Self-representation in Kleine-Levin syndrome: a single case fMRI study.

Kleine-Levin syndrome (KLS) is characterized by recurrent episodes of hypersomnia, compulsive hyperphagia, disinhibition, hypersexuality and self modifications. To investigate the Self, we used afunctional magnetic resonance imaging paradigm evaluating Self-reference processing (SRP) and Self-reference effect (SRE) in a17-year-old male adolescent at the end of an episode. We observed enhanced activations in right hemisphere and posterior areas- associated with physical Self representations- during the SRP condition, while during the SRE condition, enhanced activations in bilateral but prevailing left frontal areas- associated with the conceptual Self. These results suggest amodified Self during aKLS episode being more physically grounded.

Proteomic analysis of plasma identifies the Toll-like receptor agonists S100A8/A9 as a novel possible marker for systemic sclerosis phenotype.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis of the skin and the internal organs. Except for anticentromere, antitopoisomerase I and antipolymerase III antibodies, there are no reliable circulating markers predicting susceptibility and internal organ complications. This study has exploited a proteome-wide profiling method with the aim to identify new markers to identify SSc phenotype. METHOD: 40 SSc patients were included for proteomic identification. Patients were stratified as having diffuse cutaneous SSc (dcSSc) (n=19) or limited cutaneous SSc (lcSSc) (n=21) according to the extent of skin involvement. As controls 19 healthy donors were included. Blood was drawn and plasma was stored before analysing with the SELDI-TOF-MS. For replication in serum, the cohort was extended with 60 SSc patients. RESULTS: Proteomic analysis revealed a list of 25 masspeaks that were differentially expressed between SSc patients and healthy controls. One of the peaks was suggestive for S100A8, a masspeak we previously found in supernatant of plasmacytoid dendritic cells from SSc patients. Increased expression of S100A8/A9 in SSc patients was confirmed in replication cohort compared with controls. Intriguingly, S100A8/A9 was highest in patients with limited cutaneous SSc having lung fibrosis. CONCLUSIONS: S100A8/A9 was robustly found to be elevated in the circulation of SSc patients, suggesting its use as a biomarker for SSc lung disease and the need to further explore the role of TLR in SSc.

A rare polymorphism in the gene for Toll-like receptor 2 is associated with systemic sclerosis phenotype and increases the production of inflammatory mediators.

OBJECTIVE: To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc). METHODS: We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells. RESULTS: In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P=0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P=0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P=0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P=0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor α and interleukin-6) upon TLR-2-mediated stimulation (both P<0.0001). CONCLUSION: Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc.

A system out of breath: how hypoxia possibly contributes to the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular alterations and immunological disturbances and fibrosis, the order of which remains to be fully determined. Clinically, patients show clear signs of hypoxia in skin and internal organs. The low oxygen tension is potentially caused by a yet to be indentified circuitry involving the three features that typify SSc. In addition, once present, the hypoxia creates a vicious circle of ongoing pathology. In this paper, we provide an overview of the evidence that points towards the mechanisms causing hypoxia in SSc. In addition, data that suggest how hypoxia itself may orchestrate worsening of symptoms is presented. Altogether, it is clear that hypoxia is an important hallmark in SSc patients. By providing an overview of the mechanisms at play and the possible therapeutic avenues that have emerged, we hope to stimulate researchers to provide novel clues into the conundrum in SSc patients.

An update on an immune system that goes awry in systemic sclerosis.

PURPOSE OF REVIEW: This review aims to provide an overview of the recent data that emerged, further substantiating the critical role of innate immunity in systemic sclerosis (SSc). RECENT FINDINGS: Driven by the evidence that newly identified SSc susceptibility genes are predominantly involved in immune regulation, we discuss the aberrant antigen presenting cell (APC) activation observed in the course of disease. In particular, we report the alternate activation of 'M1' and 'M2' macrophages reflecting different clinical phenotypes and the aberrant Toll-like receptor (TLR) response, whose effect on cytokine production is mostly evident in the early phases of disease; we especially highlight the increasing importance attributed to TLR3-mediated fibrosis. We next discuss the potential role for interferon (IFN) - producing plasmacytoid dendritic cells (pDCs) in triggering or perpetuating the inflammatory loop caused by TLR hyperactivation, possibly resulting in inflammasome-derived IL-1ß-mediated fibrosis and IL-17 producing T helper cells (Th17) skewing. SUMMARY: We propose to approach SSc as a multistep immune-mediated disease that is in need of a therapeutic strategy designed to interfere with one or more of these aberrant molecular pathways. Targeting of DCs could be such a target by which dampening the immune system could modify the course of SSc.

