Journal of Clinical EEG & Neuroscience, April 2006
|Special Issue: Pharmaco-EEG at a Crossroads
S. Galderisi, Guest Editor
|Pharmaco-EEG: A History of Progress and a Missed Opportunity
S. Galderisi and W. G. Sannita
|EEG Topography and Tomography (LORETA) in the Classification and Evaluation of the Pharmacodynamics of Psychotropic Drugs
B. Saletu, P. Anderer and G. M. Saletu-Zyhlarz
|Pharmaco-EEG in Psychiatry
A. Mucci, U. Volpe, E. Merlotti, P. Bucci and S. Galderisi
|Event Related Potentials and fMRI in Neuropsychopharmacology
O. Pogarell, C. Mulert and U. Hegerl
|Quantifying Drug-Drug Interactions in Pharmaco-EEG
M. J. Barbanoj, R. M. Antonijoan, J. Riba, M. Valle, S. Romero and F. Jané
|From Neuroscience to Application in Neuropharmacology: A Generation of Progress in Electrophysiology
S. Carozzo, S. Fornaro, S. Garbarino, M. Saturno and W. G. Sannita
|The Relevance of QEEG to the Evaluation of Behavioral Disorders and Pharmacological Interventions
E. R. John and L. S. Prichep
|Abstracts: 15th Annual Conference of the Australasian Society for Psychophysiology
December 9-11, 2005
By multi-lead computer-assisted quantitative analyses of human scalp-recorded electroencephalogram (QEEG) in combination with certain statistical procedures (quantitative pharmaco-EEG) and mapping techniques (pharmaco-EEG mapping or topography), it is possible to classify psychotropic substances and objectively evaluate their bioavailability at the target organ, the human brain. Specifically, one may determine at an early stage of drug development whether a drug is effective on the central nervous system (CNS) compared with placebo, what its clinical efficacy will be like, at which dosage it acts, when it acts and the equipotent dosages of different galenic formulations. Pharmaco-EEG maps of neuroleptics, antidepressants, tranquilizers, hypnotics, psychostimulants and nootropics/cognition-enhancing drugs will be described. Methodological problems, as well as the relationships between acute and chronic drug effects, alterations in normal subjects and patients, CNS effects and therapeutic efficacy will be discussed.
Imaging of drug effects on the regional brain electrical activity of healthy subjects by means of EEG tomography such as low-resolution electromagnetic tomography (LORETA) has been used for identifying brain areas predominantly involved in psychopharmacological action. This will be shown for the representative drugs of the four main psychopharmacological classes, such as 3 mg haloperidol for neuroleptics, 20 mg citalopram for antidepressants, 2 mg lorazepam for tranquilizers and 20 mg methylphenidate for psychostimulants. LORETA demonstrates that these psychopharmacological classes affect brain structures differently.
By considering these differences between psychotropic drugs and placebo in normal subjects, as well as between mental disorder patients and normal controls, it may be possible to choose the optimum drug for a specific patient according to a key-lock principle, since the drug should normalize the deviant brain function. Thus, pharmaco-EEG topography and tomography are valuable methods in human neuropsychopharmacology, clinical psychiatry and neurology.
In spite of its origins deeply rooted in the discipline, pharmaco-EEG applications in psychiatry remain limited to its achievements in the field of psychotropic drugs classification and, in few instances, discovery.
In the present paper two attempts to transfer pharmaco-EEG methods to psychiatric clinical routine will be described: 1) monitoring of psychotropic drug toxicity at the central nervous system level, and 2) prediction of clinical response to treatment with psychotropic drugs. Both applications have been the object of several investigations providing promising and sometimes consistent findings which, however, had no impact on clinical practice. For the first topic, the review is limited to antipsychotics, lithium and recreational drugs, as for other psychotropic drugs mostly case studies are available, while for the response prediction it will include antipsychotics, antidepressants, anxiolytics, psychostimulants and nootropics.
In spite of several methodological limitations, pharmaco-EEG studies dealing with monitoring of antipsychotic- and lithium-induced EEG abnormalities went close to, but never became, a clinical routine. EEG studies of recreational drugs are flawed by several limitations, and failed, so far, to identify reliable indices of CNS toxicity to be used in clinical settings.
Several QEEG studies on early predictors of treatment response to first generation antipsychotics have produced consistent findings, but had no clinical impact. For other psychotropic drug classes few and inconsistent reports have appeared.
Pharmaco-EEG had the potential for important clinical applications, but so far none of them entered clinical routine. The ability to upgrade theories and methods and promote large scale studies represent the future challenge.
Event related potentials (ERP) are important clinical and research instruments in neuropsychiatry, particularly due to their strategic role for the investigation of brain function. These techniques are often underutilized in the evaluation of neurological and psychiatric disorders, but nevertheless they can be most useful and highly effective in the diagnostic workup of a wide range of neuropsychiatric disorders as well as in monitoring the course of the disorders and the prediction of treatment responses.
ERP are noninvasive instruments that directly reflect cortical neuronal activity. Cortical neuronal dysfunction plays a major role in variable neuropsychiatric disorders, and a change in cortical activity under medication might reflect treatment response and could be useful for monitoring drug effects.
