Nerve ultrasound as follow-up tool in treated multifocal motor neuropathy.

BACKGROUND AND PURPOSE: High-resolution ultrasound is a valuable tool in supporting the diagnosis of multifocal motor neuropathy (MMN) but longitudinal data under therapy are lacking. METHODS: The change in peripheral nerve ultrasound pattern in patients with MMN was assessed over time. Patients with MMN received a thorough initial examination and follow-up over a period of 6-12 months using high-resolution ultrasound of the cervical roots and the nerves of the arms and legs, nerve conduction studies, Medical Research Council Sum Score (MRCSS) and Rotterdam Inflammatory Neuropathy Cause and Treatment Group (INCAT) score to evaluate changes under treatment. The Ultrasound Pattern Sum Score (UPSS) was used as standardized peripheral nerve ultrasound protocol. RESULTS: Seventeen patients with MMN received initial examinations of whom 12 were successfully followed up. All patients with MMN showed at least localized but often multifocal peripheral nerve enlargement. An enlarged overall cross-sectional area as well as enlarged single fascicles (>3 mm²) in clinically and electrophysiologically affected (>90%) and unaffected (>70%) nerves were found. The UPSS did not correlate with clinical disability at both visits. However, the change in clinical disability (evaluated as difference in MRCSS) and the change in UPSS correlated significantly inversely (P = 0.004). CONCLUSIONS: High-resolution sonography of peripheral nerves revealed multifocal nerve enlargement in MMN. Distinct enlargement patterns may support the diagnosis. Ultrasound findings did not correlate well with clinical severity or electrophysiological findings at initial presentation. As changes in UPSS correlated significantly with the clinical course in terms of muscle strength (MRCSS), sonographic assessment may represent a useful tool for therapeutic monitoring.

[Hereditary Alzheimer's disease with amyloid angiopathy caused by amyloid precursor protein locus]. / Familiäre Alzheimer-Variante mit Amyloidangiopathie als Ausdruck einer APP-Gen-Duplikation.

We report a patient with early-onset autosomal dominant dementia. The CSF showed increased levels of tau protein and decreased amyloid beta (ratio 42:40) typical for Alzheimer's disease. Cerebral MRI revealed vascular lesions and white-matter changes around the posterior horns of the ventricles with only moderate atrophy of the brain. Susceptibility-weighted imaging detected multiple small hemorrhagic changes. Gene analysis revealed amyloid precursor protein (APP) locus duplication as the cause of hereditary Alzheimer's dementia. The co-occurrence of CSF changes typical for Alzheimer's disease and MRI findings of cerebral amyloid angiopathy is remarkable, as it is also described for APP locus duplication. In conjunction with a family history suggestive of hereditary dementia, such a constellation should lead to enhanced gene analysis.

Muscle ultrasonography as an additional diagnostic tool for the diagnosis of amyotrophic lateral sclerosis.

OBJECTIVE: We aimed to determine the utility of muscle ultrasonography (MUS) in addition to electromyography (EMG) in the diagnosis of amyotrophic lateral sclerosis (ALS). METHODS: In all, 60 patients with ALS and 20 with other neuromuscular disorders underwent MUS and EMG. In addition, 30 healthy controls underwent only MUS. Occurrence of fasciculations and fibrillations was evaluated. Ultrasonic echogenicity was graded semiquantitatively. RESULTS: The incidence of fasciculations was significantly higher in patients undergoing MUS than in those undergoing EMG (p<0.05), even in muscles of full strength (p<0.001). However, EMG was more sensitive in detecting fibrillations (p<0.05). MUS had an overall higher sensitivity in detecting spontaneous activity in the tongue (p<0.05). Patients with ALS showed significantly increased muscle echo intensity (EI) compared to patients who were initially suspected as having ALS and normal controls (p<0.05), irrespective of the clinical or electrophysiological status. CONCLUSION: Our results showed that the sensitivity and specificity of MUS in diagnosing ALS was almost equivalent to those of EMG, using the Awaji criteria. Combination of MUS and EMG enhances the diagnostic accuracy compared to EMG alone (p<0.05). SIGNIFICANCE: The combination of EMG and MUS can be used to evaluate the lower motor neuron affection by reducing the use of the often painful and uncomfortable EMG examinations but without decreasing the diagnostic sensitivity and specificity.