Toll-like receptors in rheumatic diseases: are we paying a high price for our defense against bugs?

In the last decade Toll-like receptor (TLR) research has led to new insights in the pathogenesis of many rheumatic diseases. In autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis TLR signaling is likely to be involved in tolerance breakthrough and chronic inflammation via combined Fc gamma receptors and TLR recognition of immune complexes. Furthermore, inflammatory diseases like psoriatic arthritis and gout also show more and more evidence for TLR involvement. In this review we will discuss the involvement of TLR signaling in several rheumatic diseases and stress their similarities and differences based on recent findings.

Gout: a clinical syndrome illustrated and discussed.

Gout is an acute inflammatory arthritis with the potency to fully destroy the integrity of the joint leading to severe disability. Besides joint destruction, gout is often associated with an accelerated atherosclerosis culminating in an increased risk of cardiovascular disease. The current existing therapy modalities allow an efficient treatment that not only controls local inflammation but might also have an effect on the generalised features that surround this condition. Here we discuss the modes of clinical appearance, how we are nowadays supposed to treat gout and the current knowledge about the pathogenesis of this clinical syndrome.

Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease and accumulating evidence suggests a role for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). OBJECTIVE: To map TLR-mediated cytokine responses of DCs from patients with SSc. METHODS: 45 patients with SSc were included. Patients were stratified as having diffuse cutaneous SSc (dSSc) or limited cutaneous SSc (lSSc) according to the extent of skin involvement, and further divided into those with late (>3 years) or early disease (<2 years). DCs were stimulated with ligands for TLR2, TLR3, TLR4, TLR7/8 or combinations. Plasma samples were collected from patients with SSc (n=167) and measured for interleukin 6 (IL-6), tumour necrosis factor alpha (TNFalpha), IL-12, IL-10 and interferon gamma. RESULTS: Stimulation of DC subsets from patients with early lSSc and dSSc with ligands for TLR2, TLR3 or TLR4 resulted in higher secretion of IL-6 and TNFalpha compared with those having late disease or healthy controls. Remarkably, the production of IL-12 was lower upon stimulation with TLR ligands in most patients with SSc, whereas the secretion of IL-10 was very high in patients with the dSSc phenotype, particularly in those having early dSSc. The combination of various TLR ligands led to reduced cytokine secretion in all patients with SSc. Circulating levels of these cytokines further underscored the presence of differences between various SSc phenotypes. DISCUSSION: The altered TLR-mediated activation of DCs may be responsible for Th2 skewed T-cell activation in SSc that may be orchestrated by fibrogenic T-cell cytokines, such as IL-4 and IL-13. DC targeting could thus offer new avenues for therapeutic intervention.

[Semantic dementia: reflexions of a French working group for diagnostic criteria and constitution of a patient cohort]. / Démence sémantique: réflexions d'un groupe de travail pour des critères de diagnostic en français et la constitution d'une cohorte de patients.

Semantic dementia (SD) is a syndrome of progressive loss of semantic knowledge for objects and people. International criteria propose that SD be included in the frontotemporal lobar degeneration syndromes, with progressive non-fluent aphasia and frontotemporal dementia (FTD). However, several related syndromes have been defined that clinically and conceptually share both similarities and differences with SD: fluent progressive aphasia, progressive prosopagnosia, temporal variant of FTD. In order to establish a French consensus for the diagnosis and modalities of evaluation and follow-up of SD, a working group, composed of neurologists, neuropsychologists and speech-therapists, was established by the Groupe de réflexion sur les évaluations cognitives (GRECO). New criteria were elaborated, based on clinical, neuropsychological, and imaging data. They define typical and atypical forms of SD. A diagnosis of typical SD relies on an isolated and progressive loss of semantic knowledge, attested by a deficit of word comprehension and a deficit of objects and/or people identification, with imaging showing temporal atrophy and/or hypometabolism. SD is atypical if the deficit of semantic knowledge is present only within a single modality (verbal versus visual), or if non-semantic deficits (mild and not present at onset) and/or neurological signs, are associated with the semantic loss.

