Bernard Bioulac

Reversal of Rigidity and Improvement in Motor Performance by Subthalamic High‐frequency Stimulation in MPTP‐treated Monkeys

In Parkinsons disease the loss of dopaminergic neurons in the substantia nigra is associated with global disorganization of basal ganglia activity and, in particular, with increased activity of the excitatory glutamatergic neurons of the subthalamic nucleus. Recent experimental studies have shown that parkinsonian symptoms can be alleviated by selective lesioning of the subthalamic nucleus in monkeys treated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). We measured the effect of high‐frequency stimulation of the subthalamic nucleus in two unilaterally MPTP‐treated monkeys in order to determine whether it was possible to obtain reversible, gradual and controllable functional impairment of this structure. Clinical, mechanographic and electromyographic results demonstrate that this technique can alleviate parkinsonian rigidity and bradykinesia without causing dyskinesia or hemiballismus. This study supports the hypothesis that the subthalamic nucleus and its excitatory projections have an important role in the mechanisms sustaining the expression of parkinsonian motor changes, and suggests that high‐frequency stimulation of the subthalamic nucleus could be included in treatment for parkinsonism.

Subthalamic Nucleus Neurons Switch from Single-Spike Activity to Burst-Firing Mode

The modification of the discharge pattern of subthalamic nucleus (STN) neurons from single-spike activity to mixed burst-firing mode is one of the characteristics of parkinsonism in rat and primates. However, the mechanism of this process is not yet understood. Intrinsic firing patterns of STN neurons were examined in rat brain slices with intracellular and patch-clamp techniques. Almost half of the STN neurons that spontaneously discharged in the single-spike mode had the intrinsic property of switching to pure or mixed burst-firing mode when the membrane was hyperpolarized from −41.3 ± 1.0 mV (range, −35 to −50 mV; n = 15) to −51.0 ± 1.0 mV (range, −42 to −60 mV; n = 20). This switch was greatly facilitated by activation of metabotropic glutamate receptors with 1S,3R-ACPD. Recurrent membrane oscillations underlying burst-firing mode were endogenous and Ca2+-dependent because they were largely reduced by nifedipine (3 μm), Ni2+ (40 μm), and BAPTA-AM (10–50 μm) at any potential tested, whereas TTX (1 μm) had no effect. In contrast, simultaneous application of TEA (1 mm) and apamin (0.2 μm) prolonged burst duration. Moreover, in response to intracellular stimulation at hyperpolarized potentials, a plateau potential with a voltage and ionic basis similar to those of spontaneous bursts was recorded in 82% of the tested STN neurons, all of which displayed a low-threshold Ni2+-sensitive spike. We propose that recurrent membrane oscillations during bursts result from the sequential activation of T/R- and L-type Ca2+ currents, a Ca2+-activated inward current, and Ca2+-activated K+ currents.

Increased D1 dopamine receptor signaling in levodopa-induced dyskinesia

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinsons disease. Although changes affecting D1 and D2 dopamine receptors have been studied in association with this condition, no causal relationship has yet been established. Taking advantage of a monkey brain bank constituted to study levodopa‐induced dyskinesia, we report changes affecting D1 and D2 dopamine receptors within the striatum of normal, parkinsonian, nondyskinetic levodopa‐treated parkinsonian, and dyskinetic levodopa‐treated parkinsonian animals. Whereas D1 receptor expression itself is not related to dyskinesia, D1 sensitivity per D1 receptor measured by D1 agonist‐induced [35S]GTPγS binding is linearly related to dyskinesia. Moreover, the striata of dyskinetic animals show higher levels of cyclin‐dependent kinase 5 (Cdk5) and of the dopamine‐ and cAMP‐regulated phosphoprotein of 32kDa (DARPP‐32). Our data suggest that levodopa‐induced dyskinesia results from increased dopamine D1 receptor–mediated transmission at the level of the direct pathway. Ann Neurol 2004

Morningness/eveningness and the need for sleep.

