Cognitive Psychophartnacology This article examines the use of compounds classified as "cognitive activators" to treat cognitive deficits from neurologic disorders, particularly brain injury. The compounds reviewed include catecholamine agonists, cholinergic agonists, nootropics, gangliosides, and thyrotropin releasing hormone (TRH). We present both our own work and the work of other investigators who have studied the effects of these drugs on cognitive-behavioral functioning. A major emphasis of this article is the examination of different types of approaches to assess the treatment efficacy of drug interventions. The different approaches discussed include physiological, psychometric, and behavioral measures. Recommendations of specific measures that IUlve been shown to be especially sensitive to treatment effects are provided.
Alvin McLean, Jr., PhD NeuroCare, Inc.; and Department of Rehabilitation Medicine University of Washington Seattle, WA
Diana D. Cardenas, MD Department of Rehabilitation Medicine University of Washington Seattle, WA
Jodie K. Haselkorn, MD, MPH Department of Rehabilitation Medicine and Department of 1ifterans Affairs University of Washington Seattle, WA
Michael Peters, PhD NeuroCare, Inc. Seattle, WA The cognitive sequelae of neurologic injury and disease is perhaps the most challenging aspect of neurologic rehabilitation. Cognitive functioning impacts every facet of an individual's daily life. Not only are the more obvious thinking skills (e.g., memory and learning, attention and concentration, problem solving, verbal and nonverbal reasoning) affected by cognitive impairment, but behaviors such as initiation, awareness of deficits, impulse control, and social appropriateness are also affected by the patient's level of cognitive functioning. Many cognitively oriented clinicians find themselves in a classic catch-22 in that the very skills that the patient needs to learn to compensate for his or her cognitive deficits are the skills in which they are deficient. Stated differently, how can you teach memory compensation to a patient who cannot remember the strategies used to compensate? NeuroRehabil 1993; 3(2): 1-14 Copyright © 1993 by Andover Medical.
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NEUROREHABILIlATION / SPRING 1993
For this reason, approximately seven years ago, our research group began to examine how we could facilitate the work that was being done by our neurologic rehabilitation clinicians by combining their treatment strategies with drugs that fall within the broad category of "cognitive activators." This article summarizes our work, as well as the work of other investigators, in examining the effects of three different classes of drugs on cognitive-behavioral functioning. These classes of drugs are (1) catecholamine agonists, (2) cholinergic agonists, and (3) nootropics. We will also briefly discuss the latest findings concerning a group of unrelated compounds that are in various stages of development. These compounds include the gangliosides and thyrotropin releasing hormone (TRH). Finally, a substantial portion of this article will focus on issues of measurement of treatment efficacy. This very critical area will be examined from the standpoint of three different types of mea3urement: physiological, psychometric, and behavioral.
CATECHOLAMINE AGONISTS The first compounds to be discussed are the catecholaminergics. Gualtieri and Evans 1 present a seven-point theoretical framework for using stimulants in brain injury treatment, which borrows heavily from Gualtieri's earlier work with attention deficit/hyperactivity disorders in adults and children. There are two lines of reasoning for the use of stimulants that appear to have empirical support from both animals and human research. First, stimulants facilitate recovery after brain i~ury, 2-6 and, second, stimulants may enhance attention and thus facilitate learning after brain injury. 7 In this section, we will discuss two of the stimulants: dextroamphetamine and methylphenidate. Additionally, a brief presentation of some of the exciting work being done with amantadine will also be reviewed.
Methylphenidate and Dextroamphetamine The most obvious choice of drug to improve attention and concentration is a central nervous
system (eNS) stimulant. SternS studied 11 traumatic brain injury (TBI) patients whose lesions were primarily frontal or prefrontal. These patients evidenced the classic frontal-lobe symptoms of apathy, excessive tiredness, indifference to the environment, and reduced attention and concentration. He initially administered a dose of dextroamphetamines in the range of 10 mg in the morning and in some of the cases raised it to 15 mg per day. He reported that 8 of the 11 patients showed a good response to the medication in terms of increased concentration, diminished daytime fatigue, increased psychomotor activity rate, and more initiative in terms of social contacts. Unfortunately, no information was available regarding how the efficaq' of the drug intervention was assessed or how the level offimctioning of the patients changed once they were taken off the medication. Using single-subject methodology, Evans, Gualtieri, and Patterson 7 have also demonstrated that methylphenidate and dextroamphetamine in moderate doses have been shown to improve long-term memory, attention, distractibility, disorganization, and impulsivity after TBI. These findings were subsequently replicated in a larger investigation of 15 closed head injury patients using a double-blind, placebo-controlled design. 1 Using a comprehensive battery of neuropsychological, behavioral, and self-report measures, the investigators found that there is some evidence of shortterm effects of methylphenidate on the cognitive and behavioral sequelae of closed head injury. In their investigation, they did not find any side effects of the stimulant medication nor was there any evidence of stimulant dependence or abuse. Gualtieri and Evans used two different doses of methylphenidate: low was 0.15 mg/kg bj.d. and high was 0.30 mglkg bj.d. The results indicated that the treatment effect was most evident with the high as compared to the low dose of methylphenidate; however, longterm benefits were not demonstrated. Stimulants, however, may impair performance at high doses 9 and can produce severe withdrawal symptoms if abruptly discontinued. It is not clear which TBI patients will most likely benefit from the use of stimulants. Perhaps the mildly impaired patient with attention difficulties will respond best.
Cognitive Psychopharmacology
Stimulants have also been shown to be useful in other neurologic disorders, such as cerebrovascular accidents (CVAs). As mentioned previously, there is a growing research literature to suggest a role for amphetamines in facilitating recovery particularly after stroke. Feeney et aP and Goldstein 4 were able to demonstrate that a single dose of d-amphetamine, administered within 24 hours after brain injury accelerated recovery of beamwalking ability in laboratory animals. Crisostomo et al, 2 using a randomized double-blind experimental design, found that treatment with amphetamine facilitated motor recovery in a small, select group of stroke patients. Clinically, we have seen effects of stimulant therapy in patients with poststroke depression, as well, especially those with psychomotor retardation that limits participation in therapy or even the ability to maintain hydration or nutrition. These findings are supported by empirical investigation.IO,11 We usually start with methylphenidate 5 mg in the morning and at noon. This dose is increased every two days, if tolerated, until a therapeutic effect is visible or a ceiling dose of 30 mg/d is reached. Typically, results are apparent at 20 mg/d. The major side effect is possible increase in blood pressure. Another side effect is insomnia, which is reduced by giving the medication early in the day.
Amantadine Amantadine may benefit cognitive function in selected TBI patients during the early stages based on reports of its effects on agitation. 12 It has been used for "negative" symptoms of schizophrenia, such as withdrawal, abulia, and bradykinesia, and reported to benefit some TBI patients with anergia, abulia, or depression. 12 Amantadine, like methylphenidate, has also been used successfully in other disorders, especially in patients with multiple sclerosis who have fatigue-induced disabilities. Clinically, approximately 50% of the patients respond to an initial dose of 100 mg b.i.d. Patients report an increased ability to complete daily tasks. 13.14 These empirical observations are supported by double-blind, placebo-controlled studies.
