In vivo MRI reveals the dynamics of pathological changes in the brains of cathepsin D-deficient mice and correlates changes in manganese-enhanced MRI with microglial activation.

Cathepsin D (CTSD; EC 3.4.23.5) is essential for normal development and/or maintenance of neurons in the central nervous system: its deficiency causes a devastating neurological disorder with severely shortened life span in man, sheep and mouse. Neuropathologically, the CTSD deficiencies are characterized by selective neuronal degeneration, gliosis and accumulation of autofluorescent proteinaceous storage material in neurons. Our aim was to study the dynamics behind the pathological alterations occurring in the brains of CTSD-deficient (CTSD-/-) mice by using in vivo magnetic resonance imaging (MRI) and histology. In order to do this, we measured T(2) signal intensity (SI), apparent diffusion coefficient, area and volume of multiple brain structures from MR images acquired using T(2)-, T(1)- and diffusion-weighted sequences at three time points during disease progression. MRI revealed no differences in the brains between CTSD-/- and control mice at postnatal day 15+/-1 (P15+/-1), representing an initial stage of the disease. In the intermediate stage of the disease, P19(+/-1), SI alterations in the thalami of the affected mice became evident in both T(1)- and T(2)-weighted images. The terminal stage of the disease, P25, was characterized by marked alterations in the T(2) SI, apparent diffusion coefficient and volume of multiple brain structures in CTSD-/- mice. In addition, manganese enhanced high-resolution T(1)-weighted 3D sequences (MEMRI) and histological stainings revealed that the hyperintense signal areas in MEMRI matched perfectly with areas of microglial activation in the brains of CTSD-/- mice at the terminal disease stage. In conclusion, the SI alterations in the thalami of CTSD-/- mice preceded other changes, and the degenerative process was greatly enhanced at the age P19(+/-1), leading to severely reduced brain volume in just 6 days.

Decreased T2 signal in the thalami may be a sign of lysosomal storage disease.

INTRODUCTION: Lysosomal disorders are rare and are caused by genetically transmitted lysosomal enzyme deficiencies. A decreased T2 signal in the thalamus has occasionally been reported. AIMS: Because the finding of bilateral abnormal signal intensity of the thalamus on T2-weighted images has not been systematically reviewed, and its value as a diagnostic tool critically evaluated, we carried out a systematic review of the literature. METHODS: Articles in English with 30 trios of keywords were collected from PubMed. Exclusion criteria were lack of conventional T2-weighted images in the protocol and not being a human study. Finally, 111 articles were included. The thalamus was considered affected only if mentioned in the text or in the figure legends. RESULTS: Some 117 patients with various lysosomal diseases and five patients with ceruloplasmin deficiency were reported to have a bilateral decrease in T2 signal intensity. At least one article reported a bilateral decrease in signal intensity of the thalami on T2-weighted images in association with GM1 and GM2 gangliosidosis and with Krabbe's disease, aspartylglucosaminuria, mannosidosis, fucosidosis, and mucolipidosis IV. Furthermore, thalamic alteration was a consistent finding in several types of neuronal ceroid lipofuscinosis (NCL) including CLN1 (infantile NCL), CLN2 (classic late infantile NCL), CLN3 (juvenile NCL), CLN5 (Finnish variant late infantile NCL), and CLN7 (Turkish variant late infantile NCL). CONCLUSION: A decrease in T2 signal intensity in the thalami seems to be a sign of lysosomal disease.

Quantification of mechanical vibration during diffusion tensor imaging at 3 T.

Subjects sense clear mechanical vibrations during diffusion tensor imaging (DTI). These vibrations, likely resulting from diffusion-sensitizing gradients, have been assumed to be of the same strength and phase in all parts of the magnetic resonance imaging (MRI) scanner so that they could be ignored. However, our measurements, carried out from several parts of the MRI scanner and its surroundings using an optical laser-based interferometer, demonstrate an uneven distribution of mechanical vibrations within the scanner. The measurements were performed during DT scanning at 3 T, with various diffusion-weighting parameters, by positioning a phantom in the head coil and/or a human subject on the patient bed. The vibration-related movement was caused by the diffusion-sensitizing gradients and was maximally 0.5 mm with typical settings used in brain imaging. The compensation for eddy currents, done with gradients in our DTI sequence, increased the vibration level by a factor of 1.5 or more with diffusion-weighting parameter b = 1000 s/mm(2) and by a factor of 3 or more with b = 3000 s/mm(2). Mechanical vibrations stayed at an acceptable level with b < or = 1000 s/mm(2), resulting in additional signal losses of 5-17%. Vibration levels might be reduced by adjusting imaging parameters, by modifying the gradient waveforms in the DTI sequence, and by redesigning the mechanics of patient bed to effectively dampen the movements.

Functional phantom for fMRI: a feasibility study.

Functional magnetic resonance imaging (fMRI) reveals changes in blood oxygen level-dependent (BOLD) signal after considerable processing. This paper describes the implementation and testing of an fMRI phantom where electric current applied to a thin wire within a proton-rich medium substituted BOLD distortion of the magnetic field; the scanner detects these two distortions as practically identical signal changes. The magnitude of the change depended on the current strength. The phantom has a number of possible applications. Signal changes across sessions, days, instruments and individuals could be monitored. Placing the phantom close to a subject during an fMRI experiment could allow differentiating sensitivity changes in the scanner due to instrumentation from changes in the subject's state and performance during the experiment. The spatial extent of brain activations and effects of various changes in the chain of image formation could be analyzed using current-induced "activations". Furthermore, the phantom could expedite fMRI sequence development by reducing the need to scan human subjects, who introduce uncertainty to the signal. Thus, this fMRI phantom could be useful for both cognitive fMRI studies and scanner calibration.

