Neuropsychobiology 2: 291-296 (1976)
ACTH4_10: Cognitive and Behavioral Effects in Hyperactive, Learning-Disabled Children Judith L. Rapoport, Patricia O. Quinn, Anne P. Copeland and Cheryl Burg Department of Pediatrics, Georgetown University School of Medicine, Washington, D.C.
Key Words. ACTH4_10 • Pituitary peptide • Hyperactivity • Learning disabilities Anxiety measures Abstract. A single dose of 30 mg Lm. ACTH4_10 or placebo was given to a sample of 20 hyperactive, learning-disabled children. No significant drug effects were obtained on mea sures of visual and auditory memory, new learning, impulsivity, attention, perceptual motor skills, anxiety, or behavior during testing. There was a slight increase in pulse rate for drug compared with the placebo group. These findings are in keeping with other recent reports of limited or insignificant cognitive effects in adults of a single dose of this peptide.
Introduction
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Numerous recent reports have described beneficial attentional and cognitive effects of pituitary peptide hormones and short-chain polypeptides such as melanocyte-stimulating hormone; analogous adrenocorticotrophic hormone frac tions such as ACTH4-10 have been reported to improve attention and visual memory while decreasing anxiety (Miller et al., 1974) and to counteract ‘fatigue’ effects during a serial reaction time (Gaillard and Samders, 1975, Miller et al, 1974). The functions of attention, arousal, visual, and auditory memory reportedly improved by the peptide are those which are frequently noted to be defective in the groups of children labeled hyperactive, minimal brain dysfunctioned, or learning disabled (Conners, 1967). As stimulant drugs have proven increasingly disappointing in counteracting the academic difficulties of such children (Riddle and Rapoport, 1976; Gittelman-Klein and Klein, 1976), it was considered of interest to investigate the effects of ACTH4. 10 in a population o f children with known learning and attentional difficulties.
Rapoport/Quinn/Copeland/Burg
292
Methods Subjects Subjects were selected to include children with both symptoms of hyperactivity and learning difficulty. Criteria for inclusion in the study were: age between 6 and 13 years, hyperactive and distractible behavior of at least 2 years duration, a mean item score of 1.5 or more on both the hyperactivity factors of the Teacher Rating Scale (Conners, 1969) and of the Parent Symptom Questionnaire (Conners, 1970). On cognitive testing, a child had to have a sum of at least 32 scaled score points on four selected W1SC subtests of the WISC-R (information, vocabulary, picture arrangement and block design) and at least a 1-year delay for age and present grade placement in either reading or arithmetic, as measured by the Wide Range Achievement Test (Jastek and Jastek. 1965). Exclusion criteria were: knowrn neuro logic disease, major psychiatric disorder, or current drug therapy. The final sample of 20 children consisted of 18 males and 2 females, ages 7-13 (mean 9.40 ± 1.84). Their mean scaled score on the four WISC subtests was 41.57 (± 6.28). Two children had specific difficulty with arithmetic; the rest had depressed WRAT scores on both reading and math.
Test Battery The Coding Subtest (WISC-R) was administered according to standardized instructions. Raw scores were recorded. Digit Span (WISC-R). Trial 1 or II digits were given at each session in counterbalanced order across subjects. Scores were the number of digits in longest series repeated correctly. Matching Familiar Figure Test (MFF) (Kagan, 1965). A matching to sample task designed as a measure of impulsivity-reflectivity. Either odd or even numbered cards were given at each session in randomized order of presentation. Error scores and latency to first response were recorded. Continuous Performance Test (CPT) (Rosvold and Mirsky, 1965). 14 different letters were presented randomly on a screen for 0.3 sec (fast) or 0.8 sec (slow) with 0.7 sec be tween letter presentation. The instructions were to press a button when an X appeared following the letter A (AX task). Both slow and fast speeds were used for a total of 10 min presentation at each session. Scores of omission and commission were recorded. Benton Visual Retention Test (BVRT). Forms C or D of the BVRT were used with 10 sec viewing time and immediate reproduction from memory. Draw-a-Person (Goodenough, 1926). Subjects were instructed to draw a same-sexed figure. Drawings were scored according to the 1963 Harris standards. Paired Associate Learning Task. This was based on the test described by Helper et al. (1963). It-was administered on the second test session only. Subjects were shown photo graphs of eight different boys, one at a time, for 5 sec each. Each photograph was accom-
Downloaded by: Nagoya University 133.6.82.173 - 1/14/2019 10:05:48 PM
Procedure After the initial screening visit, children participated in two 1-hour experimental ses sions exactly 1 week apart and at the same time of day. After each testing session blood was taken for assay for plasma cortisol. 30 min before the second experimental session, patients were given an injection of either 30 mg ACTH4_10 or placebo in 1.00 cm3 of diluent intra muscularly according to randomized double-blind schedule. Blood pressure and pulse were taken once following the first session and three times during the second session: before, 30 and 90 min after the injection of ACTH4_l0 or placebo. Inquiry as to specific side effects and any subjective effects w'ere made; children were asked whether they felt their perfor mance had improved on the second test session.
