Cardiovascular and sensory abnormalities in a rat model of insulin resistance : beneficial effect of an antioxidant and an angiotensin-1 converting enzyme inhibitor

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Central poststroke pain: somatosensory abnormalities and the presence of associated myofascial pain syndrome

Background: Central post-stroke pain (CPSP) is a neuropathic pain syndrome associated with somatosensory abnormalities due to central nervous system lesion following a cerebrovascular insult. Post-stroke pain (PSP) refers to a broader range of clinical conditions leading to pain after stroke, but not restricted to CPSP, including other types of pain such as myofascial pain syndrome (MPS), painful shoulder, lumbar and dorsal pain, complex regional pain syndrome, and spasticity-related pain. Despite its recognition as part of the general PSP diagnostic possibilities, the prevalence of MPS has never been characterized in patients with CPSP patients. We performed a cross-sectional standardized clinical and radiological evaluation of patients with definite CPSP in order to assess the presence of other non-neuropathic pain syndromes, and in particular, the role of myofascial pain syndrome in these patients. Methods: CPSP patients underwent a standardized sensory and motor neurological evaluation, and were classified according to stroke mechanism, neurological deficits, presence and profile of MPS. The Visual Analogic Scale (VAS), McGill Pain Questionnaire (MPQ), and Beck Depression Scale (BDS) were filled out by all participants. Results: Forty CPSP patients were included. Thirty-six (90.0%) had one single ischemic stroke. Pain presented during the first three months after stroke in 75.0%. Median pain intensity was 10 (5 to 10). There was no difference in pain intensity among the different lesion site groups. Neuropathic pain was continuous-ongoing in 34 (85.0%) patients and intermittent in the remainder. Burning was the most common descriptor (70%). Main aggravating factors were contact to cold (62.5%). Thermo-sensory abnormalities were universal. MPS was diagnosed in 27 (67.5%) patients and was more common in the supratentorial extra-thalamic group (P <0.001). No significant differences were observed among the different stroke location groups and pain questionnaires and scales scores. Importantly, CPSP patients with and without MPS did not differ in pain intensity (VAS), MPQ or BDS scores. Conclusions: The presence of MPS is not an exception after stroke and may present in association with CPSP as a common comorbid condition. Further studies are necessary to clarify the role of MPS in CPSP.

Neurology of ciguatera

Ciguatera is a widespread ichthyosarcotoxaemia with dramatic and clinically important neurological features. This severe form of fish poisoning may present with either acute or chronic intoxication syndromes and constitutes a global health problem. Ciguatera poisoning is little known in temperate countries as a potentially global problem associated with human ingestion of large carnivorous fish that harbour the bioaccumulated ciguatoxins of the photosynthetic dinoflagellate Gambierdiscus toxicus. This neurotoxin is stored in the viscera of fish that have eaten the dinoflagellate and concentrated it upwards throughout the food chain towards progressively larger species, including humans. Ciguatoxin accumulates in all fish tissues, especially the liver and viscera, of at risk species. Both Pacific (P-CTX-1) and Caribbean (C-CTX-1) ciguatoxins are heat stable polyether toxins and pose a health risk at concentrations above 0.1 ppb. The presenting signs of ciguatera are primarily neurotoxic in more than 80% of cases. Such include the pathognomonic features of postingestion paraesthesiae, dysaesthesiae, and heightened nociperception. Other sensory abnormalities include the subjective features of metallic taste, pruritis, arthralgia, myalgia, and dental pain. Cerebellar dysfunction, sometimes diphasic, and weakness due to both neuropathy and polymyositis may be encountered. Autonomic dysfunction leads to hypotension, bradycardia, and hypersalivation in severe cases. Ciguatoxins are potent, lipophilic sodium channel activator toxins which bind to the voltage sensitive (site 5) sodium channel on the cell membranes of all excitable tissues. Treatment depends on early diagnosis and the early administration of intravenous mannitol. The early identification of the neurological features in sentinel patients has the potential to reduce the number of secondary cases in cluster outbreaks.

Role of JNK isoforms in the development of neuropathic pain following sciatic nerve transection in the mouse.

