[Differentiating cochlear synaptopathies into different hearing disorders]. / Differenzierung cochleärer Synaptopathien in verschiedene Hörstörungen.

Due to demographic change and altered recreational behavior, a rapid increase in hearing deficits is expected in the next 20-30 years. Consequently, the risk of age-related loss of speech discrimination, tinnitus, hyperacusis, or-as recently shown-dementia, will also increase. There are increasing indications that the loss of specific hearing fibers in humans and animals is involved in various hearing disorders. This fiber loss can be caused by cochlear synaptopathy or deafferentation and does not necessarily lead to clinically measurable threshold changes. Animal experiments have shown that reduced auditory nerve activity due to acoustic trauma or aging can be centrally compensated by disproportionately elevated and faster auditory brainstem responses (ABR). The analysis of the suprathreshold amplitudes of auditory evoked brain stem potentials and their latency in combination with non-invasive imaging techniques such as magnetic resonance imaging can help to identify the central compensatory ability of subjects and to assign defined hearing deficits.

In vivo assessment of tumor heterogeneity in WHO 2016 glioma grades using diffusion kurtosis imaging: Diagnostic performance and improvement of feasibility in routine clinical practice.

PURPOSE: To assess the diagnostic performance of normalized and non-normalized diffusion kurtosis imaging (DKI) metrics extracted from different tumor volume data for grading glioma according to the integrated approach of the revised 2016 WHO classification. MATERIALS AND METHODS: Sixty patients with histopathologically confirmed glioma, who provided written informed consent, were retrospectively assessed between 01/2013 and 08/2016 from a prospective trial approved by the local institutional review board. Mean kurtosis (MK) and mean diffusivity (MD) metrics from DKI were assessed by two blinded physicians from four different volumes of interest (VOI): whole solid tumor including (VOItu-ed) and excluding perifocal edema (VOItu), infiltrative zone (VOIed), and single slice of solid tumor core (VOIslice). Intra-class correlation coefficient (ICC) was calculated to assess inter-rater agreement. One-way ANOVA was used to compare MK between 2016 CNS WHO tumor grades. Friedman's test compared MK and MD of each VOI. Spearman's correlation coefficient was used to correlate MK with 2016 CNS WHO tumor grades. ROC analysis was performed on MK for significant results. RESULTS: The MK assessment showed excellent inter-rater agreement for each VOI (ICC, 0.906-0.955). MK was significantly lower in IDHmutant astrocytoma (0.40±0.07), than in 1p/19q-confirmed oligodendroglioma (0.54±0.10, P=0.001) or IDHwild-type glioblastoma (0.68±0.13, P<0.001). MK and 2016 WHO tumor grades were strongly and positively correlated (VOItu-ed, r=0.684; VOItu, r=0.734; VOIed, r=0.625; VOIslice, r=0.698; P<0.001). CONCLUSIONS: Non-normalized MK values obtained from VOItu and VOIslice showed the best reproducibility and highest diagnostic performance for stratifying glioma according to the integrated approach of the recent 2016 WHO classification.

Improvement in imaging common temporal bone pathologies at 3 T MRI: small structures benefit from a small field of view.

AIM: To compare image quality and evaluate its clinical importance in common temporal bone pathologies of a pTX-SPACE (parallel transmit [pTX] three-dimensional turbo spin-echo with variable flip angle [SPACE]) magnetic resonance imaging (MRI) sequence improved for spatial resolution to a standard-SPACE sequence exhibiting the same scan time at 3 T. MATERIALS AND METHODS: Thirty-four patients were examined using a standard-SPACE and resolution improved pTX-SPACE sequence at 3 T MRI. The signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and image quality were assessed. Diseases investigated were vestibular schwannoma (VS), intralabyrinthine schwannoma (ILS), inner ear malformations, labyrinthitis, temporal bone fractures, and situation after VS resection. RESULTS: Edge definition, intratumoural pattern, discrimination of VS from the modiolus and edge definition of ILS, separability from the spiral lamina, and detectability within cochlear turns were improved on the pTX-SPACE sequence. Detectability of malformations, post-traumatic changes, and discrimination of the cochlear and facial nerve after VS resection was improved on the pTX-SPACE sequence. In labyrinthitis, pTX-SPACE was not superior to standard-SPACE. The SNR and CNR were significantly reduced for pTX-SPACE. CONCLUSIONS: pTX-SPACE significantly improves the detectability of temporal bone diseases, in particular, VS, ILS, and post-VS resection.