ERP are the only methods with a sufficiently high time resolution for the analysis of the dynamic patterns of neuronal brain activity, e.g., synchronization and desynchronization, oscillations, coherence, gamma band activity, latency of event related activity, etc., which are crucial for a deeper understanding of functional (neurophysiological) correlates of cognitive, emotional and behavioral disturbances in neuropsychiatric patients.
Methodological advances have further improved and strengthened the position of ERP concerning research and clinical application. The usefulness and applicability of ERP in determining and monitoring clinico-pharmacological effects will be summarized mainly by focussing on the auditory evoked P300 and the N1/P2 component of auditory evoked potentials. Owing to important recent developments in the field of brain functional diagnostics the combination of neurophysiological techniques and functional magnetic resonance imaging (fMRI) will be included.
A drug interaction refers to an event in which the usual pharmacological effect of a drug is modified by other factors, most frequently additional drugs. When two drugs are administered simultaneously, or within a short time of each other, an interaction can occur that may increase or decrease the intended magnitude or duration of the effect of one or both drugs. Drugs may interact on a pharmaceutical, pharmacokinetic or pharmacodynamic basis. Pharmacodynamic interactions arise when the alteration of the effects occurs at the site of action.
This is a wide field where not only interactions between different drugs are considered but also drug and metabolites (midazolam/a-hydroxy-midazolam), enantiomers (ketamine), as well as phenomena such as tolerance (nordiazepam) and sensitization (diazepam). Pharmacodynamic interactions can result in antagonism or synergism and can originate at a receptor level (antagonism, partial agonism, down-regulation, up-regulation), at an intraneuronal level (transduction, uptake), or at an interneuronal level (physiological pathways).
Alternatively, psychotropic drug interactions assessed through quantitative pharmaco-EEG can be viewed according to the broad underlying objective of the study: safety-oriented (ketoprofen/theophylline, lorazepam/diphenhydramine, granisetron/haloperidol), strictly pharmacologically-oriented (benzodiazepine receptors), or broadly neuro-physiologically-oriented (diazepam/buspirone). Methodological issues are stressed, particularly drug plasma concentrations, dose-response relationships and time-course of effects (fluoxetine/buspirone), and unsolved questions are addressed (yohimbine/caffeine, hydroxizyne/alcohol).
A continuum from neuronal cellular/subcellular properties to system processes appears to exist in many instances and to allow privileged approaches in neuroscience and neuropharmacology research. Brain signals and the cholinergic and GABAergic systems, in vivo and in vitro evidence from studies on the retina, or the “gamma band” oscillations in neuron membrane potential/spiking rate and neuronal assemblies are examples in this respect. However, spontaneous and stimulus-event-related signals at any location and time point reflect brain state conditions that depend on neuromodulation, neurotransmitter interaction, hormones (e.g., glucocorticois, ACTH, estrogens) and neuroendocrine interaction at different levels of complexity, as well as on the spontaneous or experimentally-induced changes in metabolism (e.g., glucose, ammonia), blood flow, pO2, pCO2, acid/base balance, K activity, etc., that occur locally or systemically. Any of these factors can account for individual differences and/or changes over time that often are (or need to be) neglected in pharmaco-EEG studies or are dealt with statistically and by controlling the experimental conditions. As a result, the electrophysiological effects of neuroactive drugs are to an extent non-specific and require adequate modeling and precise correlation with independent parameters (e.g., drug kinetics, vigilance, hormonal profile or metabolic status, etc.) to avoid biased results in otherwise controlled studies.
It has become apparent that the electrical signals recorded from the scalp of healthy individuals under standardized conditions are predictable, and that patients with a wide variety of brain disorders display activity with unusual features. It also early became apparent that centrally active medications produced striking changes in this activity. The application of computerized signal analysis to EEG recordings collected using standardized procedures has made it possible to obtain quantitative descriptions of brain electrical activity (QEEG) in normal individuals and patients with disorders of brain function or structure, as well as quantitative description of the ways in which centrally active medications alter this activity (Pharmaco-EEG or “PEEG”). With the emergence of three-dimensional EEG source localization techniques, it has recently become possible to visualize the mathematically most probable generators of QEEG abnormalities within the brain as well as the neuroanatomical regions where abnormal activity is most altered by efficacious medication.
As QEEG and PEEG have evolved, a vast body of facts has been accumulated, describing changes in the EEG or event-related potentials (ERPs) observed in a variety of brain disorders or after administration of a variety of medications. With some notable exceptions, these studies have tended to be phenomenological rather than analytic. There has not been a systematic attempt to integrate these phenomena in order to build better understanding of how the abnormal behaviors of a particular psychiatric patient might be related to the specific pattern of the deviant electrical activity, nor just how pharmacological reduction of that deviant activity may have resulted in more normal behavior.
This article is an endeavor to provide a more specific theoretical framework for understanding the relationships between the neuroanatomy and neurochemistry of the homeostatic system underlying the regulation of the QEEG, and the mechanisms revealed by Pharmaco-EEG that aid in correcting these illnesses.