Brain functional and effective connectivity underlying the information processing speed assessed by the Symbol Digit Modalities Test.

Delayed Information Processing Speed (IPS) often underlies attention deficits and is particularly evident in patients with traumatic brain injury, Parkinson's disease, depression, dementia, and multiple sclerosis. Therefore, it is of interest to determine the brain network that is responsible for such essential cognitive function to understand IPS deficits and to develop effective rehabilitation programs. We assessed brain functional connectivity and effective connectivity during the performance of an adapted version of the Symbol Digit Modalities Test. Using dynamic causal modeling, we focused on obtaining a network model for IPS function in healthy subjects. Sixteen right-handed volunteers (seven women, age: 29.7 ±â€¯5.0 years) were included in the study after giving written consent for participating. Functional magnetic resonance images were acquired in a 3T scanner. According to our results, two systems interact during the IPS task performance. One is formed by frontoparietal and fronto-occipital networks, related to the control of goal-directed (top-down) selection for stimuli and response, while the second is composed of the temporoparietal and inferior frontal cortices, which are associated with stimulus-driven attention in the brain. Additionally, the default-mode network showed a significant correlation with networks positively associated with the task, mainly those related to visual detection and processing, indicating its relevant role in functional integration involving IPS. Therefore, an IPS-related network was proposed through a methodology that may be useful for future studies considering other cognitive functions and tasks, clinical groups, and longitudinal assessments.

Symbol Digit Modalities Test adaptation for Magnetic Resonance Imaging environment: A systematic review and meta-analysis.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is widely used for cognitive evaluation of information processing speed (IPS), required in many cognitive operations. Despite being unspecific for different neurological disorders, it is sensitive to assess impaired performance related to stroke, Parkinson's disease, traumatic brain injury, and multiple sclerosis. However, in addition to evaluate the presence and severity of IPS impairment, it is of interest to determine the localization and integration of brain regions responsible for the functions assessed by the SDMT. OBJECTIVE: To review the studies that adapted the SDMT to the magnetic resonance environment and obtain the brain areas associated with the performance of the task in healthy subjects with a meta-analysis. METHODOLOGY: A systematic review was performed using ten studies published between 1990 and 2017, and selected from four databases. All studies included participants of both genders and age between 18 and 50 years, used Functional Magnetic Resonance Imaging (fMRI) and SDMT adaptation and reported brain regions associated with the task. Six of them also reported the region coordinates in a standard space, so they were included in a meta-analysis. Activation Likelihood Estimation algorithm, with significance for p < 0.05 corrected for multiple comparisons, was used to identify areas that are robustly related to the performance of the SDMT. RESULTS: The areas predominantly reported in the studies of our meta-analysis were regions of the frontoparietal attentional network and occipital cortex, as well as cuneus, precuneus, and cerebellum. Individually all regions that survived the statistical threshold are consistent with what is expected after reviewing prospective studies. CONCLUSIONS: The present study allowed the identification of brain areas activated during the performance of the SDMT in healthy subjects, and therefore it will help understanding the differences in brain activation by this task in clinical populations. Moreover, it may guide future studies of therapeutic strategies and interventions in those populations.

Defective expression of apoptosis-related molecules in multiple sclerosis patients is normalized early after autologous haematopoietic stem cell transplantation.