The in vivo influence of white matter fiber orientation towards B(0) on T2* in the human brain.

It is well known that, at higher field strength, T2*-weighted images show an extensive heterogeneity in white matter fiber bundles. The basis of this phenomenon is still under discussion, as many factors, such as iron concentration, myelination and tissue microstructure, could influence relaxation times. Furthermore, fiber direction in relation to the main magnetic field seems to influence T2* relaxation times. In this study, diffusion tensor imaging and T2* measurements were combined in seven subjects with the head in a normal and tilted position. It was shown that fiber orientation has a strong influence on T2* in the human brain, with the average T2* value changing from 49 ms for a perpendicular orientation to B(0) to 57 ms for a parallel orientation to B(0). Nevertheless, T2* times showed a wide variety of values at any orientation towards B(0).

Cellular uptake of cationic gadolinium-DOTA peptide conjugates with and without N-terminal myristoylation.

Cellular and nuclear uptake of dual labelled conjugates could be of great value for chemotherapy and cancer diagnostics. Therefore we designed conjugates in which gadolinium (Gd)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a contrast agent for magnetic resonance imaging and fluorescein isothiocyanate (FITC), a fluorescence marker were coupled to membrane translocation sequences (MTS). The MTSs we employed were the third helix of the Antennapedia homeodomain, the HIV-1 Tat peptide and the N-myristoylated HIV-1 Tat peptide. We used confocal laser scanning microscopy, fluorescence activated cell sorting, magnetic resonance imaging (MRI) and viability tests to examine the cellular and nuclear uptake of these conjugates into U373 glioma cells, as well as their cytotoxic effects. We found that the Antennapedia conjugate was taken up by no more than 20% of the cells. The HIV-1 Tat conjugate showed even lower uptake into less than 3% of cells. Interestingly, N-myristoylation of the HIV-1 Tat conjugate drastically improved its cellular uptake. Up to 70% of cells showed cellular and nuclear uptake of the N-myristoylated HIV-1 Tat conjugate. Conjugate cytotoxicity appears to correlate with cellular uptake.

Novel cell nucleus directed fluorescent tetraazacyclododecane-tetra-acetic acid compounds.

Peptide conjugates derived from the SV 40 T antigen nuclear localisation sequence (NLS) have been successfully used to translocate both fluorescein isothiocyanate (FITC) and Gadolinium (Gd)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) into the cytoplasm and nucleus of glioma cells. However, uptake occurred only in up to 35% of cells. To improve cellular uptake, we designed three novel FITC-labelled Gd-DOTA conjugates. In the first conjugate, the commonly used Gd-DOTA-complex was coupled to the nuclear localization sequence (NLS) of the Simian Virus (SV) 40 T antigen alone as a control. In the second conjugate, the Gd-DOTA-coupled SV 40 T antigen NLS was elongated by the HIV-1 tat peptide (HIV-NLS). A third conjugate, in which the Gd-DOTA-complex was coupled to the SV 40 T antigen NLS elongated by a peptide containing seven arginines and six aminohexanoic acids (Ahx6R7) was also synthesized (AHX-NLS). By means of confocal laser scanning microscopy, fluorescence activated cell sorting, magnetic resonance imaging (MRI) and viability tests we were able to demonstrate that the first conjugate containing only the NLS of the SV 40 T antigen stained the nuclei of no more than 10-12% of U373 and LN18 glioma cells, resulting in low signal intensity in MRI. The stained cells remained viable. After incubation with conjugates HIV-NLS and AHX-NLS the nuclei of up to 73% of U373 and LN18 glioma cells were stained. This was associated with high signal intensity in MRI and cell death. As previously shown, the gadolinium ion reduces cellular uptake of DOTA conjugates. To confirm this, the conjugates were produced with or without gadolinium. The gadolinium-free DOTA conjugates showed a higher cellular uptake rate and an increased cytotoxic potential.