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CHOLINERGIC AGONISTS Considerable data exist to suggest an important role for the central cholinergic system in human memory and cognitive flmction. The reader is referred to the extensive reviews of the animal literature done by Deutsch 15,16 and Bartus.'7 A comparable review of the human literature has been done by Drachman and Sahakian, 18 Mohs et al.,19 and Davies. 2o Generally these studies have shown that fluctuations in central cholinergic activity cause significant changes in memory function. This research has basically taken two approaches. An investigator will use either a cholinergic antagonist such as scopolamine 21 and demonstrate a reduction in memory function, or a cholinergic agonist such as physostigmine 22 .23 and demonstrate an enhancement of memory function. Although these data support the concept that the cholinergic system plays an important role in cognitive function and particularly in memory, this does not mean that the cholinergic system alone is responsible for this function. A report by Levine et al. focuses on the issue of neurotransmitter interactions, specifically cholinergicdopaminergic interactions. 24 Physostigmine is a drug that temporarily inhibits acetylcholinesterase, thereby slowing the destruction of acetylcholine and thus increasing its concentration at the synapse. 19 The biologic halflife of physostigmine is short, based on early gastrointestinal motility studies in which physostigmine appeared to peak at 30 to 60 minutes. 25 More recent data have shown that plasma physostigmine concentration after a single dose of oral preparation peaks in 30 minutes and is undetectable by 2 hours. 26 However, the effect after multiple dosing may be many times longer. 27 In addition to half-life considerations, studies have shown that dosing is important. There appears to be a consistent observation that the therapeutic window for response to physostigmine is very narrow and that it is critical that an individual optimal dose be determined in order to demonstrate efficacy. 19.22.23.28.29 For example, 3 mg given intravenously to normal young subjects produced a decrement in memory, whereas doses of 1 to 2 mg produced a slight improvement in memory
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storage, and 0.5 mg infused over a 30-minute period significantly improved long-term memory.23 There are very few published reports on the use of physostigmine in memory disturbances after brain injury. This may be in part due to the lack of clinical improvement found in Alzheimer's disease. However, Woerkom et al. 30 treated 38 patients with head injuries and demonstrated that with certain patients, treatment with L-dopa and/or physostigmine facilitated recovery fi'om severe head iI~ury. Their principal dependent measures were the motor and verbal scores of the Glasgow Coma Scale and the Glasgow Outcome Scale. Goldberg et a1. 3 ! combined oral physostigmine with lecithin in a double-blind study of a single patient with post-traumatic amnesia. Improvement in storage and retrieval of words in verbal memory was found. They reported no change in conceptual reasoning nor any improvement of encoding capacity and suggested that these functions may be more specific to basal forebrain structures; hence, more dependent on catecholaminergic than cholinergic mechanisms. We conducted preliminary studies with oral physostigmine administered during the course of a memory training program. 32 The results indicated that delayed recall, storage, and retrieval of verbal information was enhanced by combining physostigmine with an established memory training procedure. The subjects were suffering from anoxic brain irUury after carbon monoxide poisoning. In this study, a double-blind, singlesu~ject A-B-A design was used with A representing the baseline phase, B constituting the memory training combined with drug phase, and A representing return to the baseline condition. Memory training used a self-instruction study skills model. Data were collected over a 16-week time span with neuropsychological measures and serum cholinesterase levels obtained during the study. Improvements were shown on standardized memory measures, such as the Long-Term Storage on the Selective Reminding Test and delayed recall on the Logical Memory and Visual Reproduction tests from the Wechsler Memory Scale, as well as nonstandardized memory tasks such as
remembering daily events or organizing time. Increased performance on tasks of daily living was observed, although no quantifiable data were obtained. The research design used, however, did not allow us to determine the relative effectiveness of either the drug or the memory training procedure alone. In another study, our team studied 39 men with brain injury and memory losses in order to examine the effects of oral physostigmine on such losses and determine response to a cholinergic antagonist, scopolamine. It is generally accepted that scopolamine in high enough doses produces temporary memory impairment. However, an interesting prior study has suggested that Alzheimer's patients, who are known to have deficient cholinergic activity, are more sensitive to the cognitive effects of scopolamine than age-matched controls. 33 Animal research also supported the notion that in the presence of pathology in the central cholinergic system there is increased sensitivity to the disruptive effects of scopolamine on cognition. 34 This led us to the hypothesis that response to scopolamine could be used to predict response to physostigmine in a population with TBI. In our second study, a double-blind design was used to study the effects of physostigmine, placebo, and scopolamine on memory function in a group of36 brain injured males. A maximum dose of 4.0 mg physostigmine P.O t.i.d. was reached over the course of a week and was generally well tolerated using care to exclude medical contraindication. 5 Scopolamine was administered as single or double skin patches. In addition to neuropsychological measures, clinical tests of balance were made. Improved memory performance during administration of oral physostigmine was found. Analysis of data including response to scopolamine, computerized tomography (CT) findings, and results of balance testing is in progress to help better differentiate responders from nonresponders. Pilot testing with single-photon emission computerized tomography (SPECT) with drug and placebo has proved difficult in such subjects. Reliability studies of SPECT in patients who are distractible or have decreased attention and concentration is needed.
Cognitive Psychopharmacology
CDP-Choline In a recent investigation, Levin 35 studied the efficacy of cytidine diphosphoryl choline (CDP-choline) in the management of 14 mild to moderate brain injured subjects experiencing post-concussional symptoms. Using a double-blind, placebocontrolled design, he found that CDP-choline produced a significantly greater reduction in postconcussional symptoms, as well as a greater improvement in recognition memory than placebo. This is a very interesting finding that warrants replication and further examination of the neurophysiological mechanism that may be responsible for the improvements.
NOOTROPICS Nootropics refers to a class of drugs that are known as cognitive activators. The term nootropics (noo = mind, tropic = toward) was coined by Giurgea 36 and should display a characteristic drug profile. They should (1) enhance acquisition of certain learned behaviors, (2) enhance resistance of learned behaviors to manipulators designed to disrupt them, (3) facilitate interhemispheric transfer of infiJrmation, and (4) protect the brain against certain physical or chemical insults. 37 - 39 Two additional criteria were delineated by Giurgea, but have not been examined and do not warrant discussion here. A number of compounds have recently been classified as nootropics. The classic examples of nootropics are the compounds containing the 2-pyrrolidinone moiety, which are piracetam (the prototype), aniracetam, oxiraxcetam, and pramiracetam.
Pramiracetam Pramiracetam was selected for clinical trials in humans on the basis of its ability to reverse electroconvulsive shock-induced amnesia in mice, to reverse hippocampal stimulation-induced learning deficits in rats, and to enhance short-term memory in rats and monkeys.40 These effects occurred at doses in the 0.5 to 10 mg/kg range. Thus pramiracetam is at least 100 times more potent than piracetam (the original compound in this class). In phase 1 studies, pramiracetam was well
5
tolerated by normal volunteer subjects in single doses up to 1600 mg and in multiple doses up to 1500 mg/d for 28 days. In phase 2 open-label studies, elderly patients with dementia received 300 mg/d pramiracetam for 6 to 9 weeks with no significant drug related adverse effects. Our research group has conducted two studies that have evaluated, under double-blind conditions, the safety and efficacy ofpramiracetam versus placebo in treating memory and other cognitive problems of male su~jects who have suffered brain i~juries sufficient to cause long-term, stable losses in memory and cognitive functioning. In the first study, a double-blind, placebocontrolled design was used in which each subject received over the course of 12 weeks, two 3-week blocks of pramiracetam sulfate 400 mg P.o. Li.d. or placebo. The order of drug or placebo was decided randomly and independently for each of the two pairs of experimental conditions. Following the completion of both pairs, all su~jects were continued on pramiracetam in an open-label fashion for a total of 18 months. No side effects were reported during the experimental trial or during the open-label period of 18 months. The results of the study indicated that subjects' performance on measures of memory, especially delayed recall, evidenced clinically significant improvements after the administration of pramiracetam sulfate as compared to placebo. This improvement was maintained during an 18-month open-label period on the medication as well as during a I-month follow-up period after the pramiracetam was discontinued. The results of our first study with pramiracetam were encouraging and led to our second study regarding the effects of the drug in combination with memory training. The specific hypothesis to be tested was that pramiracetam in combination with memory training would be more efficacious in improving memory function than either procedure alone in otherwise healthy young males who had suffered brain injury sufficient to cause long-term, stable losses in memory. The design of the study was a double-blind 2 X 2 factorial, training x drug design. The two training conditions were memory training or no memory training and the two drug conditions were
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pramiracetam or placebo. The duration of training or drug administration was 8 weeks. Follow-up assessments were conducted at 1, 3, and 6 months after treatment. Fifteen subjects completed the trial. There were no statistically significant differences in age, education, severity of injury, or imaging conditions among the groups. The results were as predicted. Following is the ranking (from best to worst) of the performance for Long-Term Storage on the Selective Reminding Test and for immediate recall on the functional reading task: (1) pramiracetam with training, (2) pramiracetam without training, (3) placebo with training, and (4) placebo without training.
OTHER COMPOUNDS Gangliosides Gangliosides are a family of acidic complex lipids composed of a hydrophobic and hydrophilic moiety.41 These are "naturally occurring substances" known to be part ofthe backbone of the membrane. Over the last 20 years they have evolved, however, from being viewed as an inert substance to being viewed as having functional involvement in synaptic transmission and possessing the ability to enhance sprouting and potentially limit ischemic injury. This evolution came about as we understood more about genetic diseases resulting in accumulation of gangliosides in the CNS and the realization that more subtle changes in ganglioside levels are positive and associated with maturation processes of the CNS. Animal studies indicate that the ganglioside, GM I, reduces cerebral edema and enhances recovery after lesions in the brain or spinal cord. 41 A recent report suggests that GM I enhances recovery in humans after spinal cord injury.42 Gangliosides are capable of inducing dendritic formation in vitro. 41 No reports on the effects of gangliosides after TBI in humans were found, but there have been three double-blind investigations on the effects of GM I, on patients who have had CVAs. In two of these studies, improvement was found with GM I as measured by clinical signs and neurophysiological parameters. 43 ,44 The third study45 did not find any difference in those receiving GM I
versus placebo. Although GM I is available in Europe, it still remains experimental in the United States.
Thyrotropin Releasing Hormone Animal studies by Horita et al. demonstrate improved learning in rats with septohippocampal cholinergic system lesions when treated with an analog of TRH.46 TRH may activate the central cholinergic pathway via a D-l dopamine link. This work suggests that stable analogs ofTRH alone or in combination with an anticholinesterase agent may represent possible pharmacological approaches to the treatment of memory deficits, such as those seen after TBI.