The Effect of ACTH4_I0 in Hyperactive Children
293
Table /. Pre- and 90 min postinjection pulse and blood pressure for placebo and ACTH4_10 groups Placebo
a c t h 4.-to
pre mean
post
P
mean
SD
mean
SD
77.20
13.47
67.60
11.06 < 0.05
Blood pressure Systolic 100.00 Diastolic 66.40
8.16 5.87
97.60 66.80
Pulse
8.42 3.49
pre
0.10 NS
post SD
mean
P SD
80.00
11.31
76.80
15.06
NS
102.40 73.80
12.17 11.40
104.20 72.00
18.04 10.62
NS NS
panied by a single-syllable common male name; each name began with a different letter. Children were instructed to remember each boy’s name. After the initial presentation, pictures were presented in a new random order without the accompanying name. After the subject’s response, names were again presented with the pictures visually and auditorially. When a picture had been correctly named twice, it was removed. Score was the number of trials required to name all the pictures correctly. State Trait Anxiety Inventory (STAJ) XSpielberger et al., 1975). The children’s form of the STA1 (‘How 1 Feel’ questionnaire) was verbally administered at the end of each test session; both State and Trait scores were obtained. Behavior rating during psychological testing. The psychologist used the 19-item scale of behavior during testing (Leeds, 1973). Reported here are the ratings on a 5-point bipolar scale for self-confidence (item No. 12), attention (item No. 19) and activity (items No. 21 and 22 combined).
There were no side effects reported by the children for either placebo or drug groups. Four children from each group felt their performance had improved on the second test session. Five children from each group reported that their ‘mood’ was better following injection. Mean pulse and blood pressure preinjec tion and 90 min postinjection are shown in table I. As can be seen, there was a significant decrease in pulse rate for the placebo group 90 min after the injection (t = 2.97; p < 0.05) but not for the drug group (t = 0.76). Similarly there was a trend for the systolic blood pressure to decrease for the placebo group (p = 0.10) but not for the group receiving ACTH4-10. The Children’s Anxiety Inventory showed moderate test-retest reliability between the sessions for the group as a whole for both trait and state scores (Pearson r = 0.42 and 0.45, respectively). These anxiety inventory scores did not correlate with blood pressure or pulse at baseline or experimental sessions, how ever, nor did they correlate with the anxiety factor on the parent symptom
Downloaded by: Nagoya University 133.6.82.173 - 1/14/2019 10:05:48 PM
Results
Rapoport/Quinn/Copeland/Burg
294
Table II. Baseline and postinjection test scores for placebo and ACTH4_10 groups ACTH • - I 0
Placebo pre
post
mean SD
mean SD
Coding raw score 36.00 10.21
P*
41.60 14.46
"
10)
pre
post
mean SD
mean SD
NS
31.33
9.17
P‘
35.33 14.41
NS
Digit span forward
4.60
0.96
4.10
0.73
NS
4.40
1.07
4.40
1.17
NS
Digit span backward
3.00
0.66
3.20
0.91
NS
2.90
0.87
2.90
0.73
NS
4.20
3.48
4.80
4.98
NS
17.40 13.79
NS
9.70
9.78
14.00 20.28
NS
5.71
NS
2.37 28.86
NS NS
7.50 37.45
NS NS
CPT Omission errors Commission errors MFF Errors Time BVRT Correct, n Errors, n
5.7 65.4
2.45 31.16
4.9 64.1
13.40 11.63 5.11
5.4 58.0
4.59
3.59 28.81
3.11
7.5 61.5
5.10 7.30
2.13 4.26
4.70 9.00
3.16 4.77
NS NS
4.20 8.80
2.39 4.75
1 1 .0 0
2.43 5.39
NS NS
STA1, children’s form 37.7 Trait State -8 .5 0
6.49 3.30
35.4 -10.60
6.09 6.65
NS NS
39.1 -8.50
7.85 4.92
40.00 -7 .3 0
8.81 4.00
NS NS
ACTH4_10: Cognitive and Behavioral Effects in Hyperactive, Learning-Disabled Children Judith L. Rapoport, Patricia O. Quinn, Anne P. Copeland and Cheryl Burg Department of Pediatrics, Georgetown University School of Medicine, Washington, D.C.
