A Fragile Balance: Perturbation of GABA Mediated Circuit in Prefrontal Cortex Generates High Intraindividual Performance Variability

High intraindividual performance variability is one of the most robust findings to emerge in cognitive-experimental research of attention deficit hyperactivity disorder (ADHD). Evidences from studies incorporating structural or functional human brain mapping methods indicate that this increased intraindividual variability is not simply a sequel of general brain dysfunction, but is likely related to the functioning of neural circuits that engage the prefrontal cortex, particularly the dorsolateral areas (dlPFC). In order to examine further the anatomical and pharmacological substrate responsible for this high intraindividual variability disorder, we injected GABAA antagonist (bicuculline) or GABAA agonist (muscimol) in the dlPFC of monkeys performing a reflexive oculomotor task. Here we show that, whereas GABAA agonist injection induced no or minimal impairments, injection of GABAA antagonist dramatically increased the intraindividual variability of saccade response time and of saccade spatial accuracy (amplitude and direction). Overall, this study demonstrates that the balance between excitatory/inhibitory activities in the dlPFC is fragile but crucial, since local micro-injection of GABAA antagonist can induce marked behavioural effects. It also reveals that higher cognitive areas such as the dlPFC are markedly capable to influence the productions and metrics of reflexive movements. Altogether, this study provides promising perspectives for the development of new therapeutic strategies for the treatment of diseases in which high intravariability disorders are a prominent feature

Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non‐Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8± 4.8 years (range 2-18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with ‘slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's diseas

Frontal Non-Invasive Neurostimulation Modulates Antisaccade Preparation in Non-Human Primates

A combination of oculometric measurements, invasive electrophysiological recordings and microstimulation have proven instrumental to study the role of the Frontal Eye Field (FEF) in saccadic activity. We hereby gauged the ability of a non-invasive neurostimulation technology, Transcranial Magnetic Stimulation (TMS), to causally interfere with frontal activity in two macaque rhesus monkeys trained to perform a saccadic antisaccade task. We show that online single pulse TMS significantly modulated antisaccade latencies. Such effects proved dependent on TMS site (effects on FEF but not on an actively stimulated control site), TMS modality (present under active but not sham TMS on the FEF area), TMS intensity (intensities of at least 40% of the TMS machine maximal output required), TMS timing (more robust for pulses delivered at 150 ms than at 100 post target onset) and visual hemifield (relative latency decreases mainly for ipsilateral AS). Our results demonstrate the feasibility of using TMS to causally modulate antisaccade-associated computations in the non-human primate brain and support the use of this approach in monkeys to study brain function and its non-invasive neuromodulation for exploratory and therapeutic purposes

Short-term temporal memory in idiopathic and Parkin-associated Parkinson's disease.

In a rapidly changing environment, we often know when to do something before we have to do it. This preparation in the temporal domain is based on a 'perception' of elapsed time and short-term memory of previous stimulation in a similar context. These functions could be perturbed in Parkinson's disease. Therefore, we investigated their role in eye movement preparation in sporadic Parkinson's disease and in a very infrequent variant affecting the Parkin gene. We used a simple oculomotor task where subjects had to orient to a visual target and movement latency was measured. We found that in spite of an increased average reaction time, the influence of elapsed time on movement preparation was similar in controls and the two groups of PD patients. However, short-term temporal memory of previous stimulation was severely affected in sporadic PD patients either ON or OFF dopaminergic therapy. We conclude that the two different contributions to temporal preparation could be dissociated. Moreover, a short-term temporal memory deficit might underlie temporal cognition deficits previously observed in PD

Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation

Background: Vitamin D could play a protective role in multiple sclerosis. Methods: In an observational, uncontrolled study, vitamin D3 supplementation (3010 IU/day on average) was given to 156 consecutive patients with relapsing–remitting multiple sclerosis, under first-line immunomodulatory therapy and with initial 25-OH-D serum level lower than 100 nmol/l (40 ng/ml). Relapses were determined for 29.1 ± 8.4 months during vitamin D and 29.8 ± 10.1 months before supplementation. The 25-OH-D level was measured before supplementation and several times during supplementation. The incidence rate of relapses before and during supplementation was estimated using negative binomial regression models with follow-up durations as offset terms. The incidence rate and incidence rate ratio of relapses at various 25-OH-D levels were also calculated using negative binomial regression models. Results: In 76 patients, immunomodulatory therapy preceded vitamin D supplementation (by 4.2 ± 2.7 years) and in 80 patients both treatments were started simultaneously. Under supplementation, the 25-OH-D level increased from 49 ± 22 nmol/l to 110 ± 26 nmol/l on average. Pooling data collected before and during supplementation, we found a significant strong inverse relationship between the relapse incidence rate and the 25-OH-D level ( p < 0.0001), suggesting that vitamin D did indeed influence the relapse rate. Results of univariate, bivariate and multivariate analyses were analogous: in the multivariate model adjusted for age, disease duration and previous use of immunomodulatory therapy, every 10 nmol increase in 25-OH-D level was associated with a reduction in the relapse incidence rate of 13.7%. Dividing iteratively the population made up of pooled periods into two subgroups according to the 25-OH-D levels, the relapse incidence rate ratio decreased as the 25-OH-D level increased up to 110 nmol/l, but a plateau effect was observed beyond this limit. Conclusion: Further studies are warranted for accurate quantification of the vitamin D effect