ASSESSMENT OF TREATMENT EFFICACY Assessment of treatment efficacy is perhaps the most critical aspect of clinical practice; yet, it is an area that is given the least amount of attention. It is given little attention because most clinicians either have not been trained in this area or have not been given guidelines on how to create this aspect of their clinical service delivery. In this section, we will attempt to do this. A number of different assessment techniques can be employed in determining whether a particular medication has been effective. The specific tools would depend on what targeted behaviors the medication is being used to address. There are a few principles to bear in mind. These include (1) if you are using a standardized assessment tool to measure a change (e.g., using a Wechsler Memory Scale to measure the effects of a cholinergic agonist, such as physostigmine, on memory), use of a functional measure as well for ecological validity (e.g., patient remembers to take his medication without prompting); (2) if you are administering a medication the effects of which are supposed to be specific to a particular behavior, it is important to assess that behavior as well as similar and different behaviors to determine the specificity of the medication's effects (e.g., if you are administering a drug whose effects are supposed to be on attention and concentration, such as methylphenidate,
Cognitive Psychopharmacology
you should also measure memory, reasoning and problem solving, and motor speed to determine how general or specific the medication's effects are; (3) in most medication trials, especially double-blind, placebo-controlled trials, measures have to be repeated several times, so it is important to use instruments, whenever possible, that are not sensitive to practice effects; (4) when behavioral analysis is used as the dependent measure of behavioral change, a detailed task analysis of the targeted behavior should be done as well as an analysis ofthe antecedents and consequences of the behavior, which requires a baseline data collection phase prior to medication changes; thus, time has to be allowed for this phase; and (5) many of these medications have a narrow window of efficacy, so it is important, whenever feasible, to obtain laboratory data to confirm that the medication is within the therapeutic range. In terms of specific measurements of treatment change, they can be classified into three categories: physiological, psychometric, and behavioral or functional. Each will be discusses briefly in turn.
Physiological A number of issues must be brought to bear in conducting clinical studies that are possibly interacting with the neurotransmitters of the brain. First, is the drug capable of crossing the bloodbrain barrier if given parenterally or orally? Although intravenous drugs have the advantage of directly entering the systemic circulation, even with such a route the concentration of drug will depend on cardiac output, regional blood flow, lipid solubility, protein binding,47 and, with regard to the CNS, the drug's ability to crOss the blood-brain barrier. In the case of oral preparations, one is also dealing with factors related to absorption (such as gastric emptying), the type of drug preparation (liquid, tablet, or capsule), and the pH of the stomach. 47 Since behavioral effect is the goal, in some cases, one may only need to monitor for signs of toxicity. This may be done by clinical observation often with measurements of vital signs and mental status checks. For example, in the case of cholinergic agents, serum cholinesterase levels may assist in monitoring toxicity. Such levels have been used
7
to monitor effects of insecticides on farm workers.48 The intra-individual variation, however, ranges from 8.6 to 23% when normal subjects are sampled in two succeeding samples. 48 Thus, the serum cholinesterase level cannot be used to give precise information regarding therapeutic level for cognition as has been suggested. 49 Genetic variants occur, thus, baseline serum cholinesterase levels are needed. In general, for any drug in which a serum level is readily obtainable, such a measurement is desirable and more practical than obtaining cerebrospinal fluid levels, which are a more accurate reflection of drug concentration at the site of action. Physiological responses, particularly pupillary changes, heart rate, blood pressure, and oral temperature may be useful in the study of anticholinergics or catecholinergics. In addition, scopolamine has the potential to affect balance in brain injured individuals, and clinical measures of balance have provided useful information regarding drug activity. 50 Balance measurement are often made in a standing position, which limits the usefulness to ambulatory subjects. The use of sitting balance measurements would increase the ability to study nonambulatory subjects. The previous discussion has been limited to single-drug administration. In the case of twodrug combinations, the mechanism of action of each drug might be similar (i.e., choline and physostigmine, or arecholine and tacrine); thus, whole body toxic effects would be predictable. What would be less clear is to what extent each drug produced the toxic effects or the therapeutic effects. Hence, determining the optimal ratio of the two-drug doses is problematic. Animal research has begun to tackle this issue in the area of memory-enhancing agents. 51 If true synergism is found with certain combinations, then total drug dosage could be reduced. Finally, advances are occurring in the development of technology to examine the neurophysiological changes that occur secondary to pharmacologic interventions. Positron emiSSIOn tomography (PET) and (SPECT) both hold promise as techniques to assist in understanding the physiological basis for the efficacy or possibly lack of efficacy of various "cognitive activator"
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compounds. At a recent meeting of the Insurance Rehabilitation Study Group investigators discussed some ofthe latest applications of this technology as well as identified some of the problems of reliability and validity of the technology at this stage of development. 52.53
Psychometric Psychometric measurements refer to standardized assessment tools. The use of standardized assessment instruments allows you to compare the efficacy of the same treatment across different patients. The use of these types of measures also allows for the comparison of findings across different laboratories and clinics. In terms of cognitive psychopharmacology, the drugs that have been reviewed primarily impact attention and concentration, memory, and learning. Following is a list of the measures that have been used by our research group as well as others. All of the measures listed below have at least moderate to good test-retest reliability and solid content, predictive, or construct validity. A. Attention and concentration
1. Trailmaking Test, parts A and B54-56 2. Seashore Rhythm Test 55 3. Digit Symbol Test from the Wechsler Adult Intelligence Scale-Revised 56 4. Symbol Digit Modalities Test 54 B. Memory and learning 1. Wechsler Memory Scale- Revised 56 2. Buschke Selective Reminding Test 57 3. The California Verbal Learning Test-CVLT56 4. Benton Visual Retention Test-BVRT54 5. Rivermead Behavioral Memory Test-RBMT58 . In addition to these standardized cognitive measures, it is often valuable to obtain ratings of either the patient's or the family's perception of his or her daily cognitive functioning. One example of such a rating scale is the Baddeley or Sunderland questionnaire, which rates memory problems in everyday life. 59 Another very welldesigned and psychometrically sound measure that could be used for this purpose is the Sickness
Impact Profile (SIP).60 The SIP is a behaviorbased measure of health status composed of 136 statements about health related dysfunction in 12 areas of activity. These areas include sleep and rest, ambulation, work, recreation and pastimes, alertness behavior, and home management. While it is not traditionally done, if one were solely interested in the impact on cognitive functioning, the Alertness Behavior scale from the SIP could be administered alone. The SIP is a psychometrically sound measure that has been shown to discriminate well between normals and individuals suf~ fering from a variety of medical conditions.
Behavioral or Functional Non-standardized functional assessment of treatment efficacy is perhaps the most challenging but also the most valuable source of information for examining the ecological validity of your interventions. There are three data keeping systems commonly used in the evaluation of treatment efficacy. What follows is a brief discussion of each, organized around a general description, examples, and an analysis of strengths and weaknesses specific to each. Narrative. What is probably the most prevalent data keeping method is a running narrative or written summary of significant events. Nursing notes are examples, as are chart entries. Entries are typically made at shift's end or on a more frequent interval depending on the behavior(s) under review. Strengths of this type of data keeping system are that a variety of significant events can be tracked and often occurrence of an event can be tied to time of day and surrounding circumstances or antecedents. The narrative can be structured such that each individual making an entry does so in a consistent manner with the subjective, objective, assessment and plan (SOAP) format serving as an example. During the assessment phase oftreatment, narrative data may serve to give direction to specific regimens as well as provide direction on which data keeping method should be used. This data collection method has a number of weaknesses the first of which is that the specific data or information of interest to the physician may not necessarily be captured in the entries. Quantification of rate or intensity of behavior is problematic, often requiring an in-depth and
Cognitive Psychopharmacology
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Note: Items underlined have current Intervention Plan in effect. Please note other remarkable behaviors on the back of this sheet.
Figure 1. An example of a frequency data sheet. time-intensive review of notes attempting to extract key information. Finally, unusual or high rate behaviors are more likely to be noted and there is potential for otherwise important behaviors that are less intrusive or occurring with low frequency not being noted in the narrative. Frequency. Frequency data keeping protocols consist of making a notation for each occurrence of a specific behavior. Frequency data are easy to record and summarize. A variety ofbehaviors can be included on a single sheet as can a number of different patients. Accommodation can be made for occasional narrative type notes allowing for documentation or new or unusual behaviors.
One weakness of this type of data keeping strategy is that for high rate behaviors it may be too intrusive or time consuming to accurately note each instance ofthe behavior. As in narrative types of data, data not recorded as the behavior occurs may be forgotten. Another potential difficulty with frequency data is encountered with behaviors that do not necessarily have clear beginnings and ends or where the length of different episodes vary. "On-task" behaviors are good examples of this weakness as is "agitation." Frequency data do not typically provide time or context specific information. An example is provided in Fig. 1.