Localization of cGMP-dependent protein kinase type II in rat brain.

In brain, signaling pathways initiated by atrial natriuretic peptide, or transmitters which stimulate nitric oxide synthesis, increase cGMP as their second messenger. One important class of target molecules for cGMP is cGMP-dependent protein kinases, and in the present study, biochemical and immunocytochemical analyses demonstrate the widespread distribution of type II cGMP-dependent protein kinase in rat brain, from the cerebral cortex to the brainstem and cerebellum. Also, colocalization of cGMP-dependent protein kinase type II with its activator, cGMP, was found in several brain regions examined after in vitro stimulation of brain slices with sodium nitroprusside. In western blots, cGMP-dependent protein kinase type II was observed in all brain regions examined, although cerebellar cortex and pituitary contained comparatively less of the kinase. Immunocytochemistry revealed cGMP-dependent protein kinase type II in certain neurons, and occasionally in putative oligodendrocytes and astrocytes, however, its most striking and predominant localization was in neuropil. Electron microscopy examination of neuropil in the medial habenula showed localization of the kinase in both axon terminals and dendrites. As a membrane-associated protein, cGMP-dependent protein kinase type II often appeared to be transported to cell processes to a greater extent than being retained in the cell body. Thus, immunocytochemical labeling of cGMP-dependent protein kinase type II often did not coincide with the localization of kinase mRNA previously observed by others using in situ hybridization. We conclude that in contrast to cGMP-dependent protein kinase type I, which has a very restricted localization to cerebellar Purkinje cells and a few other sites, cGMP-dependent protein kinase type II is a very ubiquitous brain protein kinase and thus a more likely candidate for relaying myriad cGMP effects in brain requiring protein phosphorylation.

Visualization of nerve fiber orientation in gross histological sections of the human brain.

Diffusion weighted magnetic resonance imaging (DWMRI) allows visualization of the orientation of the nervous fibers in the living brain. For comparison, a method was developed to examine the orientation of fibers in histological sections of the human brain. Serial sections through the entire human brain were analyzed regarding fiber orientation using polarized light. Direction of fibers in the cutting plane was obtained by measuring the azimuth with the lowest intensity value at each point, and inclination of fibers in the section was evaluated using fuzzy logic approximations. Direction and inclination of fibers revealing their three-dimensional orientation were visualized by colored arrows mapped into the images. Using this procedure, various fiber tracts were identified (pyramidal tract, radiatio optica, radiatio acustica, arcuate fascicle, and 11 more). Intermingled fibers could be separated from each other. The orientation of the fiber tracts derived from polarized light microscopy was validated by confocal laser scanning microscopy in a defined volume of the internal capsule, where the fiber orientation was studied in four human brains. The polarization method visualizes the high degree of intermingled fiber bundles in the brain, so that distinct fiber pathways cannot be understood as solid, compact tracts: Neighbouring bundles of fibers can belong to different systems of fibers distinguishable by their orientation.

Mapping of fiber orientation in human internal capsule by means of polarized light and confocal scanning laser microscopy.

The nervous fibers in the human internal capsule were mapped according to their three-dimensional orientation. Four human cadaver brains were cut into comparable and standardized sections parallel to the ACPC-plane, stained with DiI, and analyzed using a combination of confocal and polarized light microscopy at the same time. This combination provides information about the structure and orientation of the fibers in great detail with confocal microscopy, and information about the localization and orientation of long myelinated fiber tracts with polarization microscopy. The internal capsule was parcellated in the areas CI 1 to CI 4 containing fibers of distinct orientation and structure, which enriches the macroscopically definable parcellation in the anterior and posterior limb. Fibers of the anterior thalamic peduncle intermingle with frontopontine tract fibers. Single fibers connect the caudate and the lentiform nucleus. The pyramidal tract is located in the anterior half of the posterior limb intermingled with fibers of the superior thalamic peduncle. Parietooccipitopontine fibers are located in the posterior part of the posterior limb. The slopes of the different systems of fibers change continuously in the anterior posterior direction of the internal capsule. Using the 3D orientation of fibers as a criterion for parcellation, as well as the description of bundles as a collection of fibers belonging to particular tracts leads to a more function-related description of the anatomy of the internal capsule. The method can be used for interindividual, sex- or age-related comparisons of particular systems of fibers.