Defective apoptosis might be involved in the pathogenesis of multiple sclerosis (MS). We evaluated apoptosis-related molecules in MS patients before and after autologous haematopoietic stem cell transplantation (AHSCT) using BCNU, Etoposide, AraC and Melphalan (BEAM) or cyclophosphamide (CY)-based conditioning regimens. Patients were followed for clinical and immunological parameters for 2 years after AHSCT. At baseline, MS patients had decreased proapoptotic BAD, BAX and FASL and increased A1 gene expression when compared with healthy counterparts. In the BEAM group, BAK, BIK, BIMEL , FAS, FASL, A1, BCL2, BCLXL , CFLIPL and CIAP2 genes were up-regulated after AHSCT. With the exception of BIK, BIMEL and A1, all genes reached levels similar to controls at day + 720 post-transplantation. Furthermore, in these patients, we observed increased CD8+ Fas+ T cell frequencies after AHSCT when compared to baseline. In the CY group, we observed increased BAX, BCLW, CFLIPL and CIAP1 and decreased BIK and BID gene expressions after transplantation. At day + 720 post-AHSCT, the expression of BAX, FAS, FASL, BCL2, BCLXL and CIAP1 was similar to that of controls. Protein analyses showed increased Bcl-2 expression before transplantation. At 1 year post-AHSCT, expression of Bak, Bim, Bcl-2, Bcl-xL and cFlip-L was decreased when compared to baseline values. In summary, our findings suggest that normalization of apoptosis-related molecules is associated with the early therapeutic effects of AHSCT in MS patients. These mechanisms may be involved in the re-establishment of immune tolerance during the first 2 years post-transplantation.

Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients.

Autologous hematopoietic SCT (AHSCT) has been investigated in the past as a therapeutic alternative for multiple sclerosis (MS). Despite advances in clinical management, knowledge about mechanisms involved with clinical remission post transplantation is still limited. Abnormal microRNA and gene expression patterns were described in MS and have been suggested as disease biomarkers and potential therapeutic targets. Here we assessed T- and B-cell reconstitution, microRNAs and immunoregulatory gene expression after AHSCT. Early immune reconstitution was mainly driven by peripheral homeostatic proliferation. AHSCT increased CD4(+)CD25(hi)FoxP3(+) regulatory T-cell counts and expression of CTLA-4 and GITR (glucocorticoid-induced TNFR) on CD4(+)CD25(hi) T cells. We found transient increase in exhausted PD-1(+) T cells and of suppressive CD8(+)CD28(-)CD57(+) T cells. At baseline, CD4(+) and CD8(+) T cells from MS patients presented upregulated miR-16, miR-155 and miR-142-3p and downregulated FOXP3, FOXO1, PDCD1 and IRF2BP2. After transplantation, the expression of FOXP3, FOXO1, PDCD1 and IRF2BP2 increased, reaching control levels at 2 years. Expression of miR-16, miR-155 and miR-142-3p decreased towards normal levels at 6 months post therapy, remaining downregulated until the end of follow-up. These data strongly suggest that AHSCT normalizes microRNA and gene expression, thereby improving the immunoregulatory network. These mechanisms may be important for disease control in the early periods after AHSCT.

Familial neuromyelitis optica.

BACKGROUND: Detection of aquaporin-4-specific immunoglobulin G (IgG) has expanded the spectrum of neuromyelitis optica (NMO). Rare reports of familial aggregation have suggested a component of genetic susceptibility but these reports mostly antedated the discovery of the NMO-IgG biomarker and recently updated diagnostic criteria. METHODS: We report a case series describing the demographic, clinical, neuroimaging, and NMO-IgG serologic status of 12 multiplex NMO pedigrees with a total of 25 affected individuals. RESULTS: Twenty-one patients (84%) were women. Families were Asian (n = 5), Latino (n = 4), white (n = 1), or African (n = 2). Apparent transmission was either maternal (n = 5) or paternal (n = 2). In 1 family, 3 individuals had NMO; in the others, 2 individuals were affected. Sibling pairs (n = 6), parent-child (n = 4), and aunt-niece (n = 3) pairs were observed. Nineteen patients (76%) were NMO-IgG positive. Twelve (48%) had clinical or serologic evidence of another autoimmune disease. Familial occurrence of NMO occurs in approximately 3% of patients with well-established diagnosis of NMO. CONCLUSIONS: A small proportion of patients with NMO have relatives with this condition, but familial occurrence is more common than would be expected from its frequency in the general population. Familial NMO is indistinguishable from sporadic NMO based on clinical symptoms, age at onset, sex distribution, and frequency of NMO-IgG detection. One or 2 generations were affected and affected individuals represented a small fraction of family members. Taken together, these data suggest complex genetic susceptibility in NMO.

Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG.

Studies have shown that autologous hematopoietic SCT (HSCT) can be used as an intensive immunosuppressive therapy to treat refractory patients and to prevent the progression of multiple sclerosis (MS). This is a prospective multicentric Brazilian MS trial comparing two conditioning regimens: BEAM/horse ATG and CY/rabbit ATG. Most (80.4%) of the 41 subjects in the study had the secondary progressive MS subtype and the mean age was 42 years. The baseline EDSS score in 58.5% of the subjects was 6.5 and 78% had a score of 6.0 or higher, respectively. The complication rate during the intra-transplantation period was 56% for all patients: 71.4% of the patients in the BEAM/hATG group and 40% in the CY/rATG group (P=0.04). Three subjects (7.5%) died of cardiac toxicity, sepsis and alveolar hemorrhage, all of them in the BEAM/ATG group. EFS was 58.54% for all patients: 47% in the BEAM/hATG group and 70% in the CY/rATG group (P=0.288). In conclusion, the CY/rATG regimen seems to be associated with similar outcome results, but presented less toxicity when compared with the BEAM/hATG regimen. Long-term follow-up would be required to fully assess the differences in therapeutic effectiveness between the two regimens.

Hereditary motor and autonomic neuronopathy 1 maps to chromosome 20q13.2-13.3.

The spinal muscular atrophies (SMA) or hereditary motor neuronopathies result from the continuous degeneration and death of spinal cord lower motor neurons, leading to progressive muscular weakness and atrophy. We describe a large Brazilian family exhibiting an extremely rare, late-onset, dominant, proximal, and progressive SMA accompanied by very unusual manifestations, such as an abnormal sweating pattern, and gastrointestinal and sexual dysfunctions, suggesting concomitant involvement of the autonomic nervous system. We propose a new disease category for this disorder, 'hereditary motor and autonomic neuronopathy', and attribute the term, 'survival of motor and autonomic neurons 1' (SMAN1) to the respective locus that was mapped to a 14.5 cM region on chromosome 20q13.2-13.3 by genetic linkage analysis and haplotype studies using microsatellite polymorphic markers. This locus lies between markers D20S120 and D20S173 showing a maximum LOD score of 4.6 at D20S171, defining a region with 33 known genes, including several potential candidates. Identifying the SMAN1 gene should not only improve our understanding of the molecular mechanisms underlying lower motor neuron diseases but also help to clarify the relationship between motor and autonomic neurons.

Hereditary motor and autonomic neuronopathy 1 maps to chromosome 20q13.2-13.3

The spinal muscular atrophies (SMA) or hereditary motor neuronopathies result from the continuous degeneration and death of spinal cord lower motor neurons, leading to progressive muscular weakness and atrophy. We describe a large Brazilian family exhibiting an extremely rare, late-onset, dominant, proximal, and progressive SMA accompanied by very unusual manifestations, such as an abnormal sweating pattern, and gastrointestinal and sexual dysfunctions, suggesting concomitant involvement of the autonomic nervous system. We propose a new disease category for this disorder, `hereditary motor and autonomic neuronopathy', and attribute the term, `survival of motor and autonomic neurons 1' (SMAN1) to the respective locus that was mapped to a 14.5 cM region on chromosome 20q13.2-13.3 by genetic linkage analysis and haplotype studies using microsatellite polymorphic markers. This locus lies between markers D20S120 and D20S173 showing a maximum LOD score of 4.6 at D20S171, defining a region with 33 known genes, including several potential candidates. Identifying the SMAN1 gene should not only improve our understanding of the molecular mechanisms underlying lower motor neuron diseases but also help to clarify the relationship between motor and autonomic neurons.

Dejerine-Sottas' neuropathy caused by the missense mutation PMP22 Ser72Leu.

