Principles and Role in Psychopharmacology

The Role of Psychophysiology and Breadth of Techniques

As suggested earlier, the very definition of psychophysiol-ogy is a subject of some debate. Nathan Kline (1961) took an existential approach in his paper "On the relationship between neurophysiology, psychophysiology, psychophar-macology, and other disciplines.'' He argued that ambiguities in bioscience arise from asking a question in one "universe of discourse'' (e.g., psychology) and seeking the answer in quite a different one (e.g., physiology). This is a potential issue with respect to the term psychophysiology and, indeed, psychopharmacology. Kline developed a number of laws regarding the relationship between disciplines including the "Law of Technique.'' This law states that the technique used to obtain information does not necessarily determine the "universe of discourse'' in which it is used. This remains relevant, especially to the use of psychophysi-ological methods within psychopharmacology, as this spans three or more disciplines. To illustrate this, consider an example based on one given in Furedy's (1983) discussion of the definition of psychophysiology. ► Anxiety, via effects on the autonomic nervous system (ANS), causes changes in heart rate and other cardiac parameters such as the electrocardiograph (ECG) T-wave amplitude. If during a stress-exercise test in a patient with suspected cardiac pathology, a decrease in T-wave amplitude is seen, a physiological explanation will relate to cardiac pathology. However, from a psychophysiological perspective, the effects of the ANS on the myocardium need to be considered. For example, if the patient has great anxiety regarding his or her heart, the test may constitute a psychological as well as a physical ► stressor. Further, the psychopharmacologist would also take into account the antidepressant or anxiolytic medication that the patient may be taking which may be modifying the psycho-physiological response. The technique or measurement (T-wave amplitude) is common to these three "universes of discourse,'' but each views or uses it in different ways.

It can therefore be seen that within the research area of psychopharmacology, psychophysiology is a tool to assist in the measurement of drug-induced changes in psychological processes. When studying the effects of potentially psychoactive drugs, one of the greatest challenges is having objective "outcome measures'' that demonstrate the effect of the drug. It is essential to measure the effect ofa drug on mood, for example, when developing an antidepressant. Such an outcome has fundamental importance regarding the therapeutic use of the drug. However, the psychological process involved can only be measured in a subjective way in humans and only very indirectly in animals. Alternative and additional outcome measures, which can be assessed more objectively and in a range of situations, are essential to facilitate a number of investigations including the study of the ► pharmacokinetics of a drug, understanding dose-response relationships and the mechanism of action of the drug itself, drug safety, and investigating ► drug interactions.

There is almost an infinite number of psychophysiological (as defined earlier) outcome measures used in psycho-pharmacology, limited only by the ingenuity of the scientists involved. These include, for example, direct methods of investigating the effects of a drug on the physiological function of the central nervous system such as measuring changes in the brain electrical activity using ► electroen-cephalography (EEG) and magnetoencephalography (MEG). These techniques can be utilized in a myriad of ways. A common method of using the EEG to acquire information is to record ► event-related potentials (ERPs), that is, EEG activity recorded time locked to some event such as the presentation of a stimulus to a subject, or a subject's response. Examples of ERPs include the "► P300'' (referring to a positive voltage deflection occurring around 300 ms after the presentation of rare or task relevant stimuli) and "► mismatch negativity" (a negative voltage deflection occurring after presentation of a stimulus that is deviant, for example, in terms of loudness, duration, or frequency), both of which have been widely used as outcome measures in psychopharma-cological research. In recent years, there has been an explosion of novel analysis techniques of EEG data, much of which is focused around exploration of the frequencies of the signals contained within the EEG, which further enhances its potential utility as an outcome measure. At their heart, EEG and MEG techniques offer the opportunity for investigating the effects of psycho-pharmacological agents with high temporal resolution.