Quantitative estimation of 3-D fiber course in gross histological sections of the human brain using polarized light.

Series of polarized light images can be used to achieve quantitative estimates of the angles of inclination (z-direction) and direction (in xy-plane) of central nervous fibers in histological sections of the human brain. (1) The corpus callosum of a formalin-fixed human brain was sectioned at different angles of inclination of nerve fibers and at different thicknesses of the samples. The minimum, and maximum intensities, and their differences revealed a linear relationship to the angle of inclination of fibers. It was demonstrated that sections with a thickness of 80--120 microm are best suited for estimating the angle of inclination. (2) Afterwards the optic tracts of eight formalin-fixed human brains were sliced at different angles of fiber inclination at 100 microm. Measurements of intensity in 30 pixels in each section were used to calculate a linear function of calibration. The maximum intensities and the differences between maximum and minimum values measured with two polars only were best suited for estimation of fiber inclination. (3) Gross histological brain slices of formalin-fixed human brains were digitized under azimuths from 0 to 80 degrees using two polars only. These sequences were used to estimate the inclination of fibers (in z-direction). The same slices were digitized under azimuths from 0 to 160 degrees in steps of 20 degrees using a quarter wave plate additionally. These sequences were used to estimate the direction of the fibers in xy-direction. The method can be used to produce maps of fiber orientation in gross histological sections of the human brain similar to the fiber orientation maps derived by diffusion weighted magnetic resonance imaging.

Localization and age-related changes of nitric oxide- and ANP-mediated cyclic-GMP synthesis in rat cervical spinal cord: an immunocytochemical study.

An immunocytochemical technique was used to study the localization and developmental aspects of cyclic GMP (cGMP)-synthesizing structures in the cervical spinal cord of 2-week and 3-month-old Lewis rats in response to the nitric oxide (NO) donor sodium nitroprusside (SNP) and/or atrial natriuretic peptide (ANP). By using cell-specific markers, the cell structures involved were investigated. To visualize cGMP, a combined technique of low- and high-power magnification, using a confocal laser scanning microscope was used. NOS-mediated cGMP synthesis was observed in the cervical spinal cord in laminae I, II and III in 14-day-old rats, which activity was mainly absent at the age of 3 months. The involvement of NO in the NMDA-mediated increase in cGMP immunostaining (cGMP-IS) was demonstrated by the absence of cGMP-IS in slices incubated in the presence of NMDA together with the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). This NO-mediated effect of NMDA on cGMP-IS was completely absent in the 3-month-old rats. ANP-mediated cGMP synthesis resulted in an increase in cGMP in laminae I and II, which was generally similar at both ages. Astrocytes in both white and gray matter were found to be cGMP-IS in the basal, NO- and ANP-stimulated conditions. Using confocal laser microscopy, NO-mediated cGMP synthesis was observed in large cholinergic terminals nearby motor neurons in the ventral horn. An extensive colocalization between NO-stimulated cGMP synthesis and parvalbumin-positive (GABAergic) neurons and fibers was observed in all laminae. In the ANP-stimulated condition, a colocalization with parvalbumin structures was found in laminae II and III. No NO- or ANP-mediated cGMP synthesis was found in fibers immunopositive for the presynaptic glutamate transporter, serotonin, or tyrosine hydroxylase.

Whole brain spheroid cultures as a model to study the development of nitric oxide synthase-guanylate cyclase signal transduction.

Whole brain spheroids provide a suitable model to study neurodevelopment. In the literature a role for the nitric oxide (NO)-cyclic guanosine 3',5'-monophosphate (cGMP) signalling pathway during development has frequently been suggested. In this study we investigated whether functional cGMP pathways were present in differentiated spheroids. In 3-week-old spheroids soluble guanylate cyclase was stimulated with N-methyl D-aspartic acid or sodium nitroprusside (NO donor). The results showed that the NO synthase-cGMP pathway is present in the culture system. Soluble guanylate cyclase-dependent cGMP formation was found in NO synthase containing neurons, in neurons of the GABAergic, glutamatergic and cholinergic system, and in astroglia and oligodendroglia. Activation of particulate guanylate cyclase by atrial natriuretic peptide also triggered an increase in cGMP production. Particulate guanylate cyclase was found in astroglia and in microglia as well as in glutamic acid decarboxylase and calbindin containing structures and neuronal NO synthase containing neurons. Chronic inhibition of NO synthase during culture development had no effect on soluble or particulate guanylate cyclase functioning. Similarly, inhibition of soluble guanylate cyclase during culture development did not have any effect on NO synthase and particulate guanylate cyclase functioning. It is concluded that NO synthase and both soluble and particulate guanylate cyclase are present in whole brain spheroid cultures and that their activity can be influenced by several stimuli. The spheroid culture system constitutes a suitable model to study the NO-cGMP pathway during brain development in mammals.