The purpose of this study was to determine, in a large sample of adults of all ages (17–80 years), the effect of morningness/eveningness on sleep/wake schedules, sleep needs, sleep hygiene and subjective daytime somnolence. A total of 617 subjects (219 subjects per chronotype group) matched for age, sex and employment status, completed an abridged morningness/eveningness questionnaire, a questionnaire on sleep habits and the quality of sleep, and the Epworth Sleepiness Scale. Eveningness was associated with a greater need for sleep, less time in bed during the week compared to ideal sleep needs, more time in bed at the weekend, a later bedtime and waking‐up time especially at the weekend, more irregular sleep/wake habits and greater caffeine consumption. These subjects built up a sleep debt during the week and extended their duration of sleep at the weekend. They did not, however, rate themselves more sleepy than other types, despite the fact that our results showed a clear link between subjectively evaluated daytime somnolence and sleep debt. Why they were less affected by sleep deprivation is not clear. This raises the question of individual susceptibility to the modification of sleep parameters.

Electrophysiological and metabolic evidence that high-frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata

HIGH‐FREQUENCY STIMULATION (HFS) of the subthalamic nucleus (STN) has been shown to produce a dramatic alleviation of motor symptoms in patients with advanced Parkinsons disease. Its functional mechanism, however, remains obscure. We used extracellular recording and in situ cytochrome oxidase (CoI) mRNA hybridization to investigate the effects of HFS of the STN on neuronal activity of the STN and the substantia nigra reticulata (SNr) in normal rats and rats with 6‐hydroxydopamine (6‐OHDA) lesion of the substantia nigra compacta (SNc). To allow detection of spikes and analysis of firing activity, artifacts recorded during stimulation were scaled down using a template subtraction method. In both normal and lesioned rats, the activity of a majority of STN neurons was inhibited during stimulation. In the SNr, HFS also induced an inhibition of the activity of a majority of neurons in normal and lesioned rats. In situ hybridization histochemistry confirmed these results in that it showed a significant decrease in levels of CoI mRNA expression in the STN and SNr in both normal and lesioned rats during stimulation. These data afford an interesting insight into the functional mechanism of deep brain stimulation and support the hypothesis that HFS exerts an inhibitory influence on STN neuronal firing.—Tai, C.‐H., Boraud, T., Bezard, E., Bioulac, B., Gross, C., Benazzouz, A. Electrophysiological and metabolic evidence that high‐frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata. FASEB J. 17, 1820–1830 (2003)

High frequency stimulation of the internal Globus Pallidus (GPi) simultaneously improves parkinsonian symptoms and reduces the firing frequency of GPi neurons in the MPTP-treated monkey

The firing pattern of the neurons of the internal Globus Pallidus (GPi) is greatly disturbed in Parkinsons disease. Surgical lesion or high frequency stimulation (HFS) of the GPi reduces parkinsonian rigidity and akinesia. We evaluated in this study the effects of HFS of the GPi on the firing pattern of its neurons. Extracellular recordings were carried out under three types of experimental conditions in rhesus monkeys, normal state, after MPTP treatment and during HFS of the GPi. After intracarotidian MPTP injection, the firing rate of GPi cells increased significantly. During HFS, MPTP-induced parkinsonian motor symptoms clearly improved correlatively with a significant decrease in the firing rate of GPi cells in the stimulated area. HFS restored a firing frequency similar to that in normal animals and, unexpectedly, did not completely block neuronal activity.

Meta-analysis of brain volume changes in obsessive-compulsive disorder.