Recent decades have seen an explosion of neuroimag-ing techniques including their application in psychophar-macology. In the simplest types of paradigms, the notion is that a psychoactive substance leads to changes in psychological processes that are reflected by changes in the cerebral blood flow which can be measured using positron emission tomography (► PET) or functional ► magnetic resonance imaging (fMRI). Such techniques offer the opportunity of providing high-resolution spatial information regarding the site of action of the drugs. PET and other imaging methodologies can also be utilized with radio-labeled ligands to investigate a whole range of pharmacological processes including transmitter release and receptor binding.

Perhaps the most direct method of exploring the effects ofa psychopharmacological agent on psychological processes is the use of neuropsychological tests to examine changes in cognition. ► Cognitive enhancement is a particular goal of a branch ofpsychopharmacology, for example, in the treatment of ► dementias. However, in addition, cognition can be utilized as an objective outcome measure in treatment studies using reliable neuropsychological tests of proven validity. Such tests can be combined with, for example, EEG or fMRI to provide additional information regarding which temporal and spatial component of a cognitive task is being influenced by the psychopharmacological agent.

Historically, some of the most widely used psychophysi-ological techniques have utilized the close interaction between the central nervous system and the ► neuroendocrine system. Such neuroendocrinological techniques offer the advantage of the simplicity of sample collection by measuring hormonal levels most commonly in plasma. The technique can be used in a number of different ways. For example, ► stress in a number of forms leads to the activation of the ► hypothalamic-pituitary-adrenal (HPA) axis with a consequent release of corticosteroids. The effect of a psychopharmacological agent on stress can be assessed by examining changes in peripheral corticos-teroids. This is a classic example of where Furedy's (1983) point about the measures being "unobtrusive" is a key issue. If the method by which samples are collected is stressful, this may lead to an alteration in the measured levels of corticosteroids. An alternative neuroendocrino-logical strategy is to assume that changes in transmitter systems in higher centers are reflected in similar changes in these transmitter systems that control neuroendocrine function. An example of this approach, much in evidence in the 1980s and 1990s, is the use of growth hormone and prolactin responses to serotonergic probes such as ► tryp-tophan or ► buspirone, to assess the presumed functional status of hypothalamic 5-HT1A receptors in mood disorders and following administration of ► antidepressants.

All of the above-mentioned methods can be considered as within Furedy's (1983) definition of "psychophysiological." However, within the specialty of psychopharmacolo-gy, the term in common usage usually refers to the more peripheral physiological effects of changes in the central

(psychological) function. Many, but certainly not all, of these effects relate to changes in the autonomic nervous system function as indexed by, for example, changes in pupil diameter, heart rate variability, and electrodermal responses.

Principles of Psychophysiological Methods as Applied in Psychopharmacology

Furedy (1983) argued that psychophysiology is different from physiological psychology in that the latter is related to the study of the physiological underpinnings of psychological processes. However, this is a "legitimate" area of study for the psychophysiologist, as perhaps the most important principle of psychophysiology is that the mechanism connecting the psychological process with the physiological response is known. Essentially, the issue here is the same as in any area of research when two measures are correlated; correlation does not imply causation. Heart rate may well be observed to increase when a person is anxious. However, it is necessary to be convinced that it is anxiety (a psychological process) in any particular circumstance that is leading to an increase in heart rate, to make it a viable psychophysiological measure. In psychopharmacology, the situation is even more complex when using psychophysiological outcome measures, because it is also important to know if the drug could be directly influencing the physiological response. A good example of this is the use of PET and fMRI imaging exploring blood flow changes in response to administration of a pharmacological agent. Before concluding that changes in the image signal relate to the effects of the drug on a particular psychological process, it is essential to know if the drug has direct effects on cerebral blood flow.

To illustrate the issues around the importance of understanding the mechanisms underlying psychophysiological effects and other principles of these methods, work in the area of arousal will be described.