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Interval. Interval data keeping systems are constructed such that periods of patient contact are divided into intervals of specific durations (see Fig. 2 for an example). Within each interval are listed behaviors that are being tracked. Should a behavior occur, it is circled or otherwise noted within the appropriate time interval. Additional instances of the same response require no additional notations. Absence of a specific response within an interval requires no notation. Data are typically summaJ1ized to report percentage of intervals with one or more response having occurred. The positive aspects of this type of data keeping strategy are many. The resolution of data with respect to time of occurrence is easily adjusted by increasing or decreasing the time encompassed within each interval. Behavior occurring at a high rate is readily accommodated as only the first response occurring within an interval is recorded and subsequent responses are not. Behaviors long in duration (i.e., extended episodes) are also easily accommodated as a maximum of one notation is made for each interval. The main weakness of an interval data keeping system is resolution of frequency of behavior within intervals. When using wide intervals a few or many behaviors may have occurred and the record is the same. For example, carbamazepine (Tegretol) used with a patient displaying relatively high rates of behavior dyscontrol may achieve significant decreases in behavior excess within each interval. However, as long as at least one episode occurs within an interval, no reduction in frequency will be noted (for those intervals). It is only when zero episodes occur that progress is noted. Repeated acquisition. During protracted medication regimens, it may be advantageous to the physician to monitor incremental or decremental drug effects on learning and memory on a chronic rather than an acute basis. Typical assessments oflearning and memory suffer from potential confound with repeated administration; that is, a test-retest confound may occur where increments in performance are the result of the practice of taking the test rather than true improvements secondary to the intervention. The
development of alternate forms of the test is one way of mitigating the effects of this potential confound. An alternative to standardized neuropsychological measures of learning and memory is the procedure of repeated acquisition of response (behavioral) chains. 61 ,62 As typically implemented, the procedure consists of two separate components: performance and acquisition. The patient's task is to correctly emit a prior learned response chain (e.g., entering a 20-digit sequence into a computer keyboard). In the acquisition component, the task is to learn a new response chain (e.g., a new 20-digit sequence). The performance component provides an assessment of the patient's memory and acquisition component: learning. Practice effect is not an issue and the procedure is one that can be employed numerous times during treatment, even within the same day. Thus, the physician is able to monitor drug effects over time while changes are being made in dosage levels. This procedure can also be used to monitor medications that have slowed information processing speed, reduced attention and concentration, and impaired memory as side effects. ; Perhaps the most appropriate assessment of drug effects on performance is one in which data are derived from functional tasks normally a part of the patient's daily routine or rehabilitation regimen. For example, our research group recently examined the effects of amantadine therapy on attention and concentration and memory with a severe TBI patient. Our principal measure of drug efficacy was performance on the repeated acquisition paradigm discussed previously. The reasons for choosing this technique were many, including the ability to administer the measure during the morning and the afternoon without concern for practice effects. In considering what would be potential collateral measures of drug efficacy, we considered the patient's status as an insulin-dependent diabetic. We then decided to use the patient's progress toward becoming independent in his self-monitoring of his blood glucose level as a functional measure of the drug'S efficacy. To do this, the blood glucose monitoring procedure was broken down into sequential steps. As the patient completed each step, the level of
Cognitive Psychopharmacology
AM SHIFT
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INTERVAL DATA COLLECTION
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Client:
Instructions
1. Times indicate the start of each 15 min period; i.e., the 7:00 box contains data for the interval of 7:00 -7:15.
2. If one of the listed behaviors occurs during an interval, circle that behavior or draw a line through it. 3. If one or more of the listed behaviors does not occur, do nothing.
4. Use the bottom of the sheet for comments.
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COMMENTS/NOTES: Time: Time: Time: Time: Time:
Figure 2. An example of an interval data sheet.
Time 11 :00 11 :15 11 :30 11 :45 12:00 12:15 12:30 12:45 1:00 1 :15 1:30 1:45 2:00 2:15 2:30 2:45
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NEUROREHABILITATION / SPRING 1993
assistance necessary to complete that step was recorded. Levels of assistance included independent, vocal or gestural prompt, modeling the step, or physical assistance required to complete the step. The results indicated that the patient benefited from the trial of amantadine and we found comparable improvement on both the formal repeated acquisitions measure and the functional measure. While it is critical to use standardized measures in comparing the efficacy of one medication across different patients and different diagnoses, the true clinical utility of your rehabilitation treatments lies within the assessment of ecologically valid, functional outcomes.
OTHER SYSTEMS A necessary component of any data keeping procedure when data are not collected in the laboratory, is a routine whereby data are sent to a designated location f{)r summary and analysis. The frequency with which data are forwarded to the central location will vary depending on the acuity level of the patient with weekly intervals typically being the largest. The manner by which data will be routed should be determined prior to beginning collection with an accountable individual identified. We have used a variety of methods for retrieving data including facsimile (FAX), preaddressed stamped envelopes, voice mail and electronic mail (E-mail), as well as identitying the clinicians who can bring data back to a central location.
Voice Mail The advent of economical voice or phone mail networks opens up the possibility of a primary report person calling in data at a predetermined interval. We recently had the opportunity to use this system with an adult male residing at home with daughter and mother. The patient was reported to be exhibiting low rates of four specific behaviors comprised of threats, behavioral outbursts, elopement, and assault with the onset of these behaviors tied to elimination of Tegretol. Early use of an interval data keeping strategy was ineffective with a key variable being the patient
finding the actual data kept aversive. A strategy was implemented whereby the mother called in to a collection predetermined voice mail box at noon and prior to retiring to bed each day. Information for each call included date and time of call and occurrence or nonoccurrence of each of the four behaviors. Data were easily collected, could be reviewed daily, and the reporters's consistency of data collection was easily measured. The detail and frequency of report is easily modified to meet specific circumstances.
Electronic Systems There are a variety of electronic data recording systems in use today with these systems typically requiring a host computer for data retrieval and analysis once collected. For most systems, ease of data entry is maximized as is the type and amount of information that can be recorded. Internal clocks can pinpoint time of day for each recorded behavior and other pertinent information is readily included. There is possibility for ofl~site data retrieval via phone link. The initial capital investment necessary for such systems as well as ancillary support costs limit use in general practice. For a thorough description of a system ofthis type see Eiler et al. 63
SUMMARY Cognitive psychopharmacology holds tremendous promise for neurologic rehabilitation. Extensive research is needed to replicate some of the early findings with these various compounds and to examine more closely the neurophysiologic basis for their efficacy. Most importantly, however, the focus of this article has been to stress the importance of careful assessment in examining efficacy intervention. Additionally, we have attempted to stress the importance of combining good pharmacologic management with cognitive or behavioral treatments. The m~jor value that cognitive psychopharmacology will have in the future of neurorehabilitation will be in the drug's ability to enhance or facilitate training. Finally, many of the drugs discussed in this article are not
Cognitive Psychopharmacology
commercially available at this time. More clinical efficacy studies are needed before Food and Drug Administration approval can be obtained.
REFERENCES 1. Gualtieri CT, Evans RW Stimulant treatment for the neurobehavioral sequelae of traumatic brain injury. Brain Inj 1988; 2:273-290. 2. Cr~sostomo EA, Duncan pw, Propst M, et a1. EVidence that amphetamine with physical therapy promote recovery of motor function in stroke patients. Ann Neuro11988; 23:94-97. 3. Feeney ~M, Gonzales A, Law WA. Amphetamine halopendol and experience interact to affect rate of recovery after motor cortex injury. Science 1982; 217:855-857. 4. Goldstein LB. Amphetamine-facilitated functi(!n~l recovery after stroke. In: Ginsberg MD, Dlench WD, eds. Cerebrovascular diseases: sixteenth research (Princeton) conference. New York: Raven, 1989; 303-308. 5. Goldstein LB. Pharmacology of recovery after stroke. Stroke 1990; 21 (Supp1. III): 139-142. 6. Steinberg GK, Saleh j, Kunis D, et a1. Protective effect of N-methyl-D-aspartate antagonists after focal cerebral ischemia in rabbits. Stroke 1989; 20: 1247-1252. 7. Evans RW, Gualtieri GC Patterson DR. Treat~ent of chronic closed head injury with psychostimulant drugs: a controlled case study and an appropriate evaluation procedure. J Nerv Ment Dis 1987; 175:106-110. 8. Stern jM. Cranio-cerebral injured patients: a psychiatric clinical description. Scand J Rehabil Med 1978; 10:7-10. 9. Wetz~l CD,.Squire L.R,janowsky DS. Methylphenidate Impairs learnmg and memory in normal adults. Behav Neurol BioI 1981; 31 :413-424. 10. Lingam VR, Lazarus LW, Groves L, et a1. Methylphenidate in treating post stroke depression. J Clin Psychiat 1988; 49:151-153. 11. Woods SW, Tesar GE, Murray GB, Cassem NH. Psychostimulant treatment of depressive disorders secondary to medical illness J Clin Psychiat 1986; 47:12-15. 12. Gualtieri CT, Chandler M, Coons TB, et a1. Amantadine: a new clinical profile for traumatic brain injury. Clin Neumpharmacoll989; 12:258-270. 13. Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol 1989; 46:676-680. 14. Rosenberg GA, Appenzeller O. Amantadine, fatigue and multiple sclerosis. Arch Neurol 1988; 45: 1104-1106.