ABSTRACT: BACKGROUND: Current tools for analgesia are often only partially successful, thus investigations of new targets for pain therapy stimulate great interest. Consequent to peripheral nerve injury, c-Jun N-terminal kinase (JNK) activity in cells of the dorsal root ganglia (DRGs) and spinal cord is involved in triggering neuropathic pain. However, the relative contribution of distinct JNK isoforms is unclear. Using knockout mice for single isoforms, and blockade of JNK activity by a peptide inhibitor, we have used behavioral tests to analyze the contribution of JNK in the development of neuropathic pain after unilateral sciatic nerve transection. In addition, immunohistochemical labelling for the growth associated protein (GAP)-43 and Calcitonin Gene Related Peptide (CGRP) in DRGs was used to relate injury related compensatory growth to altered sensory function. RESULTS: Peripheral nerve injury produced pain-related behavior on the ipsilateral hindpaw, accompanied by an increase in the percentage of GAP43-immunoreactive (IR) neurons and a decrease in the percentage of CGRP-IR neurons in the lumbar DRGs. The JNK inhibitor, D-JNKI-1, successfully modulated the effects of the sciatic nerve transection. The onset of neuropathic pain was not prevented by the deletion of a single JNK isoform, leading us to conclude that all JNK isoforms collectively contribute to maintain neuropathy. Autotomy behavior, typically induced by sciatic nerve axotomy, was absent in both the JNK1 and JNK3 knockout mice. CONCLUSIONS: JNK signaling plays an important role in regulating pain threshold: the inhibition of all of the JNK isoforms prevents the onset of neuropathic pain, while the deletion of a single splice JNK isoform mitigates established sensory abnormalities. JNK inactivation also has an effect on axonal sprouting following peripheral nerve injury.

Effect of the 5-HT4 receptor and serotonin transporter on visceral hypersensitivity in rats

Visceral hypersensitivity plays an important role in motor and sensory abnormalities associated with irritable bowel syndrome, but the underlying mechanisms are not fully understood. The present study was designed to evaluate the expression of the 5-HT4 receptor and the serotonin transporter (SERT) as well as their roles in chronic visceral hypersensitivity using a rat model. Neonatal male Sprague-Dawley rats received intracolonic injections of 0.5% acetic acid (0.3-0.5 mL at different times) between postnatal days 8 and 21 to establish an animal model of visceral hypersensitivity. On day 43, the threshold intensity for a visually identifiable contraction of the abdominal wall and body arching were recorded during rectal distention. Histological evaluation and the myeloperoxidase activity assay were performed to determine the severity of inflammation. The 5-HT4 receptor and SERT expression of the ascending colon were monitored using immunohistochemistry and Western blot analyses; the plasma 5-HT levels were measured using an ELISA method. As expected, transient colonic irritation at the neonatal stage led to visceral hypersensitivity, but no mucosal inflammation was later detected during adulthood. Using this model, we found reduced SERT expression (0.298 ± 0.038 vs 0.634 ± 0.200, P < 0.05) and increased 5-HT4 receptor expression (0.308 ± 0.017 vs 0.298 ± 0.021, P < 0.05). Treatment with fluoxetine (10 mg·kg-1·day-1, days 36-42), tegaserod (1 mg·kg-1·day-1, day 43), or the combination of both, reduced visceral hypersensitivity and plasma 5-HT levels. Fluoxetine treatment increased 5-HT4 receptor expression (0.322 ± 0.020 vs 0.308 ± 0.017, P < 0.01) but not SERT expression (0.219 ± 0.039 vs 0.298 ± 0.038, P = 0.654). These results indicate that both the 5-HT4 receptor and SERT play a role in the pathogenesis of visceral hypersensitivity, and its mechanism may be involved in the local 5-HT level.

Examen neurológico

Se realizó un capítulo sobre la descripción del examen neurológico como herramienta principal en el abordaje del paciente con patología neurológica.