Key Words. ACTH4_10 • Pituitary peptide • Hyperactivity • Learning disabilities Anxiety measures Abstract. A single dose of 30 mg Lm. ACTH4_10 or placebo was given to a sample of 20 hyperactive, learning-disabled children. No significant drug effects were obtained on mea sures of visual and auditory memory, new learning, impulsivity, attention, perceptual motor skills, anxiety, or behavior during testing. There was a slight increase in pulse rate for drug compared with the placebo group. These findings are in keeping with other recent reports of limited or insignificant cognitive effects in adults of a single dose of this peptide.
Introduction
Downloaded by: Nagoya University 133.6.82.173 - 1/14/2019 10:05:48 PM
Numerous recent reports have described beneficial attentional and cognitive effects of pituitary peptide hormones and short-chain polypeptides such as melanocyte-stimulating hormone; analogous adrenocorticotrophic hormone frac tions such as ACTH4-10 have been reported to improve attention and visual memory while decreasing anxiety (Miller et al., 1974) and to counteract ‘fatigue’ effects during a serial reaction time (Gaillard and Samders, 1975, Miller et al, 1974). The functions of attention, arousal, visual, and auditory memory reportedly improved by the peptide are those which are frequently noted to be defective in the groups of children labeled hyperactive, minimal brain dysfunctioned, or learning disabled (Conners, 1967). As stimulant drugs have proven increasingly disappointing in counteracting the academic difficulties of such children (Riddle and Rapoport, 1976; Gittelman-Klein and Klein, 1976), it was considered of interest to investigate the effects of ACTH4. 10 in a population o f children with known learning and attentional difficulties.
Rapoport/Quinn/Copeland/Burg
292
Methods Subjects Subjects were selected to include children with both symptoms of hyperactivity and learning difficulty. Criteria for inclusion in the study were: age between 6 and 13 years, hyperactive and distractible behavior of at least 2 years duration, a mean item score of 1.5 or more on both the hyperactivity factors of the Teacher Rating Scale (Conners, 1969) and of the Parent Symptom Questionnaire (Conners, 1970). On cognitive testing, a child had to have a sum of at least 32 scaled score points on four selected W1SC subtests of the WISC-R (information, vocabulary, picture arrangement and block design) and at least a 1-year delay for age and present grade placement in either reading or arithmetic, as measured by the Wide Range Achievement Test (Jastek and Jastek. 1965). Exclusion criteria were: knowrn neuro logic disease, major psychiatric disorder, or current drug therapy. The final sample of 20 children consisted of 18 males and 2 females, ages 7-13 (mean 9.40 ± 1.84). Their mean scaled score on the four WISC subtests was 41.57 (± 6.28). Two children had specific difficulty with arithmetic; the rest had depressed WRAT scores on both reading and math.
Test Battery The Coding Subtest (WISC-R) was administered according to standardized instructions. Raw scores were recorded. Digit Span (WISC-R). Trial 1 or II digits were given at each session in counterbalanced order across subjects. Scores were the number of digits in longest series repeated correctly. Matching Familiar Figure Test (MFF) (Kagan, 1965). A matching to sample task designed as a measure of impulsivity-reflectivity. Either odd or even numbered cards were given at each session in randomized order of presentation. Error scores and latency to first response were recorded. Continuous Performance Test (CPT) (Rosvold and Mirsky, 1965). 14 different letters were presented randomly on a screen for 0.3 sec (fast) or 0.8 sec (slow) with 0.7 sec be tween letter presentation. The instructions were to press a button when an X appeared following the letter A (AX task). Both slow and fast speeds were used for a total of 10 min presentation at each session. Scores of omission and commission were recorded. Benton Visual Retention Test (BVRT). Forms C or D of the BVRT were used with 10 sec viewing time and immediate reproduction from memory. Draw-a-Person (Goodenough, 1926). Subjects were instructed to draw a same-sexed figure. Drawings were scored according to the 1963 Harris standards. Paired Associate Learning Task. This was based on the test described by Helper et al. (1963). It-was administered on the second test session only. Subjects were shown photo graphs of eight different boys, one at a time, for 5 sec each. Each photograph was accom-
Downloaded by: Nagoya University 133.6.82.173 - 1/14/2019 10:05:48 PM
Procedure After the initial screening visit, children participated in two 1-hour experimental ses sions exactly 1 week apart and at the same time of day. After each testing session blood was taken for assay for plasma cortisol. 30 min before the second experimental session, patients were given an injection of either 30 mg ACTH4_10 or placebo in 1.00 cm3 of diluent intra muscularly according to randomized double-blind schedule. Blood pressure and pulse were taken once following the first session and three times during the second session: before, 30 and 90 min after the injection of ACTH4_l0 or placebo. Inquiry as to specific side effects and any subjective effects w'ere made; children were asked whether they felt their perfor mance had improved on the second test session.