Novel dual labelled nucleus-directed conjugates containing correct and mutant nuclear localisation sequences.

Gadolinium (Gd)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is commonly used as contrast agent in magnetic resonance imaging (MRI), but cannot enter the cytoplasm or cell nucleus. We designed a tetrapeptide carrying fluorescein isothiocyanate (FITC) and Gd-DOTA. This conjugate was coupled to the nuclear localisation sequence (NLS) of the Simian Virus (SV) 40 T antigen elongated by four arginines. In a second conjugate one lysine of the original SV 40 T antigen NLS was replaced by threonine. An FITC-labelled DOTA-tetrapeptide conjugate lacking the NLS peptide served as a negative control. We tried to achieve sequence specific entry of the Gd-DOTA-complex into the cytoplasm and nucleus of human U373 and LN18 glioma cells. Using confocal laser scanning microscopy (CLSM), fluorescence activated cell sorting (FACS), magnetic resonance imaging (MRI) and viability tests we found that both NLS conjugates stained the cell nuclei of U373 and LN18 glioma cells, represented also by a rise in signal intensity compared to the native control in MRI. The majority of stained cells remained viable. All conjugates were also produced without Gd. The Gd-free DOTA-conjugates showed an increase in cellular uptake rate. Conjugate cytotoxicity correlated closely to cellular uptake. Gd-containing DOTA-conjugates directed to the cytoplasm or the nucleus may be the basis for the development of novel diagnostic agents.

Depiction of the Superior Petrosal Vein Complex by 3D Contrast-Enhanced MR Angiography.

BACKGROUND AND PURPOSE: Intraoperative obliteration of the superior petrosal vein complex has a relevant risk of postoperative complications. A large venous diameter and the absence of anastomoses have been previously suggested as possible risk factors. 3D contrast-enhanced MRA was evaluated for the identification of superior petrosal vein anatomy. MATERIALS AND METHODS: Twenty-five patients (10 men; age, 20-77 years) with a 3D-MRA (voxel size, 0.4 × 0.4 × 0.5 mm3) at 3T, including the posterior fossa, were retrospectively identified. Image evaluation was performed independently by 2 neuroradiologists with respect to overall image quality and the presence, location, size, tributaries, and anastomotic veins of the superior petrosal vein complex. Additionally, 8 neurosurgical cases with intraoperative validation of the venous anatomy were examined. RESULTS: All studies were of diagnostic image quality. Interobserver agreement was excellent for image-quality measurements (r = 0.751-0.982) and good for measured vessel size (r = 0.563-0.828). A total of 83 superior petrosal veins were identified. The distribution of drainage locations and identification of tributaries and anastomotic veins were consistent with previous anatomic studies. The results showed that 4.8% of superior petrosal veins had a diameter of >2 mm and lacked a visible anastomosis. All surgical cases showed excellent agreement between the MRA and the intraoperative observations. CONCLUSIONS: 3D-MRA with high resolution is appropriate for analyzing the size, course, tributaries, and anastomoses of the superior petrosal vein. A total of 4.8% of the identified superior petrosal veins had to be classified as potential high-risk veins. The measurements correlated with the intraoperative findings.

Diffusion tensor imaging of the spinal cord at 1.5 and 3.0 Tesla.