Relação entre potenciais evocados auditivos de média latência e distúrbio de processamento auditivo: estudo de casos

The Auditory Evoked Middle Latency Response is one of the most promising objective tests in audiology and in revealing brain dysfunction and neuro-audiologic findings. The main advantages of its clinical use are precision and objectivity in evaluating children. This study aimed to analyze the auditory evoked middle latency response in two patients with auditory processing disorder and relate objective and behavioral measures. This case study was conducted in 2 patients (P1 = 12 years, female, P2 = 17 years old, male), both with the absence of sensory abnormalities, neurological and neuropsychiatric disorders. Both were submitted to anamnesis, inspection of the external ear canal, hearing test and evaluation of Auditory Evoked Middle latency Response. There was a significant association between behavioral test and objectives results. In the interview, there were complaints about the difficulty in listening in a noisy environment, sound localization, inattention, and phonological changes in writing and speaking, as confirmed by evaluation of auditory processing and Auditory Evoked Middle Latency Response. Changes were observed in the right decoding process hearing in both cases on the behavioral assessment of auditory processing; auditory evoked potential test middle latency shows that the right contralateral via response was deficient, confirming the difficulties of the patients in the assignment of meaning in acoustic information in a competitive sound condition at right, in both cases. In these cases it was shown the association between the results, but there is a need for further studies with larger sample population to confirm the data.

Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord

The primary sensory neurons that respond to noxious stimulation and project to the spinal cord are known to fall into two distinct groups: one sensitive to nerve growth factor and the other sensitive to glial cell-line-derived neurotrophic factor. There is currently considerable interest in the ways in which these factors may regulate nociceptor properties. Recently, however, it has emerged that another trophic factor—brain-derived neurotrophic factor (BDNF)—may play an important neuromodulatory role in the dorsal horn of the spinal cord. BDNF meets many of the criteria necessary to establish it as a neurotransmitter/neuromodulator in small-diameter nociceptive neurons. It is synthesized by these neurons and packaged in dense core vesicles in nociceptor terminals in the superficial dorsal horn. It is markedly up-regulated in inflammatory conditions in a nerve growth factor-dependent fashion. Postsynaptic cells in this region express receptors for BDNF. Spinal neurons show increased excitability to nociceptive inputs after treatment with exogenous BDNF. There are both electrophysiological and behavioral data showing that antagonism of BDNF at least partially prevents some aspects of central sensitization. Together, these findings suggest that BDNF may be released from primary sensory nociceptors with activity, particularly in some persistent pain states, and may then increase the excitability of rostrally projecting second-order systems. BDNF released from nociceptive terminals may thus contribute to the sensory abnormalities associated with some pathophysiological states, notably inflammatory conditions.

Role of gender in transthyretin-related amyloidosis: an international perspective based on the Transthyretin Amyloid Outcomes Survey (THAOS)

Background. Transthyretin amyloidosis (ATTR) is an underdiagnosed disease caused by destabilization of transthyretin (TTR) due to pathogenic mutations (ATTRm) or aging (ATTRwt). We explored the role of gender in determining clinical picture using the largest available database on ATTR, the ongoing Transthyretin Amyloid Outcomes Survey (THAOS) international registry. Methods. Data through 1st April 2019 were explored. Symptomatic ATTRm (n=3737), asymptomatic ATTRm (n=644) and ATTRwt (n=874) patients were studied. Results. Male prevalence was 61% in the entire registry, 53% in ATTRm and 95% in ATTRwt. In the overall cohort, cardiac phenotype was more frequent in males (30.7% vs 10.5%, p<0.001). Among ATTRm, 72.3% of patients with amyloidotic cardiomyopathy (ATTR-CM) were males (p<0.001) but echocardiographic features showed no substantial gender differences. Sensory abnormalities (70.1% vs 64.1%, p<0.001), autonomic abnormalities (60% vs 48.5%, p<0.001) and walking disabilities were more frequent among ATTRm males. Carpal tunnel syndrome was more frequent in ATTRm males (18.6% vs 15.5%, p=0.014). In ATTRwt cohort, females had a more pronounced (but anyhow mild) walking disability. Male-to-female ratio varied within genotype, from 0.61 in Val30Met to 11.11 in ATTRwt; furthermore, males’ imbalance was more evident among symptomatic patients rather than in asymptomatic ones. Male gender, age at presentation and specific genotype were independently associated with the presence of ATTR-CM. Conclusions. In ATTR, cardiac involvement is more frequent in men, supporting the hypothesis that some biologic characteristics may “protect” from myocardial amyloid infiltration in women. Further investigations are needed to identify possible underlying protective mechanism and orient the research for innovative, gender-tailored therapeutic approaches.

