Neuroscience
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A Computerized Test Battery to Study Pharmacodynamic Effects on the Central Nervous System of Cholinergic Drugs in Early Phase Drug Development
Chapters
Summary February 11th, 2019
A validated computerized battery of neuropsychological and neurophysiological tests is used to study pharmacodynamic effects on the central nervous system of newly developed drugs in early phase development. To demonstrate the test battery, the acute effects of mecamylamine and the reversal of these effects by two agonist drugs are described.
Transcript
In our studies, we use a test battery that consists of several different neuropsychological and neurophysiological methods. Each test is sensitive to different classes of CNS active drugs. A major advantage of this technique is that it allows repeated measurements during study days.
In this way, those in concentration effects relationships can be determined. Because the data processed and analyzed almost immediately, the results can be used for dose escalation decisions without any delay. To begin this procedure, switch on the power of the test battery computer and turn on the computer and screens.
Then, seat the subject in front of the computer screen and joystick. Confirm the preferred hand of the subject and adjust the joystick accordingly. Instruct the subject to hold the joystick as a pen with the arm resting on the table.
Subsequently, start the test script via the installed program. Fill out the requested specifics such as subject and study number. Next, execute the test by clicking start on the Test Assistance screen.
Monitor the performance of the subject on the Test Assistance screen and encourage the subject to keep the circle around the dot if the subject cannot exceed difficulty factor two. In this step, identify the outer Canthus of the right eye. Repeat this procedure for the left eye.
Then identify the place where the ground electrode, two centimeters above the Nasion. Thoroughly rub the sites of the eye electrodes using a cotton wipe skin cleansing gel for bioelectrical measurement to decrease the skin impedance. Be careful not to abrade the skin.
But do not rub too softly. After that, wipe away the residual gel with a gauze. Apply three self-adhesive electrodes at the prepared sites.
Following that, connect the wires to the eye electrodes, washed with buffer. Place your hand behind the press button of the electrode to prevent it from pushing into the skin. Direct the wires along the ears over the shoulder of the subject to prevent the wires from hanging in front of the eyes.
Then plug the three wires in the electrode impedance meter. Start the test script via the installed program and fill out the requested specifics such as subject and study number. Then start the test upon the Go instruction appears on the Test Assistance screen.
For the standard Pharmacode EEG, the electrodes are attached to the midsagittal leads. The locations are based on the 10/20 system. Here, we present the method for resting state EEG with eyes closed;but other paradigms, including event related potentials are also possible.
While four electrodes are sufficient for many cases, the number of electrodes can be varied, depending on the experiment, with the maximum of thirty-two. To perform visual, analog scale test, instruct the subject to score their current feeling by using the mouse to mark the visual along-line presented on the screen. Inform the subject that the most extreme points on the line represent the most extreme sensation imaginable.
Start the test script and fill out the requested specifics such as subject and study number. Then, instruct the subject to start the test by clicking the mouse. In the body sway test, ask the subject to stand in front of the computer with the distance between the feet of about 10 centimeters and arms hanging alongside the body.
Attach the string that originates from the potentiometer built into the test battery computer onto the waist of the subject using a clip. Next, adjust the height of the table with the computer on it, until the string is horizontal. After that, ask the subject to close his or her eyes.
Start the test script and fill out the requested specifics. Then, start the test by clicking on start body sway sampling session on the Test Assistance computer screen. In the visual, verbal learning test, instruct the subject, that during the visual presentation of the words, he or she should name the words when they appear and remember them.
And that at the end of the list, recall the words with names. Start the test script and fill out the requested specifics. Following that, instruct the subject to read the written instructions displayed on the screen.
Tell the subject that the test will start when the subject presses the Space bar. Record the recalled words by clicking on the recalled words on the Test Assistance screen. Shown here is the time course of mean values of twelve healthy male subjects for the adaptive tracking test measured at multiple time points following drug administration.
The percentage of correctly tracked is presented on the Y axis. Time point post-dose is presented on the X axis with double placebo results. 10 milligrams of Mecamylamine results, 20 milligrams Mecamylamine results and 0.5 milligrams Scopolamine.
The test battery is flexible and can be adjusted to a certain drug profile. The procedure can also be combined with other pharmacodynamic measurements or with blood sampling or medical assessments like ECG and blood pressure. This can answer additional questions about safety and pharmacokinetics.
The test battery allows researchers to explore the brain penetration and pharmacological activity of new compounds, not only in healthy volunteers but also in patients with neurological or psychiatric disorders. After watching this video, you should have a good understanding of how this test battery can be used to obtain sensitive measures of drug affects across a wide range of neuropsychological and neurophysiological functional domains.
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