PURPOSE: The feasibility of highly resolved diffusion tensor imaging (DTI) of the human cervical spinal cord was tested on a clinical MR unit operating at 3.0 Tesla. DTI parametrical maps and signal-to-noise ratios (SNRs) were compared to results recorded at 1.5 Tesla. MATERIALS AND METHODS: Eight healthy volunteers and one patient participated in the study. A transverse oriented single-shot ECG-triggered echo-planar imaging (EPI) sequence with double spin-echo diffusion preparation was applied for highly resolved DTI of the spinal cord. The signal yield, fractional anisotropy (FA), and mean diffusivity (MD) were compared for both field strengths. The clinical applicability of the protocol was also tested in one patient with amyotrophic lateral sclerosis (ALS) at 3.0 T. RESULTS: A mean increase in SNR of 95.7 +/- 4.6 % was found at 3.0 Tesla compared to 1.5 Tesla. Improved quality of the DTI parametrical maps was observed at higher field strength (p < 0.02). Comparable FA and MD (reported in units of 10 (-3) mm (2)/s) values were computed in the dorsal white matter at both field strengths (1.5 T: FA = 0.75 +/- 0.08, MD = 0.84 +/- 0.12, 3.0 T: FA = 0.74 +/- 0.04, MD = 0.93 +/- 0.14). The DTI images exhibited diagnostic image quality in the patient. At the site of the diseased corticospinal tract, a decrease of 46.0 +/- 3.8 % in FA (0.40 +/- 0.03) and an increase of 50.3 +/- 5.6 % in MD (1.40 +/- 0.05) were found in the ALS patient. CONCLUSION: The 3.0 Tesla field strength provides higher image quality in DTI of the spinal cord compared to 1.5 T. The proposed DTI protocol seems adequate for the assessment of spinal cord diseases.

Clinical Application of Fiber Visualization with LIC Maps Using Multidirectional Anisotropic Glyph Samples (A-Glyph LIC).

Recently, a fiber visualization method for high-angular resolution diffusion-weighted magnetic resonance imaging (MRI) data was proposed using a multiple-kernel line integral convolution (LIC) algorithm and an anisotropic spot pattern. This processing routine leads to high contrast color-coded LIC maps that are capable of visualizing local anisotropy information and regional fiber architecture. In this paper, we evaluate and validate this method by applying it to simulated datasets and to in vivo diffusion MRI data of children and adults with different disease conditions and healthy volunteers. Compared to routine clinical fiber visualization (color-coded fractional anisotropy, FA maps, and fiber tractography), it has the advantage of visualizing complex local fiber architecture in a fully automated way. The results indicate that this method is capable of reliably delineating normal fiber architecture and fibers infiltrated, displaced, or disrupted by lesions and is therefore a promising tool in the clinical context.

Progressive multifocal leukoencephalopathy: value of diffusion-weighted and contrast-enhanced magnetic resonance imaging for diagnosis and treatment control.

Progressive multifocal leukoencephalopathy (PML) is caused by the replication of JC virus in oligodendrocytes of immunocompromised patients. Diagnosis usually relies on the polymerase chain reaction (PCR)-based demonstration of JC virus DNA in the cerebrospinal fluid. As previous reports have suggested that some patients may benefit from antiviral therapy, non-invasive early diagnosis is highly desirable. Repetitive magnetic resonance imaging (MRI) examinations (two to nine) were obtained in seven patients (aged 40-67 years, six males, one female) with classical clinical and imaging findings of PML. Five patients had underlying hematological disorders and two acquired immune deficiency syndrome. PCR of the cerebrospinal fluid (CSF) specimen was positive for JC virus DNA in six patients. MRI sequences included T2-, T1- and diffusion-weighted (DW) images in all patients and diffusion-tensor imaging (DTI) in four cases. DTI was once performed at 3T, in the remaining patients at 1.5T. All patients received antiviral treatment with cidofovir in addition to the treatment of the underlying disorder. MRI showed areas of T2 hyperintensity with involvement of the subcortical U-fibers and restricted diffusion in all patients. Areas of diffusion abnormality correlated with disease progress. Contrast enhancement was encountered once after successful treatment and heralded clinical remission with virus elimination from the CSF. Hence, MRI including DW and contrast-enhanced images may be used to evaluate disease activity. Contrast enhancement may indicate an inflammatory response and thus herald immunologic virus elimination.

Zoomed EPI DWI of Acute Spinal Ischemia Using a Parallel Transmission System.