OBJECTIVE: To describe a patient with the Dejerine-Sottas' syndrome due to a de novo Ser72Leu amino acid substitution in the PMP22 protein and summarize the phenotype associated with this frequent mutation. CASE REPORT: The proband has a medical history of early onset, severe, and progressive demyelinating neuropathy, accompanied by mild ptosis and limitations of eye movements. Ulnar nerve motor conduction velocities were extremely reduced (2.6 and 2.2 m/s), and the sural nerve biopsy showed onion bulbs and thinly myelinated axons. Duplication of chromosome 17p11.2 was ruled out, and the Ser72Leu substitution was found upon sequencing the PMP22 gene. CONCLUSION: The Ser72Leu substitution is being confirmed as the most frequent point mutation in the PMP22 gene. This 'hot spot' should be considered in the strategy of looking for point mutations in the hereditary demyelinating neuropathies.

The end-to-side peripheral nerve repair. Functional and morphometric study using the peroneal nerve of rats.

Morphologic and functional recovery following an end-to-side repair was studied comparatively with conventional end-to-end repair in a model of peroneal nerve lesion in rats. Twenty-eight rats were used and divided into four groups according to the reparative procedure following nerve division: (1) nerve stumps buried into neighboring muscles (n = 8); (2) conventional end-to-end repair (n = 7); (3) end-to-side repair onto the tibial nerve (n = 8); (4) sham operation (n = 5). The sciatic functional index (SFI) was evaluated at weekly intervals for 8 weeks, the peroneal nerve being resected on the 56th day for histologic and morphometric studies. The SFI progressively improved in Groups 2 (-16.9) and 3 (-22.7), although it did not reach normal values (around -8). The average nerve fiber density increased to normal values in both Groups 2 and 3, although accompanied by a marked decrease of average minimal and maximal nerve fiber diameter, myelin sheath area and G quotient. The differences between Groups 2 and 3 or Groups 2 and 4 were not significant. We conclude that, although resulting in significant morphologic and functional recovery, end-to-side repair is not as efficient as the conventional end-to-end nerve repair. However, end-to-side repair has a potential for application in selected cases in humans.

Myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy.

BACKGROUND: Multicore disease and congenital fibre type disproportion myopathy are diseases assigned to the heterogeneous group of congenital myopathies. Although hypotonia and muscle weakness appearing in early life are the commonest manifestations of these diseases, distinct phenotypes and late onset cases have been described. OBJECTIVE: To report the occurrence of myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy. METHODS: The clinical cases of three patients with fibre type disproportion myopathy and one with multicore disease are described. Skeletal muscle biopsies were processed for routine histological and histochemical studies. RESULTS: The clinical picture was unusual in that the symptoms were of late onset and the predominant complaint was muscle pain exacerbated by exercise. Muscle weakness was found in only a single patient, the mother of a patient with fibre type disproportion myopathy. Physical examination was unremarkable in the other patients. Muscle biopsies from patients 1 and 2 contained type I fibres that were considerably smaller than the type II fibres, supporting the diagnosis of fibre type disproportion myopathy. Skeletal muscle of patient 4 showed multiple areas, predominantly but not exclusively in the type I fibres, from which oxidative enzyme activities were absent, as seen in multicore disease. CONCLUSIONS: Muscle pain was the main clinical manifestation in our patients. Recognition of the broader clinical expression of these myopathies is important for prognostic reasons and for genetic counselling of the family members.

Arterial baroreceptors and experimental diabetes.