A potential psychophysiological outcome measure to assess arousal is the diameter of a subject's pupil. Pupil diameter has a close relationship with arousal, with decreased arousal being accompanied by constriction of the pupil (miosis). This is believed to reflect decreased sympathetic activity as levels of arousal drop. The ► benzodiazepines, (e.g., ► diazepam), as anxiolytic and sedative drugs, cause a decrease in arousal. This can be assessed subjectively, for example, using visual analog scales (Fig. 1). Psychophysiology offers a more objective outcome measure. However, diazepam does not lead to any change in papillary diameter (Hou et al. 2007, Fig. 1). Does this paradox suggest that either diazepam is not sedating or pupillary diameter is a poor psychophysiolog-ical outcome measure? The former option seems an unlikely explanation. In the study by Hou et al. (2007), additional psychophysiological measures of alertness were also conducted. These included the ► critical flicker fusion frequency (► CFFF) test. This involves determining the frequency at which a flickering light gives rise to the sensation of a steady light. This is measured by

Psychophysiological Methods. Fig. 1. Level of alertness following a single oral dose of diazepam 10 mg given to 16 healthy male volunteers. Alertness assessed using a visual analogue scale, pupil diameter and critical flicker fusion frequency. # p <0.05 versus placebo. Full details of the study and the methods used can be found in Hou et al. 2007 from where the figures have been obtained.

exposing the subjects both to a low-frequency flicker and increasing the frequency to the point at which the subject has the sensation that the flickering stops, and a high-frequency flicker that decreases to the point at which the flicker is detected. The CFFF is the mean of the two. As in all areas of science, having well-designed methodology that is objective, valid, and replicable is essential. The CFFF is a test that has been in usage since the 1950s and it is well accepted as a psychophysiological measure of arousal (Tomkiewicz and Cohen 1970). Hou et al. (2007) showed a significant effect of diazepam on the CFFF (Fig. 1), suggesting that diazepam does indeed have an effect on arousal and this can be measured both subjectively and objectively. They provided data that suggest that the paradox of the lack of effect of diazepam on pupil diameter relates to a lack of effect on either the sympathetic or parasympathetic influence on the iris. This highlights the importance of being aware of both the pharmacology of the drug being studied and the mechanism of the psychophysi-ological tests being used.

However, it is incorrect to think that diazepam has no effect on the pupil. In addition to simply measuring the pupil diameter, Hou et al. (2007) also measured spontaneous pupillary fluctuations, by analyzing these data in two ways: first, by performing an analysis of the frequency of fluctuations using a ► Fast Fourier Transformation to obtain an assessment of power, and second, by a ''pupillary unrest index,'' (PUI) which is the distance travelled by the margin of the pupil in 1 min. These two measures reflect ''pupillary fatigue waves'' (Ludtke et al. 1998) that are believed to closely parallel fluctuations in the activity of the noradrenergic neurons of the locus coeruleus (Aston-Jones and Cohen 2005), influenced by arousal. While diazepam has no effect on static pupil diameter (Fig 1), it significantly increases the pupillary fluctuation power and PUI (Hou et al. 2007, Fig. 2), in line with its proposed sedating effects and the results from the CFFF test. The study illustrates the importance of utilizing a range of methodologies relating to different mechanisms and pathways whenever possible to be able to draw legitimate conclusions regarding the effect of the drug. Further, the study illustrates the complexity and ingenuity of many modern psychophysiological tests.

Advantages and Limitations of Psychophysiological Methods

As described earlier, the most obvious advantage of psychophysiological methods is their use in providing objective outcome measures of the effects of psychophar-macological agents, and as such, they relate to the very essence of the discipline. There is an enormous range of such techniques and it is impossible to delineate all their advantages and limitations here. The various methods span a range of ease of use, cost, and utility. Their main limitations are when there is a lack of a clear understanding of the mechanism underlying the response being measured, and the direct and indirect effects that a drug may be having on it.

Psychophysiological Methods. Fig. 2. Pupillary spontaneous fluctuations following a single oral dose of diazepam 10 mg given to 16 healthy male volunteers. Data show the effect of diazepam on both the power of the fluctuations and the pupillary unrest index (PUI). # p <0.05 vs. placebo. Full details of the study and the methods used can be found in Hou et al. 2007 from where the figures have been obtained.

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Anxiety and Depression 101

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