Henry B. Murphree

Quantitative electroencephalographic analysis of naturally occurring (schizophrenic) and drug‐induced psychotic states in human males

Analysis of the quantified electroencephalogram of the left occipital lead (Drohockis integrative method) of 21 normal male subjects revealed an average coefficient of variation in electrical energy of 15.4 per cent. In 25 male chronic schizophrenic patients, the mean coefficient of variation was 8 per cent. Placebo administration did not produce any significant change in either group. In the normal men, oral dosage with 0.3 p.g per kilogram of D‐N, N diethyllysergamide (lysergic acid diethylamide, LSD‐25) produced a 33 per cent decrease in variability without significant change in the mean energy content of the electroencephalogram. When the dose of lysergic acid diethylamide was increased to 1 p.g per kilogram, a 25 per cent decrease in variability and 23 per cent reduction of the energy content of the electroencephalogram followed. In schizophrenic patients, lysergic acid diethylamide at 1 μg per kilogram orally did not affect the mean energy content but produced a 47 per cent increase in variability. The findings indicate that the electroencephalogram of male institutionalized chronic schizophrenics tends to be hyperregulated. Similar hyperregulation is produced in normal volunteers by threshold and larger doses of lysergic acid diethylamide.

QUANTITATIVE ELECTROENCEPHALOGRAPHY IN MAN AS A MEASURE OF CNS STIMULATION

A recent development in characterization and measurement of drug actions on the brain has been the use of quantitative electroencephalographic methods.’ Although quantitation was undertaken by means of laborious manual methods at the time of the earliest EEG recordings2 and somewhat later,9.4 it was not until 1948 that a fairly simple and reliable automatic device was designed which made possible large scale longitudinal studies of the amounts and quantitative variations of the electical activity of the brain.5 This device, the electronic integrator of Drohocki, performs a continuous, cumulative measurement of the area under the successive waves, irrespective of their f requen~y.~ .~ A convenient way to visualize the kind of measurement performed by Drohocki‘s device is to consider it as summating the total energy content of the EEG within any given time period. Due to difliculties with time constants and calibration, these energy content measurements cannot be readily expressed in standard units. Instead, the results are expressed in terms of baseline settings and control measurements. From qualitative EEG studies, it has been known for a long time that drugs which are stimulants produce a characteristic EEG change defined as “alerting” or “activation.” In relation to the pattern observed before treatment this effect consists most often of a decrease in wave amplitude with a concomittant increase in wave frequency (“desynchronization”) . In the quantified EEG the overall effect appears as a decrease in energy content. On the other hand, sedative drugs produce what is loosely called “synchronization,” and this is manifested by an increase in EEG energy content. The first question concerns the sensitivity and reliability of the integrative EEG method. As is well known, the spontaneous EEG is quite variable. It is not uncommon to find during periods preceding drug administration strips of the record of various lengths in which the pattern resembles closely the one brought about by the treatment. Obviously such a situation calls for the use of statistical analysis since the problem of the signrficance of changes is of prime importance. This is where the advantage of the integrative approach becomes apparent since it permits a straightforward statistical appraisal of the changes, if any, brought about by drugs. The way in which this is achieved is the following: The integrator is

Quantitative comparisons of the electroencephalographic stimulant effects of deanol, choline, and amphetamine.

Quantitative electroencephalography is a sensitive method for assaying stimulant and depressant effects of drugs. This method was utilized to study the stimulant effect of deanol in rabbits and human subjects as compared with the efJect of amphetamine. Choline and placebo controls were applied. In both species, both deanol and amphetamine had statistically significant stimulant effects. In rabbits, deanol reversed the depressant effect of pentobarbital as did amphetamine. Amphetamine acted immediately but deanol acted only after a latent period. In humans, deanol did not show a significant latent period and appeared to act through mechanisms which can be acutely saturated.

Clinical pharmacology of potent analgesics

The object of this review is to summarize the current knowledge of morphine and morphinelike drugs. If used wisely, morphine, the oldest agent, is still one of the best. Starting in 1898 with heroin, an increasing number of morphinelike drugs have been created with the hope of improving on morphine. The array of compounds now available is made more labyrinthine by the doubtful virtuosity of trademark inventors. Whether any of the newer compounds, including meperidine, have any significant advantage over morphine or whether it is possible to separate the desired effects of these potent agents from the undesirable effects is questionable. A practical classification depends on the degree of analgesia and the duration of action. These agents can now be used more safely because of the development of such potent antagonists as nalorphine and levallorphan.

Computer analysis of drug effects on the electroencephalograms of normal and psychotic subjects

Abstract Integration of the electrical energy of the electroencephalogram (EEG) affords a quantitative method for studying in humans individual differences of both spontaneous and drug-induced origins. This kind of analysis has shown a difference between the EEGs of normals and those of male chronic schizophrenics. Objectives of the studies described in this progress report are to determine whether significant alterations in the EEGs of schizophrenics measured by this technique are produced by antipsychotic drugs, whether the EEG changes, if any, are in a direction toward normal, and whether any concomitant behavioural changes occur. This was undertaken by means of the electronic integrator of Drohocki. The schizophrenic patients initially had significantly smaller mean energies and variances than normal. The drug therapy produced correlated shifts toward normal values in the EEGs and improvements in the psychiatric ratings. Also, a newer method is repotted here in which the EEGs are recorded on magnetic tape which is then analyzed by automated operationalamplifier integrators. The integral of the EEG is read and recorded every 20 sec by an analog to digital converter. A digital computer is programmed to perform a number of statistical operations on the data. Preliminary results are presented.

Effects in human volunteers of subparalytic doses of dihydro‐β‐erythroidine

Dihydro‐β‐erythroidine is a curariform alkaloid of interest to neuropharmacologists because unlike curare it is a tertiary amine. Hence, it can be given orally and may cross the blood‐brain barriers. In the studies described here, this compound was given in single oral doses of 200 mg. total dose and 6 mg. per kilogram to trained human volunteers. At 200 mg. the effects were bradycardia and visual difficulty most often described as blurring of vision or double vision. The 6 mg. per kilogram dose produced these effects plus hypotension and reduction in grip strength with accompanying feelings of sedation. Visual effects, reduction in grip strength, and recognition of the drug were highly correlated. Dihydro‐β‐erythroidine appears to be reliably absorbed by the oral route, but its skeletal muscle effect is not reliable and does not appear until much larger doses are given than those which produce visual effects and bradycardia.