Alterations of the autonomic reflex control of the cardiovasclar system have been demonstrated in clinical and animal models of insulin-dependent diabetes mellitus. Established neuroaxonal dystrophy is considered the neuropathological hallmark of chronic experimental diabetes. However, the afferent arm of the arterial baroreflex, that is, the carotid sinus nerve and the aortic depressor nerve, has received much less attention in studies dealing with this physiopathological model. The attenuation of the pressure response to bilateral carotid occlusion in conscious rats indicates a derangement of the baroreflex, probably involving an alteration of the carotid sinus nerve. There is histological evidence obtained from adult spontaneous insulin-dependent diabetic rats (strain BB/S) of a carotid sinus nerve with signs of axonal swelling and intramyelinic edema, suggesting diabetic neuropathy. The study of aortic baroreceptor activity in anesthetized rats with short- and long-term streptozotocin diabetes by means of cross-spectral analysis of baroreceptor activity versus arterial pressure revealed a dysfunction in the afferent arm of the baroreflex even during a short period of diabetes. The morphology of the aortic depressor nerve of streptozotocin-diabetic rats indicated axonal atrophy by visual analysis remarkably at the distal segments of the nerves. This finding was confirmed by morphometric study of the myelinated fibers. In conclusion, although studies of the arterial baroreceptors related to experimental diabetes are scanty in the literature, there is electrophysiological and histological evidence demonstrating that the carotid sinus and the aortic depressor nerves are abnormal in this experimental model.

Aortic depressor nerve unmyelinated fibers in spontaneously hypertensive rats.

The objective of the present study was to compare the morphology of the unmyelinated fibers in the aortic depressor nerves (ADN) of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). In anesthetized rats, the ADN was identified by its spontaneous activity synchronous with the arterial pulses. Thin sections of the proximal and distal segments of the ADN were analyzed by electron microscopy, and a morphometric study of the unmyelinated fibers and Schwann cells was performed. The proximal segments of WKY and SHR ADN contain an average of 335 +/- 68 and 130 +/- 14 unmyelinated fibers, respectively (P < 0.05), and the distal segments contain an average of 337 +/- 46 and 242 +/- 77 unmyelinated fibers, respectively (P < 0.05). The distribution of the diameters of unmyelinated fibers was unimodal for both strains, with the histogram from the SHR significantly shifted to the left. Because the unmyelinated fibers play a role in the tonic inhibition of the medullary vasomotor centers, especially in the presence of hypertension, the morphological differences observed in the ADN from SHR may account, at least in part, for the blunted baroreflex of SHR.

Limitations on the clinical utility of the ulnar dorsal cutaneous sensory nerve action potential.

OBJECTIVE: To validate the clinical use of the ulnar dorsal cutaneous (UDCN) sensory nerve action potential (SNAP) in the topographical analysis of ulnar mononeuropathies and in the process of choosing a sensory nerve for biopsy. METHODS: We surveyed the UDCN SNAP electrophysiological characteristics in both hands of 97 normal volunteers aged 10-84 years. The nerve was recorded from the 4th intermetacarpal space with subcutaneous needle electrodes and percutaneous stimulation was carried out at the wrist. RESULTS: In agreement with other studies, the mean conduction velocity was 58. 6+/-6.7 m/s, but the mean and the lower normal value of the amplitude (32 and 14.7 microV) were significantly higher than previous known data. An important finding was that in 21% of our population study, the UDCN SNAP was absent on at least one side, or a significant degree of asymmetry between the left and right sides was present. CONCLUSION: The UDCN SNAP is technically easy to obtain, but the high frequency of asymmetric or absent potentials detected in this study implies that caution should be taken in using this SNAP in clinical practice.

Morphology of aortic depressor nerve myelinated fibers in normotensive Wistar-Kyoto and spontaneously hypertensive rats.

Reports on the morphology of the baroreceptor terminal of spontaneously hypertensive rats (SHR) did not demonstrate any difference when compared to the axonal terminal of normotensive rats. Although several studies reporting baroreceptor terminal and blood vessel wall morphology have been carried out to better understand the baroreceptor function and resetting to hypertensive levels, there are no reports examining the morphology of the fibers of the aortic depressor nerve (ADN) in hypertensive models. Therefore, the objective of the present study was to investigate the morphological aspects of SHR ADN compared to Wistar-Kyoto (WKY) rats. Before the morphologic study, the nerves were isolated and the pressure-nerve activity curve was determined for each ADN. SHR exhibited an increase in the threshold pressure for baroreceptor activation, a rightward shift in the pressure-nerve activity curve with decreases in slope and maximum activity. Semithin (0.3 to 0.5 microm thick) sections of the proximal (close to the nodose ganglion) and distal (close to the aortic arch) segments of the ADN were analyzed by light microscopy. A morphometric study of the nerve fascicles and myelinated fibers was performed. Comparison between proximal and distal segments of the two strains revealed that the ADN of WKY rats were consistently larger. All morphometric parameters studied in myelinated fibers and their respective axons were smaller in SHR. The area of the myelin sheath was comparatively larger in WKY rats. These data show morphologic differences between the ADN of SHR and WKY rats, which may explain, at least in part, the decreased slope and maximum activity of the pressure-nerve activity curve observed with the baroreceptor resetting in SHR.