Auditory-motor and cognitive aspects in area 8B of macaque monkey's frontal cortex: a premotor ear-eye field (PEEF).

In previous reports, we showed the involvement of area 8B neurons in both spontaneous ear and eye movement and in auditory information processing. Audition-related cells responded to complex environmental stimuli, but not to pure tones, and their activity changed during visual fixation as a possible inhibitory expression of the engagement of attention. We observed auditory, auditory-motor and motor cells for both eye and ear movements. This finding suggests that area 8B may be involved in the integration of auditory input with ear and eye motor output. In this paper, we extended these previous studies by examining area 8B activity in relation to auditive orienting behaviour, as well as the ocular orientation (i.e., visual fixation) studied previously. Visual fixation led to inhibition of activity in auditory and auditory-motor cells, which suggests that attention may be involved in both, maintaining the eye position and reducing the response of these cell types. Accordingly, during a given task or natural behaviour, spatial attention seems to affect more than one sensorimotor channel simultaneously. These data add to our understanding of how the neural network, through a two-channel attentive process, accomplishes to switch between two effectors, namely eyes and ears. Considering the functional, anatomical and cytoarchitectonic differences among the frontal eye field (FEF), the supplementary eye field (SEF) and area 8B, we propose to consider area 8B as a separate premotor ear-eye field (PEEF).

Time-modulated neuronal activity in the premotor cortex of macaque monkeys.

A voluntary motor act, executed in response to a stimulus, requires both spatial and temporal computation. Even though electrophysiological and positron emission tomography (PET) investigations on humans suggest that SMA, medial prefrontal cortex and primary motor cortex play a role in temporal mechanisms, we have few data about neuronal time computation in the premotor cortex. The involvement of monkey premotor area (PM) in motor learning and cognitive processes, and the presence of buildup neurons, whose activity is closely related to the motor action, prompted us to investigate the involvement of these set-related neurons in the time domain. To this end we manipulated the duration of a pre-cue in a visuomotor task while recording unit activity. We found that, when the duration of the pre-cue was predictable and long (5 s), delay of the onset of cell activity in consecutive trials gradually increased. On the other hand, when the duration was unpredictable or predictable and short (1 s), this phenomenon could not be detected. The inconsistent discharge correlations with expected reward and attentional processes, and the specific discharge relationship to the time instruction, suggest that these buildup neurons reflect a learning process in the time domain.

Neglect syndrome for aversive stimuli in a macaque monkey with dorsomedial frontal cortex lesion.

After a session of unit activity recording, one of our monkeys presented an epileptic attack, which provoked contralateral tilting movements. The following days, the animal performed saccades and fixation tasks correctly in all directions, while contralateral arm reaching movements were severely impaired. To establish if the neurological lesion had changed the orienting performance we considered two types of stimuli, pleasant and aversive. Pleasant stimuli, presented in the ipsilateral or contralateral hemifield, readily drew the attention of the animal. If the same stimuli were presented simultaneously in both hemifields, the monkey oriented itself only toward the ipsilateral one. Aversive stimuli evoked an aggressive reaction only when the stimulus was localized in the ipsilateral hemifield. The animal clearly neglected the aversive stimulus presented in the contralateral hemifield. The animal recovered completely in 30 days. The postmortem examination revealed a lesion in the dorsomedial frontal cortex. The combined attentional and motor deficits suggest that this area may be involved in the preparation and execution of movements triggered by the affective meaning of the stimulus.

Activity of neurons related to eye movements during drowsiness in the frontal cortex of the macaca monkey.

During our extensive study of the supplementary eye field (SEF) in relation to eye and arm movements, we had the opportunity to record the activity of 25 out of 315 cells during both saccade task and drowsiness states. All 25 cells showed a phasic, spatially selective postsaccadic activity that was not related to fixation. During drowsiness, the discharge was time locked with the onset of the slow movement, had increased duration, and was not spatially selective. These preliminary data suggest that saccade neurons present in SEF are also involved in the motor processes of slow eye movements during drowsiness.