PURPOSE: A new method for diffusion-weighted imaging (DWI) using independent parallel transmission technique resulting in zoomed DWI was applied in four patients suffering from acute spinal cord ischemia. METHODS: Four patients with clinical symptoms of acute spinal cord ischemia were examined on a 3 T MR-system equipped with a two-channel transmit array. Scans included T2-weighted turbo spin echo, conventional DWI, and zoomed DWI. Image evaluation was performed with regard to overall image quality, anatomic delineation of the spinal cord, and the level of confidence to establish the diagnosis of spinal cord ischemia. RESULTS: Through spatially selective excitation, zoomed DWI allows for acquisition of high-resolution images with reduced scan time due to a reduced field of view in phase-encoding direction, resulting in zoomed images. In all cases the ischemia was demonstrated in conventional DWI as well as zoomed DWI. CONCLUSIONS: Compared to conventional DWI, zoomed DWI enables a faster image acquisition and allowed a more detailed analysis of the spinal lesion which may be critical to attribute the lesion to a particular vessel territory.

The influence of pulse and respiration on spinal cerebrospinal fluid pulsation.

RATIONALE AND OBJECTIVES: The aim of the study is to elucidate the location and amount of spinal cerebrospinal fluid pulsations and to differentiate and quantify the cardiac and the respiratory influence. MATERIALS AND METHODS: An echo planar imaging sequence was applied to 5 different levels of the spinal canal of 7 healthy volunteers. The amount of maximal flow and respiratory signal variation were determined by a time and frequency domain analysis, respectively. RESULTS: CSF pulsation was high in the anterior cervical and in the thoracolumbar spine. Respiratory influence rose by 19% at C1 and by 28% at T12. The systolic flow was elevated during late expiration and the diastolic upward movement was pronounced by early expiration. CONCLUSION: The pulsation in the lower spine seems to be related to a second motor of CSF movement because there is a rising respiratory influence and a reappearance of pulsation waves. Physiological spinal CSF pulsation contains a relevant respiratory component.

Dynamic pattern of brain activation during sequencing of word strings evaluated by fMRI.

An impaired ability to recite highly automated word strings (e.g., the names of the months of the year) in reverse order concomitant with preserved production of the conventional sequence has been considered a salient sign of frontal lobe dysfunction. Using functional magnetic resonance imaging (fMRI), the spatial and temporal pattern of brain activation during covert performance of these tasks was evaluated in healthy subjects. As compared to the response obtained during forward recitation, re-sequencing of the word string yielded additional activation of the bilateral middle and inferior frontal gyri, the posterior parietal cortex and the left anterior cingulate gyrus. The prefrontal responses are in accordance with the clinical findings referred to. However, the set of activated areas, as a whole, presumably reflects contribution of the various components of the working memory system to the sequencing of word strings. During successive periods of task administration, subjects showed a linear increase of production speed. Analysis of corresponding dynamic changes of regional hemodynamic responses revealed a significant increase at the level of the left inferior parietal cortex and a decrease within the mesial aspect of the left superior frontal gyrus. Presumably, the former finding reflects increasing demands on the phonological short-term memory store, due to faster updating of its content under increased word production rate. Decreasing activation within the superior frontal gyrus might indicate contribution of this area to the initiation of the cognitive processes subserving the sequencing of verbal items. These findings demonstrate the capability of fMRI as a powerful tool for the analysis of dynamic brain activation.

Functional lateralization of speech production at primary motor cortex: a fMRI study.

To evaluate lateralization of speech production at the level of the Rolandic cortex, functional magnetic resonance imaging (1.5 Tesla, 27 parallel axial slices, EPI-technique) was performed during a speech task (continuous silent recitation of the names of the months of the year). As control conditions, non-speech tongue movements and silent singing of a well-known melody with the syllable 'la' as its carrier were considered. Tongue movements produced symmetrical activation at the lower primary motor cortex. During automatic speech a strong functional lateralization to the left hemisphere emerged within the same area. In contrast, singing yielded a predominant right-sided activation of the Rolandic region. Functional lateralization of speech production therefore seems to include the precentral gyrus as well as Broca's area.

fMRI reveals amygdala activation to human faces in social phobics.

Functional magnetic resonance imaging was used to determine the activation of the amygdala while seven social phobics and five healthy controls were exposed to slides of neutral faces as well as aversive odor stimuli. The amygdala was selectively activated in the social phobics during presentation of the face stimuli. The data show for the first time that the amygdala is active in human phobics when they are exposed to potentially fear-relevant stimuli. Further research is needed to determine the extent to which overactivation of the amygdala precedes or is a consequence of phobia.