Normal median near nerve potential

In routine studies of sensory nerve conduction, only fibers 37 mum in diameter are analyzed. The late components which originate from thinner fibers are not detected. This explains why a normal sensory action potential (SAP) may be recorded in patients with peripheral neuropathies and sensory loss. In the present study we investigated the late component of the median SAP with a near nerve needle electrode technique in 14 normal volunteers (7 men and 7 women), aged 34.5 + 14.8 years. The stimulus consisted of rectangular pluses of 0.2-ms duration at a frequency of 1 Hz with an intensity at least 6 times greater than the threshold value for the main component. Five hundred to 2000 sweep averagings were performed. The duration of analysis was 40 or 50 ms and the wave analysis frequency was 200 (-6 dB/oct) to 3000 Hz (-12 dB/oct). We used an apparatus with a two-channel amplifier system, 200 MW or more of entry impedance and a noise level of 0.7 muVrms or less. The main component mean amplitude, conduction velocity and lactency and the late component mean amplitude, conduction velocity and latency were respectively (mean + SD): 26.5 + 5.42 muV, 56.8 + 5.42 m/s, 3.01 + 0.31 ms, 0.12 + 0.04 muV, 16.4 + 2.95 m/s and 10.6 + 2.48 ms. More sophisticated equipment has an internal noise of 0.6 muVrms. These data demonstrate that the technique can now be employed study thin fiber neuropathies, like in leprosy, using commercial electromyographs, even in non-academic practices.

A descriptive and quantitative light and electron microscopy study of the aortic depressor nerve in normotensive rats.

There is no literature report of a detailed morphologic study of the aortic depressor nerve. The aim of this study was to describe the general morphological aspects and to obtain morphometric parameters for the aortic depressor nerve of normotensive Wistar rats (n=12). Before the morphologic studies, nerves were isolated and pressure-nerve activity curves were obtained. Basal mean arterial pressure was 117+/-5 mm Hg, the systolic pressure threshold was 100+/-7 mm Hg, and mean arterial pressure at 50% of maximal activity was 115+/-5 mm Hg and the baroreceptor gain 1.99+/-0.09%/mm Hg. Semithin and thin sections of proximal and distal nerve segments were then examined by light and electron microscopy, respectively. The main nerve components were (1) unmyelinated and myelinated axons; (2) Schwann cells; (3) capillary wall endothelial cells and pericytes; (4) collagen fibers in the epineurium and endoneurium and between perineurial cell layers; and (5) fibroblasts and mast cells. The depressor nerves were found to contain 204-996 axons per nerve, 80% of which, on average, were unmyelinated, with a 4:1 unmyelinated/myelinated axon ratio. The unmyelinated axon histogram was unimodal, with a mean diameter of 0.5+/-0.02 microm. Myelinated fibers had axons averaging 1.3+/-0.06 microm in diameter and representing 53% of the total fiber diameter. The ratio between axonal and total fiber diameter of myelinated fiber ranged from 0.4 to 0.8 and tended to increase with axon size. Proximal and distal segments were morphologically similar. In conclusion, the morphologic description of the depressor nerve provides important data for further investigations of the structural basis of altered baroreflex responses in conditions such as arterial hypertension, aging, atherosclerosis, and peripheral neuropathies.