13
15. DeutschjA. The cholinergic synapse and the site of memory. Science 1971; 174:788-794. 16. ~eutschjA. Physiology ofacetyicholine in learnmg and memory. In: Barbeau A, Growdon jH, Wurtman Rj, (eds.) Nutrition and the brain. New York: Raven, 1979; 5:342-350. 17. Bartus. RT. Physostigmine and recent memory: effects m young and aged nonhuman primates. Science 1979; 206: 1087-1089. 18. Drachman DA, Sahakian BJ. Effects of cholinergic agents on human learning and memory. In: ~~rbeau A, Growdon jH, Wurtman Rj, ed. Nutrztzon and the brain. New York: Raven, 1979; 5:351-366. 19. Mohs ~C, Davis KL, Datiey C. Cholinergic drug effects m memory and cognition in humans. In: Poon LW, ed. Aging in the 1980s. Washington DC: American Psychological Association, 1980; 181-190. 20. Davies P. A critical review of the role of cholinergic systems in human memory and cognition. Ann NY A cad Sciences 1985; 444:212-217. 21. Sit~ram N, .Weingartner H, Gillin Je. Human senal learnmg: enhancement with arecholine and choline and impairment with scopolamine. Science 1978; 201:274-276. 22. Davis KL, Mohs RC, Tinklenberg JR, Hollister ~E, Pfefferbaum A, Kopell BS. Physostigmine Improvement of long-term memory process in normal subjects. Science 1978; 201:272-274. 23. I?~vis. KL, Yamamura HI. Cholinergic underactlVlty m human memory disorders. Life Sci 1978; 23: 1729-1734. 24. Levine ED, McGurk SR, Rose JE, Butcher LL. C:holinergic-dopaminergic interactions in cognitive performance, Behavioral and neur. biol. 1990; 54:271-299. 25. ~utl~r PR, Ritvo M. Physostigmine as a peristaltIC stimulant.JAMA 1932; 99:1329-1332. 26. Sharpless ~S, ThaI LJ. Plasma physostigmine concentrations after oral administration. Lancet 1985; 1397-1398. 27. ThaI LJ, Fuld PA. Memory enhancement with oral physostigmine in Alzheimer's disease. N Engl J Med 1983; 308-720. 28. P
Alvin McLean, Jr., PhD NeuroCare, Inc.; and Department of Rehabilitation Medicine University of Washington Seattle, WA
Diana D. Cardenas, MD Department of Rehabilitation Medicine University of Washington Seattle, WA
Jodie K. Haselkorn, MD, MPH Department of Rehabilitation Medicine and Department of 1ifterans Affairs University of Washington Seattle, WA
Michael Peters, PhD NeuroCare, Inc. Seattle, WA The cognitive sequelae of neurologic injury and disease is perhaps the most challenging aspect of neurologic rehabilitation. Cognitive functioning impacts every facet of an individual's daily life. Not only are the more obvious thinking skills (e.g., memory and learning, attention and concentration, problem solving, verbal and nonverbal reasoning) affected by cognitive impairment, but behaviors such as initiation, awareness of deficits, impulse control, and social appropriateness are also affected by the patient's level of cognitive functioning. Many cognitively oriented clinicians find themselves in a classic catch-22 in that the very skills that the patient needs to learn to compensate for his or her cognitive deficits are the skills in which they are deficient. Stated differently, how can you teach memory compensation to a patient who cannot remember the strategies used to compensate? NeuroRehabil 1993; 3(2): 1-14 Copyright © 1993 by Andover Medical.
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NEUROREHABILIlATION / SPRING 1993
For this reason, approximately seven years ago, our research group began to examine how we could facilitate the work that was being done by our neurologic rehabilitation clinicians by combining their treatment strategies with drugs that fall within the broad category of "cognitive activators." This article summarizes our work, as well as the work of other investigators, in examining the effects of three different classes of drugs on cognitive-behavioral functioning. These classes of drugs are (1) catecholamine agonists, (2) cholinergic agonists, and (3) nootropics. We will also briefly discuss the latest findings concerning a group of unrelated compounds that are in various stages of development. These compounds include the gangliosides and thyrotropin releasing hormone (TRH). Finally, a substantial portion of this article will focus on issues of measurement of treatment efficacy. This very critical area will be examined from the standpoint of three different types of mea3urement: physiological, psychometric, and behavioral.
CATECHOLAMINE AGONISTS The first compounds to be discussed are the catecholaminergics. Gualtieri and Evans 1 present a seven-point theoretical framework for using stimulants in brain injury treatment, which borrows heavily from Gualtieri's earlier work with attention deficit/hyperactivity disorders in adults and children. There are two lines of reasoning for the use of stimulants that appear to have empirical support from both animals and human research. First, stimulants facilitate recovery after brain i~ury, 2-6 and, second, stimulants may enhance attention and thus facilitate learning after brain injury. 7 In this section, we will discuss two of the stimulants: dextroamphetamine and methylphenidate. Additionally, a brief presentation of some of the exciting work being done with amantadine will also be reviewed.
Methylphenidate and Dextroamphetamine The most obvious choice of drug to improve attention and concentration is a central nervous
system (eNS) stimulant. SternS studied 11 traumatic brain injury (TBI) patients whose lesions were primarily frontal or prefrontal. These patients evidenced the classic frontal-lobe symptoms of apathy, excessive tiredness, indifference to the environment, and reduced attention and concentration. He initially administered a dose of dextroamphetamines in the range of 10 mg in the morning and in some of the cases raised it to 15 mg per day. He reported that 8 of the 11 patients showed a good response to the medication in terms of increased concentration, diminished daytime fatigue, increased psychomotor activity rate, and more initiative in terms of social contacts. Unfortunately, no information was available regarding how the efficaq' of the drug intervention was assessed or how the level offimctioning of the patients changed once they were taken off the medication. Using single-subject methodology, Evans, Gualtieri, and Patterson 7 have also demonstrated that methylphenidate and dextroamphetamine in moderate doses have been shown to improve long-term memory, attention, distractibility, disorganization, and impulsivity after TBI. These findings were subsequently replicated in a larger investigation of 15 closed head injury patients using a double-blind, placebo-controlled design. 1 Using a comprehensive battery of neuropsychological, behavioral, and self-report measures, the investigators found that there is some evidence of shortterm effects of methylphenidate on the cognitive and behavioral sequelae of closed head injury. In their investigation, they did not find any side effects of the stimulant medication nor was there any evidence of stimulant dependence or abuse. Gualtieri and Evans used two different doses of methylphenidate: low was 0.15 mg/kg bj.d. and high was 0.30 mglkg bj.d. The results indicated that the treatment effect was most evident with the high as compared to the low dose of methylphenidate; however, longterm benefits were not demonstrated. Stimulants, however, may impair performance at high doses 9 and can produce severe withdrawal symptoms if abruptly discontinued. It is not clear which TBI patients will most likely benefit from the use of stimulants. Perhaps the mildly impaired patient with attention difficulties will respond best.
Cognitive Psychopharmacology
Stimulants have also been shown to be useful in other neurologic disorders, such as cerebrovascular accidents (CVAs). As mentioned previously, there is a growing research literature to suggest a role for amphetamines in facilitating recovery particularly after stroke. Feeney et aP and Goldstein 4 were able to demonstrate that a single dose of d-amphetamine, administered within 24 hours after brain injury accelerated recovery of beamwalking ability in laboratory animals. Crisostomo et al, 2 using a randomized double-blind experimental design, found that treatment with amphetamine facilitated motor recovery in a small, select group of stroke patients. Clinically, we have seen effects of stimulant therapy in patients with poststroke depression, as well, especially those with psychomotor retardation that limits participation in therapy or even the ability to maintain hydration or nutrition. These findings are supported by empirical investigation.IO,11 We usually start with methylphenidate 5 mg in the morning and at noon. This dose is increased every two days, if tolerated, until a therapeutic effect is visible or a ceiling dose of 30 mg/d is reached. Typically, results are apparent at 20 mg/d. The major side effect is possible increase in blood pressure. Another side effect is insomnia, which is reduced by giving the medication early in the day.
Amantadine Amantadine may benefit cognitive function in selected TBI patients during the early stages based on reports of its effects on agitation. 12 It has been used for "negative" symptoms of schizophrenia, such as withdrawal, abulia, and bradykinesia, and reported to benefit some TBI patients with anergia, abulia, or depression. 12 Amantadine, like methylphenidate, has also been used successfully in other disorders, especially in patients with multiple sclerosis who have fatigue-induced disabilities. Clinically, approximately 50% of the patients respond to an initial dose of 100 mg b.i.d. Patients report an increased ability to complete daily tasks. 13.14 These empirical observations are supported by double-blind, placebo-controlled studies.
