in response to limb stimulation following mild or moderate thoracic spinal cord weight drop injury in Sprague-Dawley rats. While there was recovery of close to normal hindlimb motor function as determined by open field locomotor testing following both degrees of injury, recovery of hindlimb sensory function as determined by fMRI and hot plate testing was only seen following mild injury and not following moderate injury. Thus, moderate injury can lead to near normal hindlimb motor function in animals with major sensory deficits. Recovered fMRI signals following mild injury had a partly altered cortical distribution engaging also ipsilateral somatosensory cortex and the cingulate gyrus. Importantly, thoracic spinal cord injury also affected sensory representation of the upper nonaffected limbs. Thus, cortical and thalamic activation in response to forelimb stimulation was significantly increased 16 weeks after spinal cord injury compared to control animals. We conclude that both forelimb and hindlimb cortical sensory representation is altered following thoracic spinal cord injury. Furthermore tests of sensory function that are independent of motor behaviour are needed in rodent spinal cord injury research.

In vivo observation of dynamic perilymph formation using 4.7 T MRI with gadolinium as a tracer.

OBJECTIVE: To investigate the pharmacokinetics of gadolinium in the perilymphatic fluid spaces of the cochlea in vivo using high-resolution MRI to obtain information concerning perilymph formation. MATERIAL AND METHODS: A Bruker Biospec Avance 47/40 experimental MRI system with a magnetic field strength of 4.7 T was used. Anesthetized pigmented guinea pigs were injected with the contrast agent Gd-diethylenetriaminepentaacetic acid-bismethylamide and placed in the magnet. The signal intensity of Gd in the tissues was used as a biomarker for dynamic changes in the perilymphatic fluid. RESULTS: The most rapid uptake of Gd in the perilymphatic fluid spaces occurred in the lower part of the modiolus, followed by the second turn of the scala tympani. Within the scala tympani, the distribution of Gd in the basal turn was significantly lower than that in the other turns. Destruction of the cochlear aqueduct was followed by an increase in Gd uptake in the perilymph instead of a reduction. CONCLUSIONS: These findings offer further evidence that the pervasive perilymphatic fluid derives from the cochlear blood supply via the cochlear glomeruli, which are in close proximity to the scala tympani within the modiolus, and the capillary in the spiral ligament. Cerebrospinal fluid communicates with perilymph via the cochlear aqueduct but is not the main source of perilymph. These findings are of relevance to the treatment of inner ear diseases, as well as to our understanding of the flow and source of perilymphatic fluid.

3D MRI of the in vivo vestibulo-cochlea labyrinth during Gd-DTPA-BMA uptake.

The morphology, time-course and volume of the in vivo uptake of the T1 contrast agent gadolinium (Gd) in the perilymphatic vestibulo-cochlea labyrinth, including the utricle, saccule, semicircular canals and scalae of the guinea pig inner ear were analyzed as Fourier transform signal intensity enhancement levels by 3D MRI at 4.7 T. The uptake of Gd as a function of time in the perilymphatic space of the vestibular labyrinth was shown by ANOVA and PLSD post hoc tests to be significantly less (p < 0.05) than that of the scala tympani of the cochlea 10, 30, 60 and 90 min after i.v. injection. Experimentally induced fistulae resulted in MRI detected morphological and quantitative alterations in Gd concentration in the perilymphatic labyrinthine space. The findings demonstrate that Gd-enhanced 3D MRI of the perilymphatic space may be used to examine the morphology, kinetics and intravenous substance delivery in the in vivo mammalian vestibulo-cochlea labyrinth.

In vivo visualization of endolymphatic hydrops in guinea pigs: magnetic resonance imaging evaluation at 4.7 tesla.

In order to find out whether it is possible to visualize experimental endolymphatic hydrops in the cochlea with magnetic resonance imaging (MRI) at 4.7 T, we used 11 guinea pigs. Five normal guinea pigs were used as controls. Early manifestation of endolymphatic hydrops was evaluated in endolymphatic sac (ES)-intact animals (n = 6), and advanced manifestation in ES-damaged animals (n = 5) by means of MRI with gadolinium-diethylenetriaminepentaacetate-bismethylamide (Gd-DTPA-BMA) contrast agent. Hearing was tested with electrocochleography. The surface area of 3 partitions of the cochlea was used to quantify endolymphatic hydrops. The fine structure of the 3 partitions of the cochlea was visualized with MRI in all animals, as Gd-DTPA-BMA appeared mainly in the scala tympani and scala vestibuli. As early as 5 days after endolymphatic sac surgery, endolymphatic hydrops started to appear as visualized by MRI and also verified with histology. Severe damage to the inner ear barrier with Gd-DTPA-BMA leakage into the scala media was detected with MRI in 1 ES-damaged animal that had a 60-dB hearing loss. To conclude, endolymphatic hydrops can be visualized with high-resolution MRI by means of Gd-DTPA-BMA, and it is possible to quantify the extent of endolymphatic hydrops. Damage to the inner ear barrier or possible rupture of membranes can be shown with the assistance of Gd-DTPA-BMA.