Case Series: Sensory Intolerance as a Primary Symptom of Pediatric OCD

Introduction. Marked intolerance or intrusive re-experiencing of ordinary sensory stimuli that in turn drive functionally impairing compulsive behaviors are occasionally seen in voting children with OCD. Methods. We describe a number of children with DSM-IV OCD ascertained from of family genetic study of pediatric OCD, whose intolerance: of ordinary sensory stimuli created significant subjective distress and time-consuming ritualistic behavior that was clinically impairing. Results. In each case these sensory symptoms were the primary presenting symptoms and were experienced in the absence of intrusive thoughts, images, or ideas associated with ""conventional"" OCD symptoms. Conclusions. These symptoms suggest abnormalities in sensory processing and integration in at least a subset of OCD patients. Recognition of these sensory symptoms and sensory-driven behaviors as part of the broad phenotypic Variation in children with OCD could help clinicians more easily identify OCD patients and,facilitate treatment.

Regional gray matter abnormalities in panic disorder: A voxel-based morphometry study

Although abnonnalities in brain structures involved in the neurobiology of fear and anxiety have been implicated in the pathophysiology of panic disorder (PD), relatively few studies have made use of voxel-based morphometry (VBM) magnetic resonance imaging (MRI) to determine structural brain abnormalities in PD. We have assessed gray matter volume in 19 PD patients and 20 healthy volunteers using VBM. Images were acquired using a 1.5 T MRI scanner, and were spatially normalized and segmented using optimized VBM. Statistical comparisons were performed using the general linear model. A relative increase in gay matter volume was found in the left insula of PD patients compared with controls. Additional structures showing differential increases were the left superior temporal gyrus, the midbrain, and the pons. A relative gray matter deficit was found in the right anterior cingulate cortex. The insula and anterior cingulate abnormalities may be relevant to the pathophysiology of PD, since these structures participate in the evaluation process that ascribes negative emotional meaning to potentially distressing cognitive and interoceptive sensory information. The abnormal brain stem structures may be involved in the generation of panic attacks. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

Abnormalities in the processing of emotional prosody from single words in schizophrenia

Background: Abnormalities in emotional prosody processing have been consistently reported in schizophrenia and are related to poor social outcomes. However, the role of stimulus complexity in abnormal emotional prosody processing is still unclear. Method: We recorded event-related potentials in 16 patients with chronic schizophrenia and 16 healthy controls to investigate: 1) the temporal course of emotional prosody processing; and 2) the relative contribution of prosodic and semantic cues in emotional prosody processing. Stimuli were prosodic single words presented in two conditions: with intelligible (semantic content condition—SCC) and unintelligible semantic content (pure prosody condition—PPC). Results: Relative to healthy controls, schizophrenia patients showed reduced P50 for happy PPC words, and reduced N100 for both neutral and emotional SCC words and for neutral PPC stimuli. Also, increased P200 was observed in schizophrenia for happy prosody in SCC only. Behavioral results revealed higher error rates in schizophrenia for angry prosody in SCC and for happy prosody in PPC. Conclusions: Together, these data further demonstrate the interactions between abnormal sensory processes and higher-order processes in bringing about emotional prosody processing dysfunction in schizophrenia. They further suggest that impaired emotional prosody processing is dependent on stimulus complexity.

Validation of diagnosis criteria for acquired sensory neuronopathy. a francophone multicenter study