In vivo 3D visualization of normal pyramidal tracts in human subjects using diffusion weighted magnetic resonance imaging and a neuronavigation system.

We describe the potential of anisotropic diffusion weighted imaging to visualize the course of large cerebral fiber tracts. Five healthy volunteers were investigated at a field strength of 1.5 Tesla, employing a spin-echo diffusion weighted sequence with gradient sensitivity in six non-collinear directions to visualize the course of the pyramidal tracts. The pyramidal tracts were segmented and reconstructed for three-dimensional visualization. Reconstruction results together with a fusioned high resolution 3D T1 weighted image data set were available in a customized neuronavigation system. Origination in the primary motor cortex, convergence in the centrum semiovale, the posterior limb of the internal capsule, the cerebral peduncles, the splitting at the level of the pons, and the pyramidal decussation were identified in all subjects. Fiber tract maps might have the prospect of guiding neurosurgical interventions, especially when being linked to a neuronavigation system. Other potential applications include the demonstration of the anatomical substrate of functional connectivity in the human brain.

Comparison of tissue impedance measurements with nerve fiber architecture in human telencephalon: value in identification of intact subcortical structures.

OBJECT: After establishing the general possibility of real-time impedance monitoring during stereotactic procedures in five postmortem human brains, the authors proceeded to analyze the value of impedance measurements in intact cerebral structures. METHODS: The authors performed impedance measurements at 24 selected points in the brain of a human cadaver and labeled the points by using 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). The texture of the nerve fibers was visualized using confocal laser scanning microscopy, which allowed classification of distinct anatomical regions in the white and gray matter according to their fiber structure (density, direction, structure, and diameter). These regions displayed characteristic differences in impedances according to their fiber structure at frequencies between 8000 and 10,000 Hz. Differences in tissue impedance are not removed, although they are shifted to higher values by fixation with formalin. The reference frequency used in clinical environments (50,000 Hz) is not useful for distinct localization purposes. Finally, the orientation of the electrode in relation to the tissue is a crucial factor. CONCLUSIONS: It should be possible to draw conclusions about the correct position of the stereotactic needle on the basis of the proposed location, the texture of the fibers (orientation and density), and the orientation of the electrode.

Morphological asymmetry in anterior limb of human internal capsule revealed by confocal laser and polarized light microscopy.

The fiber structure in the anterior limb of the internal capsule was investigated in a region where stereotactic lesions (anterior capsulotomy) result in successful treatment of obsessive-compulsive disorder (OCD). Eight human hemispheres were sectioned in comparable planes parallel to the ACPC plane. Microscopic slices were labeled with DiI and analyzed with confocal laser and polarized light microscopy. Three distinct systems of fibers were detected. Single fibers run from the caudate nucleus to the lentiform nucleus. The anterior thalamic peduncle connects the mediodorsal and partially the anterior thalamic nucleus with the frontal lobe. The frontopontine tract system connects the frontal lobe with the pons. This fiber tract occupies 38% of the anterior limb and is arranged in small bands. Right-left comparison of morphometric parameters of these bundles demonstrated that more and smaller bundles were located on the left-hand side than on the right-hand side. Tendencies for this configuration were noticeable in all brains investigated, with statistical significance in one brain. These morphological differences correlate with functional differences, as it was possible to demonstrate right hemispheric dysfunctions in cases of OCD. The benefit of anterior capsulotomy in OCD is generally seen in the interruption of fronto-basal ganglia-thalamic loops by disconnecting the anterior thalamic peduncle. In addition, the frontopontine fiber tract is disconnected in this stereotactic procedure.

Fuzzy sets in human anatomy.