Motor programs of spontaneous and visually guided saccades in macaque monkey: an electrophysiological approach.

The discharge activity of 37 burst neurons in the paramedian pontine reticular formation and the saccades performed in the dark (spontaneous saccades) and between visual targets (attentive visually guided) were recorded in two macaque monkeys. Forty-five % of spontaneous saccades showed more than one maximum of velocity (irregular velocity profiles), while visually guided saccades were always characterized by a single maximum of velocity (regular velocity profiles). The discharge pattern of each burst neuron (short lead neuron) was different according to the saccade velocity profile. We observed a clear inhibition within the burst neuron discharge for irregular velocity profiles, thus giving rise to multiple maxima of discharge frequency, and to a clearly interrupted saccade. The same neuron showed only one maximum of discharge frequency for regular saccades. Then the hypothesis of two different neural networks generating the different motor programs of spontaneous and attentive visual guided saccades is put forward and discussed.

Attention-related neurons in the supplementary eye field of the macaque monkey.

This study investigated whether the neuronal activity of a cortical area involved in the control of eye fixation is affected by the covert orienting of attention. We recorded single-unit activity from the supplementary eye field (SEF) of two macaque monkeys performing fixation and peripheral-attention tasks. Ninety-nine out of four hundred and fifteen cells were related to eye movements. The other neurons showed relationship with postural adjustments, and arm and ear movements. Fifty-five neurons were active during fixation (fixation cells) and 44 discharged in relation to saccades. The experiments reported here primarily concern the fixation cells. The activity of 64% (35/55) of fixation cells started with the onset of visual stimulus, before the visual input reached the fovea, and continued during active fixation. The activity of 27% (15/55) of fixation cells started with the onset of fixation. The activity of 9% (5/55) of fixation cells modified their timing trial by trial. Sixty-four percent of the fixation cells (35/55) were position-dependent, showing a selective spatial field of activity, 36% (20/55) were position-independent and characterized by a full spatial field. None of the 55 cells showed a visual receptive field. We tested both types of fixation cells by means of a peripheral attention task. When attention was oriented peripherally toward a target located in the selective spatial field, the cells discharged as if the gaze was held toward it. When attention was oriented peripherally toward a target, lying outside the selective spatial field the cells were inactive as if gaze was held in that position. These results suggest that the supplementary eye field neurons may code for oriented attention in space and might be involved in the preparation of motor action.

Ear and eye representation in the frontal cortex, area 8b, of the macaque monkey: an electrophysiological study.

We evoked both ear and eye movements in area 8b, the rostral area of frontal cortex, in two monkeys. In some sites it was possible to evoke only ear movements or only eye movements; in other locations we evoked both ear and eye movements by varying the intensity of electrical stimulation. The electrically evoked ear movements were forward, or backward, or oblique (upward-forward; upward-backward). In two penetrations the ear movements were bilateral, in the other penetrations they were contralateral. Ipsilateral ear movements were not observed. The evoked eye movements were mainly fixed-vector saccades, contralateral and with an upward orientation of about 45 degrees. If we considered only the sites where the threshold was equal to or lower than 50 microA, the stimulation of this area evoked mainly ear movements. In addition we recorded the electrical activity of 195 neurons. Of these neurons: 74% (145/195) discharged before ear movements (ear cells); 20% (40/195) discharged before ear and eye movements (ear-eye cells); 5% (10/195) discharged only before eye movements (eye cells). Ninety-one percent (132/145) of ear cells presented a preferred direction; 90% (36/40) of ear-eye cells presented a preferred direction for ear movements, and 15% (6/40) presented a preferred direction for eye movements. Eighty-five percent (34/40) of cells did not present a preferred direction for visually guided saccades and were active when the monkey made saccades toward the unlit targets (checking saccades). Our results show that a field of area 8b is related to ear movements and to eye-ear movements. The findings that it is possible to obtain both ear and eye movements with low-intensity currents and that there are cells firing for the two types of movements suggest that area 8b may be involved in the orientation and coordination of both ear and eye. This area might be considered a rostral extension of supplementary eye field (SEF) or a different region. However, based on its distinct functional characteristics and connectivity, it is probably better regarded as a separate field. Regardless, the combination of 8b and SEF may constitute a cortical center for orienting processes.