Recently published criteria using clinical (ataxia or asymmetrical distribution at onset or full development, and sensory loss not restricted to the lower limbs) and electrophysiological items (less than two abnormal lower limb motor nerves and at least an abolished SAP or three SAP below 30% of lower limit of normal in the upper limbs) were sensitive and specific for the diagnosis of sensory neuronopathy (SNN) (Camdessanche et al., Brain, 2009). However, these criteria need to be validated on a large multicenter population. For this, a database collecting cases from fifteen Reference Centers for Neuromuscular diseases in France and Switzerland is currently developed. So far, data from 120 patients with clinically pure sensory neuropathy have been collected. Cases were classified independently from the evaluated criteria as SNN (53), non-SNN (46) or suspected SNN (21) according to the expert's diagnosis. Using the criteria, SNN was possible in 83% (44/53), 23.9% (11/46) and 71.4% (15/21) of cases, respectively. In the non-SSN group, half of the patients with a diagnosis of possible SSN had an ataxic form of inflammatory demyelinating neuropathy. In the SNN group, half of those not retained as possible SNN had CANOMAD, paraneoplasia, or B12 deficiency. In a second step, after application of the items necessary to reach the level of probable SNN (no biological or electrophysiological abnormalities excluding SNN; presence of onconeural antibody, cisplatin treatment, Sj ¨ ogren's syndrome or spinal cord MRI high signal in the posterior column), a final diagnosis of possible or probable SNN was obtained in, respectively, 90.6% (48/53), 8.8% (4/45), and 71.4% (15/21) of patients in the three groups. Among the 5 patients with a final non-SNN but initial SNN diagnosis, 3 had motor conduction abnormalities (one with CANOMAD) and among the 4 patients with a final SNN but initial non-SSN diagnosis, one had anti-Hu antibody and one was discussed as a possible ataxic CIDP. These preliminary results confirm the sensitivity and specificity of the proposed criteria for the diagnosis of SNN.

The expansion of 300 CTG repeats in myotonic dystrophy transgenic mice does not induce sensory or motor neuropathy.

Although many studies have been carried out to verify the involvement of the peripheral nervous system (PNS) in dystrophia myotonica (DM1) patients, the results remain controversial. The generation of DM1 transgenic mice displaying the human DM1 phenotype provides a useful tool to investigate the type and incidence of structural abnormalities in the PNS. In the present study, the morphological and morphometric analysis of semi-thin sections of sciatic and sural nerves, lumbar dorsal root ganglia (DRG) and lumbar spinal cords revealed that in DM1 transgenic mice carrying 300 CTG repeats, there is no change in the number and diameter of myelinated axons compared to wild type. Only a non-significant reduction in the percentage of thin myelinated axons was detected in electron micrographs of ultra-thin sciatic nerve sections. Analysis of the number of neurons did not reveal a loss in number of either sensory neurons in the lumbar DRG or motor neurons in the lumbar spinal cord in these DM1 mice. Furthermore, in hind limb muscle sections, stained with a neurofilament antibody and alpha-bungarotoxin, the intramuscular axon arborization appeared normal in DM1 mice and undistinguishable from that in wild-type mice. Moreover, in DM1 mice, there was no irregularity in the structure or an increase in the endplate area. Also statistical analysis did not show an increase in endplate density or in the concentration of acetylcholine receptors. Altogether, these results suggest that 300 CTG repeats are not sufficient to induce axonopathy, demyelination or neuronopathies in this transgenic mouse model.

Focal dystonia and the Sensory-Motor Integrative Loop for Enacting (SMILE).

Performing accurate movements requires preparation, execution, and monitoring mechanisms. The first two are coded by the motor system, the latter by the sensory system. To provide an adaptive neural basis to overt behaviors, motor and sensory information has to be properly integrated in a reciprocal feedback loop. Abnormalities in this sensory-motor loop are involved in movement disorders such as focal dystonia, a hyperkinetic alteration affecting only a specific body part and characterized by sensory and motor deficits in the absence of basic motor impairments. Despite the fundamental impact of sensory-motor integration mechanisms on daily life, the general principles of healthy and pathological anatomic-functional organization of sensory-motor integration remain to be clarified. Based on the available data from experimental psychology, neurophysiology, and neuroimaging, we propose a bio-computational model of sensory-motor integration: the Sensory-Motor Integrative Loop for Enacting (SMILE). Aiming at direct therapeutic implementations and with the final target of implementing novel intervention protocols for motor rehabilitation, our main goal is to provide the information necessary for further validating the SMILE model. By translating neuroscientific hypotheses into empirical investigations and clinically relevant questions, the prediction based on the SMILE model can be further extended to other pathological conditions characterized by impaired sensory-motor integration.