BACKGROUND Many neuroimaging studies exploring the volumes of brain structures in obsessive-compulsive disorder (OCD) have been published in the past 2 decades. In this study, we attempted to provide a complete overview of structural alterations in OCD by meta-analyzing magnetic resonance imaging (MRI) data. METHODS We conducted a systematic search of MRI studies that reported volumetric measurements in both OCD patients and healthy subjects. Data were entered into the meta-analysis through calculation of the standardized mean differences (SMDs) between the volumes of cerebral regions in OCD patients and the corresponding volumes in control subjects. We then performed a meta-regression to explore the influence of clinical covariates on effect sizes. RESULTS Although no volumetric differences were found for the whole brain, intracranial region, gray matter, or prefrontal cortex, OCD patients did show a reduced volume of the left anterior cingulate cortex (ACC) and the left and right orbitofrontal cortex (OFC). No significant volumetric differences within the basal ganglia were observed, although the left and right thalamic volumes were significantly increased in OCD patients. The severity of obsessive or compulsive symptoms correlated significantly with the effect sizes for the left and right thalamus. CONCLUSIONS Our findings indicate volumetric differences between OCD patients and control subjects in the cortical and thalamic regions, suggesting that structural alteration of the thalamocortical pathways may contribute to the functional disruptions of frontosubcortical circuits observed in OCD.

Validation of Horne and Ostberg Morningness-Eveningness Questionnaire in a Middle-Aged Population of French Workers:

As suggested by the authors, the Horne and Ostberg morning/evening questionnaire (MEQ) has never been adapted to evaluate a nonstudent population. The purpose of this study was to validate this MEQ in a sample of middle-aged workers by modifying only the cutoffs. It was administered in 566 non-shift-workers aged 51.2 to 3.2 years who presented no sleep disorders. According to the Horne and Ostberg classification, the sample consisted of 62.1% morning type, 36.6% neither type, and 2.2% evening type. Multiple correspondence analysis, which determines the principal components, was performed on all MEQ items. Then an ascending hierarchical classification was applied to determine 3 clusters from these principal components. On the basis of these 3 clusters, new cutoffs were determined: evening types were considered as scoring under 53 and morning types above 64, thus giving 28.1% morning type, 51.7% neither type, and 20.2% evening type. As an external validation, eveningness was associated with later bedtime and waking-up time (more pronounced at the weekend), greater need for sleep, larger daily sleep debt, greater morning sleepiness, and ease of returning to sleep in the early morning. A positive correlation between age and morningness was again found. This study confirms that “owls” are not rare in a middle-aged sample. We conclude that this adapted MEQ could be useful when investigating age-related changes in sleep.

The circadian and homeostatic modulation of sleep pressure during wakefulness differs between morning and evening chronotypes

The purpose of this study was to evaluate homeostatic and circadian sleep process in ‘larks’ and ‘owls’ under daily life conditions. Core body temperature, subjective sleepiness and waking electroencephalogram (EEG) theta–alpha activity (6.25–9 Hz) were assessed in 18 healthy men (nine morning and nine evening chronotypes, 21.4 ± 1.9 years) during a 36‐h constant routine that followed a week of a normal ‘working’ sleep–wake schedule (bedtime: 23.30 h, wake time: 07.30 h). The phase of the circadian rhythm of temperature and sleepiness occurred respectively, 1.5 h (P = 0.01) and 2 h (P = 0.009) later in evening‐ than in morning‐type subjects. Only morning‐type subjects showed a bimodal rhythm of sleep–wake propensity. The buildup of subjective sleepiness, as quantified by linear regression, was slower in evening than in morning types (P = 0.04). The time course of EEG theta–alpha activity of both chronotypes could be closely fitted by an exponential curve. The time constant of evening types was longer than that of morning types (P = 0.03), indicating a slower increase in sleep pressure during extended wakefulness. These results suggest that both the circadian signal and the kinetics of sleep pressure buildup differ between the two chronotypes even under prior naturalistic conditions mimicking the usual working day.

Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey

We studied the effects of L-DOPA on the firing patterns of pallidal neurons in experimental parkinsonism. After a unilateral injection of MPTP, we observed a decrease in the firing rate of GPe neurons, and a slight increase in their bursting activity. In the GPi, there was a considerable augmentation of both neuronal firing frequency and the number of bursting cells. During l-DOPA treatment (10 mg/kg), GPe neurons.pattern is almost unmodified. The firing frequency of GPi neurons, on the contrary, decreased even lower than the control level. A slight reduction was observed in bursting activity. These unexpected results would show that the normalizing effect of L-DOPA on GPi output is limited.