Multimodal EEG Recordings, Psychometrics and Behavioural Analysis.

High spatial and temporal resolution measurements of neuronal activity are preferably combined. In an overview on how this approach can take shape, multimodal electroencephalography (EEG) is treated in 2 main parts: by experiments without a task and in the experimentally cued working brain. It concentrates first on the alpha rhythm properties and next on data-driven search for patterns such as the default mode network. The high-resolution volumic distributions of neuronal metabolic indices result in distributed cortical regions and possibly relate to numerous nuclei, observable in a non-invasive manner in the central nervous system of humans. The second part deals with paradigms in which nowadays assessment of target-related networks can align level-dependent blood oxygenation, electrical responses and behaviour, taking the temporal resolution advantages of event-related potentials. Evidence-based electrical propagation in serial tasks during performance is now to a large extent attributed to interconnected pathways, particularly chronometry-dependent ones, throughout a chain including a dorsal stream, next ventral cortical areas taking the flow of information towards inferior temporal domains. The influence of aging is documented, and results of the first multimodal studies in neuropharmacology are consistent. Finally a scope on implementation of advanced clinical applications and personalized marker strategies in neuropsychiatry is indicated.

Structured multiplicity and confirmatory statistical analyses in pharmacodynamic studies using the quantitative electroencephalogram.

Pharmacodynamic (PD) clinical studies are characterised by a high degree of multiplicity. This multiplicity is the result of the design of these studies that typically investigate effects of a number of biomarkers at various doses and multiple time points. Measurements are taken at many or all points of a "hyper-grid" that can be understood as the cross-product of a number of dimensions each of which has typically 3-30 discrete values. This exploratory design helps understanding the phenomena under investigation, but has made a confirmatory statistical analysis of these studies difficult, so that such an analysis is often missing in this type of studies. In this contribution we show that the cross-product structure of PD studies allows to combine several well-known techniques to address multiplicity in an effective way, so that a confirmatory analysis of these studies becomes feasible without unrealistic loss of power. We demonstrate the application of this technique in two studies that use the quantitative EEG (qEEG) as biomarker for drug activity at the GABA-A receptor. QEEG studies suffer particularly from the curse of multiplicity, since, in addition to the common dimensions like dose and time, the qEEG is measured at many locations over the scalp and in a number of frequency bands which inflate the multiplicity by a factor of about 250.

Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device.

OBJECTIVES: The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared. METHODS: The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design. KEY FINDINGS: Following intranasal delivery, median t(max) was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean +/- SD values for C(max) were 96 +/- 25, 11 +/- 7 and 16 +/- 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure. CONCLUSIONS: Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.

Ketamine effects on CNS responses assessed with MEG/EEG in a passive auditory sensory-gating paradigm: an attempt for modelling some symptoms of psychosis in man.

Disturbances in integrative function have been consistentLy described in psychotic disorder; for instance, prepulse inhibition of the startle reflex (startle-PPI) which is a marker of sensory gating, is deficient in persons with schizophrenia. The N-methyl-D-aspartate antagonist ketamine produces in control subjects a spectrum of neurobehavioural symptoms like encountered in schizophrenia, and disrupts startle-PPI in animals. In the present study, we investigated in 12 healthy subjects whether ketamine would reduce sensory-gating in auditory responses at doses which produce psychotic symptoms. In a double-blind, crossover design loading doses of 0.024, 0.081 and 0.27 mg/kg or saline were employed, followed by maintenance infusion for 120 min. A passive paradigm has been developed which consisted in tone bursts, preceded or not by a (near-threshold) click at intervals of 100 ms or 500 ms. Brain electromagnetic activity imaging of the responses to sound stimuli has been carried out by way of a 148-channel magnetoencephalography-system. Actual evoked response amplitudes and underlying equivalent current dipole strengths have been compared to multi-electrode evoked potentials from the scalp. A click stimulus is capable to inhibit test responses under placebo at the 100 ms interval. During maintenance infusion of ketamine at steady-state (for >30 min) after 0.27 mg/kg, no such amplitude changes were observed anymore (p <0.05) and under these circumstances significant increases in Brief Psychiatric Rating scale and Scale for the Assessment of Negative Symptoms scores were evidenced (p < 0.001). Intermediate effects have been observed when the dose was lowered to 0.081 mg/kg. The present results have shown that ketamine may induce a psychotic-like clinical state associated with gating deficits in healthy subjects.