Artificial intelligence will have a great impact on the rather traditional field of anatomy. Techniques of artificial intelligence can advance anatomical research in a wide range of applications. Fuzzy logic is especially useful in facilitating the use of natural language in the mathematical description of structures or functions. Examples presented demonstrate the broad use of information technology in anatomical applications, including description and classification, knowledge representation, image processing, and three-dimensional anatomical atlases.

An aphasia database on the internet: a model for computer-assisted analysis in aphasiology.

A web-based software model was developed as an example for data mining in aphasiology. It is used for educating medical and engineering students. It is based upon a database of 254 aphasic patients which contains the diagnosis of the aphasia type, profiles of an aphasia test battery (Aachen Aphasia Test), and some further clinical information. In addition, the cerebral lesion profiles of 147 of these cases were standardized by transferring the coordinates of the lesions to a 3D reference brain based upon the ACPC coordinate system. Two artificial neural networks were used to perform a classification of the aphasia type. First, a coarse classification was achieved by using an assessment of spontaneous speech of the patient which produced correct results in 87% of the test cases. Data analysis tools were used to select four features of the 30 available test features to yield a more accurate diagnosis. This classifier produced correct results in 92% of the test cases. The neural network approach is similar to grouping performed in group studies, while the nearest-neighbor method shows a design more similar to case studies. It finds the neurolinguistic and the lesion data of patients whose AAT profiles are most similar to the user's input. This way lesion profiles can be compared to each other interindividually. The Aphasia Diagnoser is available on the Web address http://fuzzy.iau.dtu.dk/aphasia.nsf and thus should facilitate a discussion about the reliability and possibilities of data-mining techniques in aphasiology.

Supra- and infrasylvian conduction aphasia.

Fifteen cases of conduction aphasia which were tested with the Aachen Aphasia Test (AAT), are presented. The CT lesion data were transformed to a standard 3D-reference brain referring to the ACPC line. According to the lesion profiles a group of 6 patients had pure suprasylvian lesions, a group of 4 patients had pure infrasylvian lesions, and a group of 5 patients had lesions in both supra- and infrasylvian regions. Suprasylvian conduction aphasics are superior to infrasylvian conduction aphasics in the token test and in repetition tasks. Infrasylvian conduction aphasics use more stereotypes in spontaneous speech than suprasylvian conduction aphasics. Conduction aphasics with both lesion sites perform less well in tests of naming, writing, and comprehension than the pure types. Thus conduction aphasia is a heterogeneous syndrome anatomically and linguistically.

Terminology of the thalamus and its representation in a part-whole relation.

In stereotaxic neurosurgery, a variety of operative procedures focus on thalamic targets. The nomenclature of thalamic nuclei and subnuclei, however, has not yet been settled. In clinical and laboratory environments several terminologies coexist. This is an obstacle to both communication and a better understanding of recent electrophysiological findings. In the late 1980s, the application of new histochemical and immunohistochemical methods led to a deeper insight into existing correlationships between the nomenclatures. As a uniform terminology of the thalamus is still lacking, we created a knowledge-based system (THALAMUS) which gives a comprehensible survey about the most important terminologies. The different nomenclatures are related to each other by organizing them in a component-integral relation. This part-whole relation contains both the knowledge on the subdivisions of the thalamus as well as the knowledge on the correlations between the various nomenclatures.

Helping chronic psychiatric patients adjust to sociopolitical changes in Poland.

According to the stress-diathesis model, persons with serious mental disorders, such as schizophrenia, have cognitive and psychophysiological vulnerabilities that under conditions of stress, lead to psychotic symptoms and diminished interpersonal functioning (Nuechterlein and Dawson 1984; Zubin and Spring 1977). Pharmacological and psychosocial treatments provide buffers to disease vulnerabilities by compensating for neurotransmitter abnormalities, directly reducing the experience of stress, teaching a range of social and instrumental skills that help patients cope with life problems, and dispersing patients' stress through a well-functioning support network (Liberman et al. 1984). To conduct psychosocial treatments well, clinicians must have knowledge regarding the community stressors that impact upon the patient, the range of skills necessary to navigate the hurdles of everyday life (Goldfried and D'Zurilla 1969), and the interpersonal factors that facilitate formation and maintenance of support systems (Tolsdorf 1976). Clinicians can develop individual rehabilitation plans that reflect patients' strengths and weaknesses in each of these areas.