The Effect of ACTH4_I0 in Hyperactive Children
293
Table /. Pre- and 90 min postinjection pulse and blood pressure for placebo and ACTH4_10 groups Placebo
a c t h 4.-to
pre mean
post
P
mean
SD
mean
SD
77.20
13.47
67.60
11.06 < 0.05
Blood pressure Systolic 100.00 Diastolic 66.40
8.16 5.87
97.60 66.80
Pulse
8.42 3.49
pre
0.10 NS
post SD
mean
P SD
80.00
11.31
76.80
15.06
NS
102.40 73.80
12.17 11.40
104.20 72.00
18.04 10.62
NS NS
panied by a single-syllable common male name; each name began with a different letter. Children were instructed to remember each boy’s name. After the initial presentation, pictures were presented in a new random order without the accompanying name. After the subject’s response, names were again presented with the pictures visually and auditorially. When a picture had been correctly named twice, it was removed. Score was the number of trials required to name all the pictures correctly. State Trait Anxiety Inventory (STAJ) XSpielberger et al., 1975). The children’s form of the STA1 (‘How 1 Feel’ questionnaire) was verbally administered at the end of each test session; both State and Trait scores were obtained. Behavior rating during psychological testing. The psychologist used the 19-item scale of behavior during testing (Leeds, 1973). Reported here are the ratings on a 5-point bipolar scale for self-confidence (item No. 12), attention (item No. 19) and activity (items No. 21 and 22 combined).
There were no side effects reported by the children for either placebo or drug groups. Four children from each group felt their performance had improved on the second test session. Five children from each group reported that their ‘mood’ was better following injection. Mean pulse and blood pressure preinjec tion and 90 min postinjection are shown in table I. As can be seen, there was a significant decrease in pulse rate for the placebo group 90 min after the injection (t = 2.97; p < 0.05) but not for the drug group (t = 0.76). Similarly there was a trend for the systolic blood pressure to decrease for the placebo group (p = 0.10) but not for the group receiving ACTH4-10. The Children’s Anxiety Inventory showed moderate test-retest reliability between the sessions for the group as a whole for both trait and state scores (Pearson r = 0.42 and 0.45, respectively). These anxiety inventory scores did not correlate with blood pressure or pulse at baseline or experimental sessions, how ever, nor did they correlate with the anxiety factor on the parent symptom
Downloaded by: Nagoya University 133.6.82.173 - 1/14/2019 10:05:48 PM
Results
Rapoport/Quinn/Copeland/Burg
294
Table II. Baseline and postinjection test scores for placebo and ACTH4_10 groups ACTH • - I 0
Placebo pre
post
mean SD
mean SD
Coding raw score 36.00 10.21
P*
41.60 14.46
"
10)
pre
post
mean SD
mean SD
NS
31.33
9.17
P‘
35.33 14.41
NS
Digit span forward
4.60
0.96
4.10
0.73
NS
4.40
1.07
4.40
1.17
NS
Digit span backward
3.00
0.66
3.20
0.91
NS
2.90
0.87
2.90
0.73
NS
4.20
3.48
4.80
4.98
NS
17.40 13.79
NS
9.70
9.78
14.00 20.28
NS
5.71
NS
2.37 28.86
NS NS
7.50 37.45
NS NS
CPT Omission errors Commission errors MFF Errors Time BVRT Correct, n Errors, n
5.7 65.4
2.45 31.16
4.9 64.1
13.40 11.63 5.11
5.4 58.0
4.59
3.59 28.81
3.11
7.5 61.5
5.10 7.30
2.13 4.26
4.70 9.00
3.16 4.77
NS NS
4.20 8.80
2.39 4.75
1 1 .0 0
2.43 5.39
NS NS
STA1, children’s form 37.7 Trait State -8 .5 0
6.49 3.30
35.4 -10.60
6.09 6.65
NS NS
39.1 -8.50
7.85 4.92
40.00 -7 .3 0
8.81 4.00
NS NS