A clinical and neurophysiological motor signature of Unverricht–Lundborg disease

International audienceObjectives: Unverricht–Lundborg disease (ULD) is the most common form of progressive myoclonus epilepsy. Cerebellar dysfunction may appear over time, contributing along with myoclonus to motor disability. The purpose of the present work was to clarify the motor and neurophysiological characteristics of ULD patients.Methods: Nine patients with genetically proven ULD were evaluated clinically (medical history collected from patient charts, the Scale for the Assessment and Rating of Ataxia and Unified Myoclonus Rating Scale). Neurophysiological investigations included EEG, surface polymyography, long-loop C-reflexes, somatosensory evoked potentials, EEG jerk-locked back-averaging (JLBA) and oculomotor recordings. All patients underwent brain MRI. Non-parametric Mann-Whitney tests were used to compare ULD patients’ oculomotor parameters with those of a matched group of healthy volunteers (HV).Results: Myoclonus was activated by action but was virtually absent at rest and poorly induced by stimuli. Positive myoclonus was multifocal, often rhythmic and of brief duration, with top-down pyramidal temporospatial propagation. Cortical neurophysiology revealed a transient wave preceding myoclonus on EEG JLBA (n = 8), enlarged somatosensory evoked potentials (n = 7) and positive long-loop C-reflexes at rest (n = 5). Compared with HV, ULD patients demonstrated decreased saccadic gain, increased gain dispersion and a higher frequency of hypermetric saccades associated with decreased peak velocity.Conclusion: A homogeneous motor pattern was delineated that may represent a ULD clinical and neurophysiological signature. Clinical and neurophysiological findings confirmed the pure cortical origin of the permanent myoclonus. Also, oculomotor findings shed new light on ULD pathophysiology by evidencing combined midbrain and cerebellar dysfunction

Impaired saccadic adaptation in DYT11 dystonia

International audienceBackground: Recent neuroimaging studies point to a possible pathophysiological role of cerebellar dysfunction in dystonia. The authors investigated the association between sensorimotor adaptation, cerebellar dysfunction and the myoclonus-dystonia phenotype.Methods: The authors prospectively analysed reactive saccade adaptation in a genetically homogeneous group of 14 patients with DYT11 dystonia owing to a mutation of the SGCE gene. The authors used a backward reactive saccade adaptation task, a well-characterised experimental oculomotor paradigm involving the cerebellum. The principle of this paradigm is to simulate a spatial error in saccade generation by systematically shifting a visual target during saccade execution. Repetition of this systematic error induces a gradual decrease in the initial saccade amplitude, reflecting an adaptive phenomenon.Results: Saccade adaptation was significantly lower in the DYT11 patients than in healthy controls (mean value: 8.9%±4.5% vs 21.6%±4.5%; p=8.3×10(-6)). The time course of adaptation also differed between the patients and controls (p=0.002), reflecting the slower saccadic adaptation in the patients.Conclusions: This study provides the first neurophysiological evidence of cerebellar dysfunction in DYT11 dystonia and supports a role of cerebellar dysfunction in the myoclonus-dystonia phenotype

Behavioral paradigm illustrating the experimental antisaccade paradigm.

<p>(<i>Upper panel)</i> Antisaccade paradigm practiced by the two monkeys under the online impact of sham (left panel) or active (right panel) TMS single pulses. After fixating on a central stimulus (red), monkeys were to initiate a fast saccade to a location in the opposite direction with respect to a peripheral target (green) appearing on the screen, simultaneously (no gap) to the disappearance of the central fixation. Animals performed within each block, no-TMS trials (white small rectangles) yielding no stimulation at all (Upper Left) and TMS trials (grey small rectangles) during which a single TMS pulse was delivered at a given postarget onset SOA prior to the AS initiation, to modulate the planning of visually guided oculomotor activity <i>(Bottom panel)</i> Example of an experimental session. Animals performed a total of 4 blocks of AS training per session. In one of the blocks they did not receive TMS (white long rectangle), whereas in the remaining 3, they received in half of the trials TMS pulses (see long grey-filled rectangles) at one of the 3 intensities used in the study (30%, 40% and 50%). The order of the four blocks (3 TMS blocks at 30%, 40% or 50% absolute TMS intensities and 1 noTMS block) was randomized within each session. Monkeys performed 100 trials per block (50 no-TMS and 50 TMS trials) for a total of 400 trials per session, and received 50 pulses per TMS block (i.e., only in 50% of the trials), amounting to 150 pulses per experimental session. Independent sessions comprising active TMS pulses delivered at 100 ms or 150 ms SOA post target onset on the FEF, sham TMS pulses and active TMS stimulation in a control location were carried over.</p

Schematic of TMS sites.

<p>Modified picture showing a top view of each of the two monkey’s scalp profiles (animals ‘Y’ and ‘C’), while posted and under training. The dotted line corresponds to the stereotaxic zero bar; the grey dot signals the location and size of the head-post; the orange dot corresponds to the location where digit movements were evoked by TMS pulses; the red dot FEF region of stimulation; the double white/grey dots is an approximate schematic representation of the TMS figure-of-eight coil which was located on the FEF region.</p