Effects of acamprosate on sleep during alcohol withdrawal: A double-blind placebo-controlled polysomnographic study in alcohol-dependent subjects.

BACKGROUND: Sleep disturbances are frequently encountered in alcohol-dependent patients. Drugs improving sleep during abstinence from alcohol may play an important role in the recovery process. METHODS: In the present study, the effects of acamprosate, a drug successfully used in maintaining abstinence following alcohol withdrawal, were assessed by polysomnographic recordings. A parallel double-blind placebo-controlled study was conducted in 24 male DSM-IV alcohol-dependent subjects aged 35.9+/-1.2 years. Treatments (2 tablets of 333 mg acamprosate vs placebo t.i.d.) were initiated 8 days before alcohol withdrawal and continued during the 15 days following alcohol withdrawal. Polysomnographic assessments were recorded during acute withdrawal (the first 2 nights following withdrawal) and during postwithdrawal abstinence (the last 2 nights of the trial). RESULTS: Results show that, compared with placebo, acamprosate decreased wake time after sleep onset and increased stage 3 and REM sleep latency (all treatment effects with a p < 0.05 significance). Withdrawal effects themselves were also demonstrated as sleep efficiency (p < 0.01) and total sleep time (p < 0.05) were lower in abstinence nights versus withdrawal nights, whereas no significant treatment x withdrawal effect could be evidenced. Acamprosate was well tolerated during the entire course of the study. CONCLUSIONS: The present study shows that acamprosate ameliorates both sleep continuity and sleep architecture parameters classically described as disturbed in alcohol-dependent patients. From a clinical perspective, it suggests that an 8-day acamprosate prewithdrawal treatment is well tolerated and can attenuate the sleep disturbances engendered by alcohol withdrawal in alcohol-dependent subjects.

Linear inverse solutions: simulations from a realistic head model in MEG.

Distributed linear solutions are widely used in source localization to solve the ill-posed EEG/MEG inverse problem. In the classical approach based on dipole sources, these methods estimate the current densities at a great number of brain sites, typically at the nodes of a 3-D grid which discretizes the chosen solution space. The estimated current density distributions are displayed as brain electromagnetic tomography (BET) images. We have tested well known minimum norm solutions (MN, WMN, LORETA) and other linear inverse solutions [WROP, sLORETA, interference uniform, gain uniform, weight vector normalized (WVN), and a new solution named SLF (Standardized Lead Field)], using a MEG configuration (BTi Magnes 2500 WH with 148 axial magnetometers) and a realistic head model using BEM (Boundary Element Method). The solutions were compared in a noise-free condition and in the presence of noise using the classical dipole localization errors (DLE) together with a new figure of merit that we called max gain uniformity, which measures the capability of an inverse linear solution to show spots of activity with similar amplitudes on the brain electromagnetic tomographies when multiple dipole sources with similar moments are simultaneously active. Whereas some solutions (sLORETA, interference uniform and SLF) were capable of zero dipole localization errors in the noise-free case, none of them reached 100% of correct dipole localizations in the presence of a high level of Gaussian noise. The SLF solution, which has the advantage to be independent from any regularization parameter, presented the best results with the lowest max gain uniformities, with almost 100% of correct dipole localizations with 10% of noise and more than 90% of correct localizations with 30% of noise added to the data. Nevertheless, no solution was able to combine at the same time a correct localization of single sources and the capability to visualize multiple sources with comparable amplitudes on the brain electromagnetic tomographies.

Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring.