3
CHOLINERGIC AGONISTS Considerable data exist to suggest an important role for the central cholinergic system in human memory and cognitive flmction. The reader is referred to the extensive reviews of the animal literature done by Deutsch 15,16 and Bartus.'7 A comparable review of the human literature has been done by Drachman and Sahakian, 18 Mohs et al.,19 and Davies. 2o Generally these studies have shown that fluctuations in central cholinergic activity cause significant changes in memory function. This research has basically taken two approaches. An investigator will use either a cholinergic antagonist such as scopolamine 21 and demonstrate a reduction in memory function, or a cholinergic agonist such as physostigmine 22 .23 and demonstrate an enhancement of memory function. Although these data support the concept that the cholinergic system plays an important role in cognitive function and particularly in memory, this does not mean that the cholinergic system alone is responsible for this function. A report by Levine et al. focuses on the issue of neurotransmitter interactions, specifically cholinergicdopaminergic interactions. 24 Physostigmine is a drug that temporarily inhibits acetylcholinesterase, thereby slowing the destruction of acetylcholine and thus increasing its concentration at the synapse. 19 The biologic halflife of physostigmine is short, based on early gastrointestinal motility studies in which physostigmine appeared to peak at 30 to 60 minutes. 25 More recent data have shown that plasma physostigmine concentration after a single dose of oral preparation peaks in 30 minutes and is undetectable by 2 hours. 26 However, the effect after multiple dosing may be many times longer. 27 In addition to half-life considerations, studies have shown that dosing is important. There appears to be a consistent observation that the therapeutic window for response to physostigmine is very narrow and that it is critical that an individual optimal dose be determined in order to demonstrate efficacy. 19.22.23.28.29 For example, 3 mg given intravenously to normal young subjects produced a decrement in memory, whereas doses of 1 to 2 mg produced a slight improvement in memory
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NEUROREHABILITATION / SPRING 1993
storage, and 0.5 mg infused over a 30-minute period significantly improved long-term memory.23 There are very few published reports on the use of physostigmine in memory disturbances after brain injury. This may be in part due to the lack of clinical improvement found in Alzheimer's disease. However, Woerkom et al. 30 treated 38 patients with head injuries and demonstrated that with certain patients, treatment with L-dopa and/or physostigmine facilitated recovery fi'om severe head iI~ury. Their principal dependent measures were the motor and verbal scores of the Glasgow Coma Scale and the Glasgow Outcome Scale. Goldberg et a1. 3 ! combined oral physostigmine with lecithin in a double-blind study of a single patient with post-traumatic amnesia. Improvement in storage and retrieval of words in verbal memory was found. They reported no change in conceptual reasoning nor any improvement of encoding capacity and suggested that these functions may be more specific to basal forebrain structures; hence, more dependent on catecholaminergic than cholinergic mechanisms. We conducted preliminary studies with oral physostigmine administered during the course of a memory training program. 32 The results indicated that delayed recall, storage, and retrieval of verbal information was enhanced by combining physostigmine with an established memory training procedure. The subjects were suffering from anoxic brain irUury after carbon monoxide poisoning. In this study, a double-blind, singlesu~ject A-B-A design was used with A representing the baseline phase, B constituting the memory training combined with drug phase, and A representing return to the baseline condition. Memory training used a self-instruction study skills model. Data were collected over a 16-week time span with neuropsychological measures and serum cholinesterase levels obtained during the study. Improvements were shown on standardized memory measures, such as the Long-Term Storage on the Selective Reminding Test and delayed recall on the Logical Memory and Visual Reproduction tests from the Wechsler Memory Scale, as well as nonstandardized memory tasks such as
remembering daily events or organizing time. Increased performance on tasks of daily living was observed, although no quantifiable data were obtained. The research design used, however, did not allow us to determine the relative effectiveness of either the drug or the memory training procedure alone. In another study, our team studied 39 men with brain injury and memory losses in order to examine the effects of oral physostigmine on such losses and determine response to a cholinergic antagonist, scopolamine. It is generally accepted that scopolamine in high enough doses produces temporary memory impairment. However, an interesting prior study has suggested that Alzheimer's patients, who are known to have deficient cholinergic activity, are more sensitive to the cognitive effects of scopolamine than age-matched controls. 33 Animal research also supported the notion that in the presence of pathology in the central cholinergic system there is increased sensitivity to the disruptive effects of scopolamine on cognition. 34 This led us to the hypothesis that response to scopolamine could be used to predict response to physostigmine in a population with TBI. In our second study, a double-blind design was used to study the effects of physostigmine, placebo, and scopolamine on memory function in a group of36 brain injured males. A maximum dose of 4.0 mg physostigmine P.O t.i.d. was reached over the course of a week and was generally well tolerated using care to exclude medical contraindication. 5 Scopolamine was administered as single or double skin patches. In addition to neuropsychological measures, clinical tests of balance were made. Improved memory performance during administration of oral physostigmine was found. Analysis of data including response to scopolamine, computerized tomography (CT) findings, and results of balance testing is in progress to help better differentiate responders from nonresponders. Pilot testing with single-photon emission computerized tomography (SPECT) with drug and placebo has proved difficult in such subjects. Reliability studies of SPECT in patients who are distractible or have decreased attention and concentration is needed.
Cognitive Psychopharmacology
CDP-Choline In a recent investigation, Levin 35 studied the efficacy of cytidine diphosphoryl choline (CDP-choline) in the management of 14 mild to moderate brain injured subjects experiencing post-concussional symptoms. Using a double-blind, placebocontrolled design, he found that CDP-choline produced a significantly greater reduction in postconcussional symptoms, as well as a greater improvement in recognition memory than placebo. This is a very interesting finding that warrants replication and further examination of the neurophysiological mechanism that may be responsible for the improvements.
NOOTROPICS Nootropics refers to a class of drugs that are known as cognitive activators. The term nootropics (noo = mind, tropic = toward) was coined by Giurgea 36 and should display a characteristic drug profile. They should (1) enhance acquisition of certain learned behaviors, (2) enhance resistance of learned behaviors to manipulators designed to disrupt them, (3) facilitate interhemispheric transfer of infiJrmation, and (4) protect the brain against certain physical or chemical insults. 37 - 39 Two additional criteria were delineated by Giurgea, but have not been examined and do not warrant discussion here. A number of compounds have recently been classified as nootropics. The classic examples of nootropics are the compounds containing the 2-pyrrolidinone moiety, which are piracetam (the prototype), aniracetam, oxiraxcetam, and pramiracetam.
Pramiracetam Pramiracetam was selected for clinical trials in humans on the basis of its ability to reverse electroconvulsive shock-induced amnesia in mice, to reverse hippocampal stimulation-induced learning deficits in rats, and to enhance short-term memory in rats and monkeys.40 These effects occurred at doses in the 0.5 to 10 mg/kg range. Thus pramiracetam is at least 100 times more potent than piracetam (the original compound in this class). In phase 1 studies, pramiracetam was well
5
tolerated by normal volunteer subjects in single doses up to 1600 mg and in multiple doses up to 1500 mg/d for 28 days. In phase 2 open-label studies, elderly patients with dementia received 300 mg/d pramiracetam for 6 to 9 weeks with no significant drug related adverse effects. Our research group has conducted two studies that have evaluated, under double-blind conditions, the safety and efficacy ofpramiracetam versus placebo in treating memory and other cognitive problems of male su~jects who have suffered brain i~juries sufficient to cause long-term, stable losses in memory and cognitive functioning. In the first study, a double-blind, placebocontrolled design was used in which each subject received over the course of 12 weeks, two 3-week blocks of pramiracetam sulfate 400 mg P.o. Li.d. or placebo. The order of drug or placebo was decided randomly and independently for each of the two pairs of experimental conditions. Following the completion of both pairs, all su~jects were continued on pramiracetam in an open-label fashion for a total of 18 months. No side effects were reported during the experimental trial or during the open-label period of 18 months. The results of the study indicated that subjects' performance on measures of memory, especially delayed recall, evidenced clinically significant improvements after the administration of pramiracetam sulfate as compared to placebo. This improvement was maintained during an 18-month open-label period on the medication as well as during a I-month follow-up period after the pramiracetam was discontinued. The results of our first study with pramiracetam were encouraging and led to our second study regarding the effects of the drug in combination with memory training. The specific hypothesis to be tested was that pramiracetam in combination with memory training would be more efficacious in improving memory function than either procedure alone in otherwise healthy young males who had suffered brain injury sufficient to cause long-term, stable losses in memory. The design of the study was a double-blind 2 X 2 factorial, training x drug design. The two training conditions were memory training or no memory training and the two drug conditions were
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NEUROREHABILITATION / SPRING 1993
pramiracetam or placebo. The duration of training or drug administration was 8 weeks. Follow-up assessments were conducted at 1, 3, and 6 months after treatment. Fifteen subjects completed the trial. There were no statistically significant differences in age, education, severity of injury, or imaging conditions among the groups. The results were as predicted. Following is the ranking (from best to worst) of the performance for Long-Term Storage on the Selective Reminding Test and for immediate recall on the functional reading task: (1) pramiracetam with training, (2) pramiracetam without training, (3) placebo with training, and (4) placebo without training.
OTHER COMPOUNDS Gangliosides Gangliosides are a family of acidic complex lipids composed of a hydrophobic and hydrophilic moiety.41 These are "naturally occurring substances" known to be part ofthe backbone of the membrane. Over the last 20 years they have evolved, however, from being viewed as an inert substance to being viewed as having functional involvement in synaptic transmission and possessing the ability to enhance sprouting and potentially limit ischemic injury. This evolution came about as we understood more about genetic diseases resulting in accumulation of gangliosides in the CNS and the realization that more subtle changes in ganglioside levels are positive and associated with maturation processes of the CNS. Animal studies indicate that the ganglioside, GM I, reduces cerebral edema and enhances recovery after lesions in the brain or spinal cord. 41 A recent report suggests that GM I enhances recovery in humans after spinal cord injury.42 Gangliosides are capable of inducing dendritic formation in vitro. 41 No reports on the effects of gangliosides after TBI in humans were found, but there have been three double-blind investigations on the effects of GM I, on patients who have had CVAs. In two of these studies, improvement was found with GM I as measured by clinical signs and neurophysiological parameters. 43 ,44 The third study45 did not find any difference in those receiving GM I
versus placebo. Although GM I is available in Europe, it still remains experimental in the United States.