Influence of magnetic resonance imaging on somatosensory and brain-stem auditory evoked potentials in man.

There is still a need to prove that even static magnetic fields up to 1.5 T used in magnetic resonance imaging (MRI) are biologically safe and harmless for humans. Recordings of median and ulnar nerves and brain-stem auditory evoked potentials in 20 patients were completed prior to and after MRI investigation of the central nervous system. Neither the somatosensory nor the auditory evoked potentials exhibited any significant change of latencies, interpeak latencies or amplitudes. Since these electrophysiological parameters are highly dependent on the quality of nerve conduction and integrity of information processing in various nuclei, it may be assumed that MRI causes no lasting changes in either respect.

Ultrasonography and contrast-enhanced MRA in ICA-stenosis: is conventional angiography obsolete?

BACKGROUND: The standard techniques for the screening and staging of internal carotid artery (ICA) stenosis are Doppler (continuous wave) and Duplex sonography. For the imaging of ICA occlusive disease, magnetic resonance angiography (MRA) is replacing digital subtraction angiography (DSA). The purpose of this observational study was to assess whether contrast enhanced MRA (CE-MRA) combined with ultrasound provided sufficient information for the planning of surgical treatment. METHODS: CE-MRA was performed in 195 patients (mean age 67.5 years) with sonographic evidence of severe ICA stenosis. The MRA examination protocol contained a heavily T1-weighted contrast bolus enhanced 3D-gradient echo sequence. The degree of stenosis was estimated retrospectively by two experienced neuroradiologists who were blinded to the sonographic findings. RESULTS: The consistency of MRA and ultrasound was sufficient to plan thrombendarterectomy in 182/195 patients. The estimations of the degree of stenosis were congruent between MRA and ultrasound in 91% of 197 vessels with high-degree carotid artery stenosis. CE-MRA evaluation had a high interobserver agreement. In 3 cases ultrasound examination diagnosed a filiform ICA stenosis which was not visible with MRA. In all these cases, DSA and the intraoperative findings revealed very short (1-2 mm), high-grade, excentric stenosis. CE-MRA correctly detected patency in 5 patients with high-grade and low-flow carotid artery stenosis, which had been regarded as occluded by ultrasound. Conversely with, in CE-MRA two occluded vessels were falsely considered as open. CONCLUSION: The combination of sonography and CE-MRA is a powerful tool for the non-invasive presurgical evaluation of the carotid arteries. DSA should be reserved for selected cases.

T(2) selectivity: comparison between different kinds of RF pulses.

Techniques allowing characterization of specific T(2) species are used to perform MR imaging of structures whose signal intensity is poor on conventional methodologies. T(2)-selective pulses can be used to discriminate signals from tissues with different T(2) values. In case of soliton pulses, the magnetization from all the T(2) species is inverted, with the exception of specific T(2) structures which have both the longitudinal and the transverse magnetization nulled on resonance. Solitons have the drawback of being very long even if the selected T(2) value is in the order of tens of milliseconds. The aim of this paper is to examine whether it is possible to use pulses shorter then solitons keeping their T(2) selectivity, that is keeping null longitudinal magnetization, while accepting some residual transverse magnetization for structures with the selected T(2). Different kinds of inversion pulses were generated, all to select the same T(2) species. Pulses performance was analyzed by studying the dependence of the residual transverse magnetization on resonance from the length of the pulse. An exponential relationship between transverse magnetization and pulse length was found, which was not dependent on the pulse type.

Relaxation effects on transverse magnetization using RF pulses long compared to T(2).

The transverse relaxation effects which occur during the application of optimized slice-selective Shinnar-Le Roux pulses are studied. The behavior of both longitudinal and transverse magnetization is examined, focusing the attention on changes which affect the absorption and dispersion components. Besides the reduction in amplitude, the absorption component was found to be unaffected by transverse relaxation times, whereas the dispersion component was strongly distorted. A comparison between the distortion components from pulses having same length but different bandwidths is given.