Diffusion tensor imaging and tractography of distal peripheral nerves at 3 T.

OBJECTIVE: We studied whether distal peripheral nerves could be imaged using quantitative diffusion tensor imaging (DTI) with a 3-T MRI scanner, and visualized using tractography. METHODS: Altogether 6 healthy subjects were studied. The diffusion was quantified with apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps, and the direction of main diffusivity was visualized with color-coded orientation maps and tractography. RESULTS: We present the first DTI and tractography results of human distal peripheral nerves. The courses of median, ulnar, and radial nerves in the upper limb and of tibial and peroneal nerves in the lower limb were first analyzed quantifying ADC and FA, and then visualized in 3D with tractography. Tractography illustrated nicely the 3D courses of both upper and lower limb nerves which were reliably distinguished from the surrounding muscle tissue and ligaments. CONCLUSIONS: Quantitative DTI and tractography can be used to image and visualize distal peripheral nerves. SIGNIFICANCE: DTI is a quantitative method that could provide useful information for the diagnosis and follow-up of nerve lesions, entrapments, and regeneration. Peripheral nerves as well-delineated structures also containing abundant branching into bundles of different diameters, could be used as 'living phantoms' for testing and validating different tractography methods.

Processing of audiovisual speech in Broca's area.

We investigated cerebral processing of audiovisual speech stimuli in humans using functional magnetic resonance imaging (fMRI). Ten healthy volunteers were scanned with a 'clustered volume acquisition' paradigm at 3 T during observation of phonetically matching (e.g., visual and acoustic /y/) and conflicting (e.g., visual /a/ and acoustic /y/) audiovisual vowels. Both stimuli activated the sensory-specific auditory and visual cortices, along with the superior temporal, inferior frontal (Broca's area), premotor, and visual-parietal regions bilaterally. Phonetically conflicting vowels, contrasted with matching ones, specifically increased activity in Broca's area. Activity during phonetically matching stimuli, contrasted with conflicting ones, was not enhanced in any brain region. We suggest that the increased activity in Broca's area reflects processing of conflicting visual and acoustic phonetic inputs in partly disparate neuron populations. On the other hand, matching acoustic and visual inputs would converge on the same neurons.

Cortical activation during a spatiotemporal tactile comparison task.

Tactile sensory memory is needed to infer shape or motion from the spatiotemporal pattern of sensory input during manual exploration. Here we applied triplets of pressure pulses to the fingertips of subjects who were asked to respond when successive triplets were the same (COMPARE task) or when a particular stimulus was included in a triplet (CONTROL task). Stimulus sequences (30 s) alternated with rest blocks (30 s) and functional magnetic resonance images (fMRIs) were acquired in a 1.5-T scanner. During the COMPARE task, we found enhanced activation in inferior parietal cortex, supplementary motor area (SMA), and right dorsolateral prefrontal cortex (DLPFC). Activation of DLPFC is likely to be related to the attempt to memorize the stimulus sequences and activations of SMA and inferior parietal cortex to the analysis of temporospatial tactile patterns and, more generally, to guidance of haptic exploration. In addition, task-specific activation was seen in anterior cingulate gyrus, possibly related to the high mental effort required by the comparison task. Our rhythmic tactile stimulus as such, without any task-specific enhancement, activated also left cerebellum and (mainly left) putamen, supporting the idea that these structures are related to perception of temporal order of tactile stimuli.

Late radiation effects in the dog brain: correlation of MRI and histological changes.

PURPOSE: To determine the correlation between sequential changes in the brain of dogs after irradiation, as detected by magnetic resonance imaging (MRI), with the eventual appearance of histological lesions. Histology was performed 77-115 weeks after irradiation. MATERIALS AND METHODS: Groups of five beagle dogs were irradiated to the brain with single doses of 10, 12, 14 or 16 Gy of 6 MV photons, at the 100% iso-dose. Sequential MRIs were taken to detect changes in the brain for 77-115 weeks after irradiation. Dose-effect relationships were established for changes in the brain as detected by MRI, computerized tomography (CT), gross morphology and histology. The doses that caused a specified response in 50% of the animals (ED(50)+/-SE) were calculated from these dose-effect relationships for each endpoint. RESULTS: The ED50 values (+/-SE) for focal and diffuse changes on T2-weighted MR images were 11.0+/-1.1 and 10.8+/-0.9 Gy, respectively. The ED50 values (+/-SE) for contrast enhancement on T1-weighted MR images and on CT were 13.4+/-0.6 and 13.0+/-0.6 Gy, respectively. It was 11.4+/-0.6 Gy for any type of histological lesion (haemorrhage, reactive change or glial scar) 77-115 weeks after irradiation. For a macroscopic lesion the ED50 (+/-SE) value was 13.0+/-1.1 Gy. CONCLUSIONS: The presence of focal or diffuse changes on T2-weighted MR images was the best indicator for the eventual appearance of any type of histological lesion in the dog brain after irradiation with single doses of photons. The ED50 for any histological lesion did not differ significantly from the ED50 for a focal (P>0.35) or diffuse (P=0.3) change on T2-weighted MR images.