Thyrotropin Releasing Hormone Animal studies by Horita et al. demonstrate improved learning in rats with septohippocampal cholinergic system lesions when treated with an analog of TRH.46 TRH may activate the central cholinergic pathway via a D-l dopamine link. This work suggests that stable analogs ofTRH alone or in combination with an anticholinesterase agent may represent possible pharmacological approaches to the treatment of memory deficits, such as those seen after TBI.
ASSESSMENT OF TREATMENT EFFICACY Assessment of treatment efficacy is perhaps the most critical aspect of clinical practice; yet, it is an area that is given the least amount of attention. It is given little attention because most clinicians either have not been trained in this area or have not been given guidelines on how to create this aspect of their clinical service delivery. In this section, we will attempt to do this. A number of different assessment techniques can be employed in determining whether a particular medication has been effective. The specific tools would depend on what targeted behaviors the medication is being used to address. There are a few principles to bear in mind. These include (1) if you are using a standardized assessment tool to measure a change (e.g., using a Wechsler Memory Scale to measure the effects of a cholinergic agonist, such as physostigmine, on memory), use of a functional measure as well for ecological validity (e.g., patient remembers to take his medication without prompting); (2) if you are administering a medication the effects of which are supposed to be specific to a particular behavior, it is important to assess that behavior as well as similar and different behaviors to determine the specificity of the medication's effects (e.g., if you are administering a drug whose effects are supposed to be on attention and concentration, such as methylphenidate,
Cognitive Psychopharmacology
you should also measure memory, reasoning and problem solving, and motor speed to determine how general or specific the medication's effects are; (3) in most medication trials, especially double-blind, placebo-controlled trials, measures have to be repeated several times, so it is important to use instruments, whenever possible, that are not sensitive to practice effects; (4) when behavioral analysis is used as the dependent measure of behavioral change, a detailed task analysis of the targeted behavior should be done as well as an analysis ofthe antecedents and consequences of the behavior, which requires a baseline data collection phase prior to medication changes; thus, time has to be allowed for this phase; and (5) many of these medications have a narrow window of efficacy, so it is important, whenever feasible, to obtain laboratory data to confirm that the medication is within the therapeutic range. In terms of specific measurements of treatment change, they can be classified into three categories: physiological, psychometric, and behavioral or functional. Each will be discusses briefly in turn.
Physiological A number of issues must be brought to bear in conducting clinical studies that are possibly interacting with the neurotransmitters of the brain. First, is the drug capable of crossing the bloodbrain barrier if given parenterally or orally? Although intravenous drugs have the advantage of directly entering the systemic circulation, even with such a route the concentration of drug will depend on cardiac output, regional blood flow, lipid solubility, protein binding,47 and, with regard to the CNS, the drug's ability to crOss the blood-brain barrier. In the case of oral preparations, one is also dealing with factors related to absorption (such as gastric emptying), the type of drug preparation (liquid, tablet, or capsule), and the pH of the stomach. 47 Since behavioral effect is the goal, in some cases, one may only need to monitor for signs of toxicity. This may be done by clinical observation often with measurements of vital signs and mental status checks. For example, in the case of cholinergic agents, serum cholinesterase levels may assist in monitoring toxicity. Such levels have been used
7
to monitor effects of insecticides on farm workers.48 The intra-individual variation, however, ranges from 8.6 to 23% when normal subjects are sampled in two succeeding samples. 48 Thus, the serum cholinesterase level cannot be used to give precise information regarding therapeutic level for cognition as has been suggested. 49 Genetic variants occur, thus, baseline serum cholinesterase levels are needed. In general, for any drug in which a serum level is readily obtainable, such a measurement is desirable and more practical than obtaining cerebrospinal fluid levels, which are a more accurate reflection of drug concentration at the site of action. Physiological responses, particularly pupillary changes, heart rate, blood pressure, and oral temperature may be useful in the study of anticholinergics or catecholinergics. In addition, scopolamine has the potential to affect balance in brain injured individuals, and clinical measures of balance have provided useful information regarding drug activity. 50 Balance measurement are often made in a standing position, which limits the usefulness to ambulatory subjects. The use of sitting balance measurements would increase the ability to study nonambulatory subjects. The previous discussion has been limited to single-drug administration. In the case of twodrug combinations, the mechanism of action of each drug might be similar (i.e., choline and physostigmine, or arecholine and tacrine); thus, whole body toxic effects would be predictable. What would be less clear is to what extent each drug produced the toxic effects or the therapeutic effects. Hence, determining the optimal ratio of the two-drug doses is problematic. Animal research has begun to tackle this issue in the area of memory-enhancing agents. 51 If true synergism is found with certain combinations, then total drug dosage could be reduced. Finally, advances are occurring in the development of technology to examine the neurophysiological changes that occur secondary to pharmacologic interventions. Positron emiSSIOn tomography (PET) and (SPECT) both hold promise as techniques to assist in understanding the physiological basis for the efficacy or possibly lack of efficacy of various "cognitive activator"
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NEUROREHABILITATION / SPRING 1993
compounds. At a recent meeting of the Insurance Rehabilitation Study Group investigators discussed some ofthe latest applications of this technology as well as identified some of the problems of reliability and validity of the technology at this stage of development. 52.53
Psychometric Psychometric measurements refer to standardized assessment tools. The use of standardized assessment instruments allows you to compare the efficacy of the same treatment across different patients. The use of these types of measures also allows for the comparison of findings across different laboratories and clinics. In terms of cognitive psychopharmacology, the drugs that have been reviewed primarily impact attention and concentration, memory, and learning. Following is a list of the measures that have been used by our research group as well as others. All of the measures listed below have at least moderate to good test-retest reliability and solid content, predictive, or construct validity. A. Attention and concentration
1. Trailmaking Test, parts A and B54-56 2. Seashore Rhythm Test 55 3. Digit Symbol Test from the Wechsler Adult Intelligence Scale-Revised 56 4. Symbol Digit Modalities Test 54 B. Memory and learning 1. Wechsler Memory Scale- Revised 56 2. Buschke Selective Reminding Test 57 3. The California Verbal Learning Test-CVLT56 4. Benton Visual Retention Test-BVRT54 5. Rivermead Behavioral Memory Test-RBMT58 . In addition to these standardized cognitive measures, it is often valuable to obtain ratings of either the patient's or the family's perception of his or her daily cognitive functioning. One example of such a rating scale is the Baddeley or Sunderland questionnaire, which rates memory problems in everyday life. 59 Another very welldesigned and psychometrically sound measure that could be used for this purpose is the Sickness
Impact Profile (SIP).60 The SIP is a behaviorbased measure of health status composed of 136 statements about health related dysfunction in 12 areas of activity. These areas include sleep and rest, ambulation, work, recreation and pastimes, alertness behavior, and home management. While it is not traditionally done, if one were solely interested in the impact on cognitive functioning, the Alertness Behavior scale from the SIP could be administered alone. The SIP is a psychometrically sound measure that has been shown to discriminate well between normals and individuals suf~ fering from a variety of medical conditions.
Behavioral or Functional Non-standardized functional assessment of treatment efficacy is perhaps the most challenging but also the most valuable source of information for examining the ecological validity of your interventions. There are three data keeping systems commonly used in the evaluation of treatment efficacy. What follows is a brief discussion of each, organized around a general description, examples, and an analysis of strengths and weaknesses specific to each. Narrative. What is probably the most prevalent data keeping method is a running narrative or written summary of significant events. Nursing notes are examples, as are chart entries. Entries are typically made at shift's end or on a more frequent interval depending on the behavior(s) under review. Strengths of this type of data keeping system are that a variety of significant events can be tracked and often occurrence of an event can be tied to time of day and surrounding circumstances or antecedents. The narrative can be structured such that each individual making an entry does so in a consistent manner with the subjective, objective, assessment and plan (SOAP) format serving as an example. During the assessment phase oftreatment, narrative data may serve to give direction to specific regimens as well as provide direction on which data keeping method should be used. This data collection method has a number of weaknesses the first of which is that the specific data or information of interest to the physician may not necessarily be captured in the entries. Quantification of rate or intensity of behavior is problematic, often requiring an in-depth and
Cognitive Psychopharmacology
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Note: Items underlined have current Intervention Plan in effect. Please note other remarkable behaviors on the back of this sheet.
Figure 1. An example of a frequency data sheet. time-intensive review of notes attempting to extract key information. Finally, unusual or high rate behaviors are more likely to be noted and there is potential for otherwise important behaviors that are less intrusive or occurring with low frequency not being noted in the narrative. Frequency. Frequency data keeping protocols consist of making a notation for each occurrence of a specific behavior. Frequency data are easy to record and summarize. A variety ofbehaviors can be included on a single sheet as can a number of different patients. Accommodation can be made for occasional narrative type notes allowing for documentation or new or unusual behaviors.
One weakness of this type of data keeping strategy is that for high rate behaviors it may be too intrusive or time consuming to accurately note each instance ofthe behavior. As in narrative types of data, data not recorded as the behavior occurs may be forgotten. Another potential difficulty with frequency data is encountered with behaviors that do not necessarily have clear beginnings and ends or where the length of different episodes vary. "On-task" behaviors are good examples of this weakness as is "agitation." Frequency data do not typically provide time or context specific information. An example is provided in Fig. 1.