The dorsomedial frontal cortex of the macaca monkey: fixation and saccade-related activity.

The activity of 249 neurons in the dorsomedial frontal cortex was studied in two macaque monkeys. The animals were trained to release a bar when a visual stimulus changed color in order to receive reward. An acoustic cue signaled the start of a series of trials to the animal, which was then free to begin each trial at will. The monkeys tended to fixate the visual stimuli and to make saccades when the stimuli moved. The monkeys were neither rewarded for making proper eye movements nor punished for making extraneous ones. We found neurons whose discharge was related to various movements including those of the eye, neck, and arm. In this report, we describe the properties of neurons that showed activity related to visual fixation and saccadic eye movement. Fixation neurons discharged during active fixation with the eye in a given position in the orbit, but did not discharge when the eye occupied the same orbital positions during nonactive fixation. These neurons showed neither a classic nor a complex visual receptive field, nor a foveal receptive visual field. Electrical stimulation at the site of the fixation neurons often drove the eye to the orbital position associated with maximal activity of the cell. Several different kinds of neurons were found to discharge before saccades: 1) checking-saccade neurons, which discharged when the monkeys made self-generated saccades to extinguish LED's; 2) novelty-detection saccade neurons, which discharged before the first saccade made to a new visual target but whose activity waned with successive presentations of the same target. These results suggest that the dorsomedial frontal cortex is involved in attentive fixation. We hypothesize that the fixation neurons may be involved in codifying the saccade toward a target. We propose that their involvement in arm-eye-head motor-planning rests primarily in targeting the goal of the movement. The fact that saccade-related neurons discharge when the saccades are self initiated, implies that this area of the cortex may share the control of voluntary saccades with the frontal eye fields and that the activation is involved in intentional motor processes.

Behavioral and motor mechanisms of dorsomedial frontal cortex of macaca monkey.

The activity of 249 neurons in the dorsomedial frontal cortex was recorded in two macaca monkeys. The animals had been trained for saccades and fixation tasks in an unrestrained condition. We found 51 burst neurons that showed a double-firing discharge. We observed two different patterns of discharge. In one case the first burst occurred before the arm movement, the second before the related eye movement. In the second case, the first discharge took place before a neck contraction followed by a second burst before eye movement. Some cells showed two discharges, one that preceded the bar-press and the other the saccade. With other cells the discharges preceded the bar-release and then saccade. Still other cells discharged three times: first before the bar-press, second before release and third before the orienting saccade. Some cells were active for the bar-press and for the first orienting saccades. These cells were active also for a large range of movement tested at the presentation of natural stimuli. Electrical stimulation failed to evoke either arm or eye movement. Neck-eye cells are related to movement of the eye and to an increase of EMG activity independent of eye position. The electrical stimulation evoked eye movements and EMG increases at low threshold. The activity of arm-eye cells related to purposeful movement with the ineffectiveness of electrical stimulation may be ascribed to a motor reactivation or an ordering signal. The neck-eye cells may be considered trigger commands for neck-eye coordination.(ABSTRACT TRUNCATED AT 250 WORDS)

Does attention affect the motor programs of pharmacologically induced eye movements?

Attention plays an important role in oculomotor function. We studied the effect of attentional stimuli on eye movements induced by ketamine. The experiments were carried out on three monkeys. Ketamine injected intramuscularly induced nystagmus. When we switched on a new stimulus these eye movements stopped and the animal made a saccade toward it. This may be due to a new motor program, triggered by a visual stimulus, that among its characteristics is able to engage the animal's attention. The program of evoked saccade is overwritten on induced oculomotor activity. Our results suggest that attentional processes modify the dynamic characteristics and induce in particular behavioral condition a new motor program.

Neurons signalling the maintenance of attentive fixation in frontal area 6a beta of macaque monkey.

Twelve out of 140 neurons recorded in a restricted region of the frontal agranular cortex (area 6a beta) of trained macaque monkeys, discharged only during attentive fixation of a target in the straight ahead position. These cells, lacking a visual receptive field, were silent when the animal's eye was in the same position during spontaneous oculomotor behaviour. Our preliminary results suggest that this area is involved in the codification of attentive fixation.