RATIONALE: Most studies that investigated the next-day residual effects of hypnotic drugs on daytime driving performances were performed on healthy subjects and after a single drug administration. OBJECTIVES: In the present study, we further examine whether the results of these studies could be generalised to insomniac patients and after repeated drug administration. METHOD: Single and repeated (7 day) doses of zolpidem (10 mg), zopiclone (7.5 mg), lormetazepam (1 mg) or placebo were administered at bedtime in a crossover design to 23 patients (9 men and 14 women aged 38.8+/-2.0 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) primary insomnia. Driving tests were performed 9-11 h post-dose. RESULTS: Results showed that treatment effects were evidenced for subjective sleep, for driving abilities, and for electroencephalogram (EEG) recorded before (resting EEG) and during the driving simulation test (driving EEG). Compared to placebo, zopiclone increased the number of collisions and lormetazepam increased deviation from speed limit and deviation from absolute speed, whereas zolpidem did not differentiate from placebo on these analyses. EEG recordings showed that in contrast to zolpidem, lormetazepam and zopiclone induced typical benzodiazepine-like alterations, suggesting that next-day poor driving performance could relate to a prolonged central nervous system effect of these two hypnotics. CONCLUSION: The present results corroborate studies on healthy volunteers showing that residual effects of hypnotics increase with their half-lives. The results further suggest that drugs preserving physiological EEG rhythms before and during the driving simulation test 9-11 h post-dose, such as zolpidem, do not influence next-day driving abilities.

EEG source identification: frequency analysis during sleep.

This article deals with a new approach in sleep characterization that combines EEG source localisation methods with standard frequency analysis of multielectrode EEGs. First, we describe the theoretical methodology and the benefits that we get from a three-dimensional image (LORETA) of the cerebral activity related to a frequency band. Then, this new application is used as signal-processing technique on sleep EEG recordings obtained from young male adults using four frequency bands (delta 0.5-3.5 Hz, theta 4.0-7.5 Hz, alpha 8.0-12.5 Hz and beta 13.0-32.0 Hz) in different sleep stages. Finally, we show that the obtained results are highly consistent with other physiological assessments (standard EEG mapping, functional magnetic resonance imaging, etc.), but give us more realistic additional information on the generators of electromagnetic cerebral activity.

Objective markers of drug effects on brain function from recordings of scalp potential in healthy volunteers.

In order to stress the importance of P300 responses in drug development, we describe the spatiotemporal characteristics of this objective, evoked event-related potential. These brain activations reflect mnemonic function, in which limbic structures play a role. It is demonstrated that a pharmacological challenge concerning, for example, the cholinergic system in young healthy volunteers induces modifications in P300 reminiscent of the aging brain. We use this type of observation to build a model in which it can be verified whether the deterioration can be counteracted by treatment with "cognition-enhancing" drugs. If we accept the extrapolation of the pharmacological effects to symptomatology, scalp potential analysis offers an appropriate tool for the study of drug interactions in early proof-of-concept models.

Human models as tools in the development of psychotropic drugs.

Despite the growing means devoted to research and development (R α D) and refinements in the preclinical stages, the efficiency of central nervous system (CMS) drug development is disappointing. Many drugs reach patient studies with an erroneous therapeutic indication andlor in incorrect doses. Apart from the first clinical studies, which are conducted in healthy volunteers and focus only on safety, iolerability, and pharmacokinetics, drug development mostly relies on patient studies. Psychiatric disorders are characterized by heterogeneity and a high rate of comorbidity. It is becoming increasingly difficult to recruit patients for clinical trials and there are many confounding factors in this population, for example, those related to treatments. In order to keep patient exposure and financial expenditure to a minimum, it is important to avoid ill-designed and inconclusive studies. This risk could be minimized by gathering pharmacodynamic data earlier in development and considering that the goal of a phase 1 plan is to reach patient studies with clear ideas about the compound's pharmacodynamic profile, its efficacy in the putative indication (proof of concept), and pharmacokinetic/pharmacodynamic relationships, in addition to safety, tolerability, and pharmacokinetics. Human models in healthy volunteers may be useful tools for this purpose, but their use necessitates a global adaptation of the phase scheme, favoring pharmacodynamic assessments without neglecting safety. We are engaged in an R α D program aimed to adapt existing models and develop new paradigms suitable for early proof of concept substantiation.