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Interval. Interval data keeping systems are constructed such that periods of patient contact are divided into intervals of specific durations (see Fig. 2 for an example). Within each interval are listed behaviors that are being tracked. Should a behavior occur, it is circled or otherwise noted within the appropriate time interval. Additional instances of the same response require no additional notations. Absence of a specific response within an interval requires no notation. Data are typically summaJ1ized to report percentage of intervals with one or more response having occurred. The positive aspects of this type of data keeping strategy are many. The resolution of data with respect to time of occurrence is easily adjusted by increasing or decreasing the time encompassed within each interval. Behavior occurring at a high rate is readily accommodated as only the first response occurring within an interval is recorded and subsequent responses are not. Behaviors long in duration (i.e., extended episodes) are also easily accommodated as a maximum of one notation is made for each interval. The main weakness of an interval data keeping system is resolution of frequency of behavior within intervals. When using wide intervals a few or many behaviors may have occurred and the record is the same. For example, carbamazepine (Tegretol) used with a patient displaying relatively high rates of behavior dyscontrol may achieve significant decreases in behavior excess within each interval. However, as long as at least one episode occurs within an interval, no reduction in frequency will be noted (for those intervals). It is only when zero episodes occur that progress is noted. Repeated acquisition. During protracted medication regimens, it may be advantageous to the physician to monitor incremental or decremental drug effects on learning and memory on a chronic rather than an acute basis. Typical assessments oflearning and memory suffer from potential confound with repeated administration; that is, a test-retest confound may occur where increments in performance are the result of the practice of taking the test rather than true improvements secondary to the intervention. The
development of alternate forms of the test is one way of mitigating the effects of this potential confound. An alternative to standardized neuropsychological measures of learning and memory is the procedure of repeated acquisition of response (behavioral) chains. 61 ,62 As typically implemented, the procedure consists of two separate components: performance and acquisition. The patient's task is to correctly emit a prior learned response chain (e.g., entering a 20-digit sequence into a computer keyboard). In the acquisition component, the task is to learn a new response chain (e.g., a new 20-digit sequence). The performance component provides an assessment of the patient's memory and acquisition component: learning. Practice effect is not an issue and the procedure is one that can be employed numerous times during treatment, even within the same day. Thus, the physician is able to monitor drug effects over time while changes are being made in dosage levels. This procedure can also be used to monitor medications that have slowed information processing speed, reduced attention and concentration, and impaired memory as side effects. ; Perhaps the most appropriate assessment of drug effects on performance is one in which data are derived from functional tasks normally a part of the patient's daily routine or rehabilitation regimen. For example, our research group recently examined the effects of amantadine therapy on attention and concentration and memory with a severe TBI patient. Our principal measure of drug efficacy was performance on the repeated acquisition paradigm discussed previously. The reasons for choosing this technique were many, including the ability to administer the measure during the morning and the afternoon without concern for practice effects. In considering what would be potential collateral measures of drug efficacy, we considered the patient's status as an insulin-dependent diabetic. We then decided to use the patient's progress toward becoming independent in his self-monitoring of his blood glucose level as a functional measure of the drug'S efficacy. To do this, the blood glucose monitoring procedure was broken down into sequential steps. As the patient completed each step, the level of
Cognitive Psychopharmacology
AM SHIFT
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Client:
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1. Times indicate the start of each 15 min period; i.e., the 7:00 box contains data for the interval of 7:00 -7:15.
2. If one of the listed behaviors occurs during an interval, circle that behavior or draw a line through it. 3. If one or more of the listed behaviors does not occur, do nothing.
4. Use the bottom of the sheet for comments.
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Figure 2. An example of an interval data sheet.
Time 11 :00 11 :15 11 :30 11 :45 12:00 12:15 12:30 12:45 1:00 1 :15 1:30 1:45 2:00 2:15 2:30 2:45
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NEUROREHABILITATION / SPRING 1993
assistance necessary to complete that step was recorded. Levels of assistance included independent, vocal or gestural prompt, modeling the step, or physical assistance required to complete the step. The results indicated that the patient benefited from the trial of amantadine and we found comparable improvement on both the formal repeated acquisitions measure and the functional measure. While it is critical to use standardized measures in comparing the efficacy of one medication across different patients and different diagnoses, the true clinical utility of your rehabilitation treatments lies within the assessment of ecologically valid, functional outcomes.
OTHER SYSTEMS A necessary component of any data keeping procedure when data are not collected in the laboratory, is a routine whereby data are sent to a designated location f{)r summary and analysis. The frequency with which data are forwarded to the central location will vary depending on the acuity level of the patient with weekly intervals typically being the largest. The manner by which data will be routed should be determined prior to beginning collection with an accountable individual identified. We have used a variety of methods for retrieving data including facsimile (FAX), preaddressed stamped envelopes, voice mail and electronic mail (E-mail), as well as identitying the clinicians who can bring data back to a central location.
Voice Mail The advent of economical voice or phone mail networks opens up the possibility of a primary report person calling in data at a predetermined interval. We recently had the opportunity to use this system with an adult male residing at home with daughter and mother. The patient was reported to be exhibiting low rates of four specific behaviors comprised of threats, behavioral outbursts, elopement, and assault with the onset of these behaviors tied to elimination of Tegretol. Early use of an interval data keeping strategy was ineffective with a key variable being the patient
finding the actual data kept aversive. A strategy was implemented whereby the mother called in to a collection predetermined voice mail box at noon and prior to retiring to bed each day. Information for each call included date and time of call and occurrence or nonoccurrence of each of the four behaviors. Data were easily collected, could be reviewed daily, and the reporters's consistency of data collection was easily measured. The detail and frequency of report is easily modified to meet specific circumstances.
Electronic Systems There are a variety of electronic data recording systems in use today with these systems typically requiring a host computer for data retrieval and analysis once collected. For most systems, ease of data entry is maximized as is the type and amount of information that can be recorded. Internal clocks can pinpoint time of day for each recorded behavior and other pertinent information is readily included. There is possibility for ofl~site data retrieval via phone link. The initial capital investment necessary for such systems as well as ancillary support costs limit use in general practice. For a thorough description of a system ofthis type see Eiler et al. 63
SUMMARY Cognitive psychopharmacology holds tremendous promise for neurologic rehabilitation. Extensive research is needed to replicate some of the early findings with these various compounds and to examine more closely the neurophysiologic basis for their efficacy. Most importantly, however, the focus of this article has been to stress the importance of careful assessment in examining efficacy intervention. Additionally, we have attempted to stress the importance of combining good pharmacologic management with cognitive or behavioral treatments. The m~jor value that cognitive psychopharmacology will have in the future of neurorehabilitation will be in the drug's ability to enhance or facilitate training. Finally, many of the drugs discussed in this article are not
Cognitive Psychopharmacology
commercially available at this time. More clinical efficacy studies are needed before Food and Drug Administration approval can be obtained.
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15. DeutschjA. The cholinergic synapse and the site of memory. Science 1971; 174:788-794. 16. ~eutschjA. Physiology ofacetyicholine in learnmg and memory. In: Barbeau A, Growdon jH, Wurtman Rj, (eds.) Nutrition and the brain. New York: Raven, 1979; 5:342-350. 17. Bartus. RT. Physostigmine and recent memory: effects m young and aged nonhuman primates. Science 1979; 206: 1087-1089. 18. Drachman DA, Sahakian BJ. Effects of cholinergic agents on human learning and memory. In: ~~rbeau A, Growdon jH, Wurtman Rj, ed. Nutrztzon and the brain. New York: Raven, 1979; 5:351-366. 19. Mohs ~C, Davis KL, Datiey C. Cholinergic drug effects m memory and cognition in humans. In: Poon LW, ed. Aging in the 1980s. Washington DC: American Psychological Association, 1980; 181-190. 20. Davies P. A critical review of the role of cholinergic systems in human memory and cognition. Ann NY A cad Sciences 1985; 444:212-217. 21. Sit~ram N, .Weingartner H, Gillin Je. Human senal learnmg: enhancement with arecholine and choline and impairment with scopolamine. Science 1978; 201:274-276. 22. Davis KL, Mohs RC, Tinklenberg JR, Hollister ~E, Pfefferbaum A, Kopell BS. Physostigmine Improvement of long-term memory process in normal subjects. Science 1978; 201:272-274. 23. I?~vis. KL, Yamamura HI. Cholinergic underactlVlty m human memory disorders. Life Sci 1978; 23: 1729-1734. 24. Levine ED, McGurk SR, Rose JE, Butcher LL. C:holinergic-dopaminergic interactions in cognitive performance, Behavioral and neur. biol. 1990; 54:271-299. 25. ~utl~r PR, Ritvo M. Physostigmine as a peristaltIC stimulant.JAMA 1932; 99:1329-1332. 26. Sharpless ~S, ThaI LJ. Plasma physostigmine concentrations after oral administration. Lancet 1985; 1397-1398. 27. ThaI LJ, Fuld PA. Memory enhancement with oral physostigmine in Alzheimer's disease. N Engl J Med 1983; 308-720. 28. P
