© 1990 S. Karger AG, Basel 0028-3835/90/0522-0169 S 2.75/0
Neuroendocrinology 1990; 52: 169-174
Time Course of ACTH 4-10 Effects on Human Attention Jan Borna. Ulrike Unseld\ Reinhard Pietrowskya. Ulrich Bickelh. Karlheinz Voigtc, Horst L Fehrn■' ‘■Angewandte Physiologie, Innere Medizin I, Universität Ulm, FRG; o Institut für Klinische Pharmakologie, Freie Universität Berlin, Berlin; cInstitut für Normale und Pathologische Physiologie, Universität Marburg, FRG
KeyWords. ACTH • ACTH 4-10 • Attention • Event-related potentials • Time course
The adrenocorticotropic hormone (ACTH) is one of several hypophyseal hormones released in response to stressful stimuli into the blood stream. A number of studies have provided evi dence that this hormone feeds back to the brain to modify be havior [1-4], Structure activity studies showed that the 4-10 fragment of ACTH is essential for the behavioral potency of ACTH [5, 6]. ACTH 4-10 lacks any corticotropic action. In a series of studies in humans, we have shown that ACTH as well as its 4-10 fragment affect auditory event-related poten tial (ERP) indicators of attention [7-10]. In these studies effects of ACTH on basically two different ERP components were in vestigated; these were the Nd ('negative displacement', some times termed processing negativity), which is a sign of 'con trolled' or selective attention, and the mismatch negativity (MMN) reflecting the 'automatic' processing of stimulus de viance [11-17]. The Nd, in these studies, appeared to be most sensitive to the peptides' central nervous actions. Its amplitude
Received: November 6, 1989 Accepted after revision: January 17, 1990
linearly decreased with logarithmically increasing doses (0.1, 1, 10 mg) of ACTH 4-10, indicating that the peptide impairs se lective attention [7], The MMN, on the other hand, was not af fected by ACTH and related peptides. Presently, little is known of the time course of central ner vous effects of ACTH or ACTH 4-10 in humans. In rats, effects of fragments of ACTH on retention of avoidance behavior ap peared to be of a short-term nature which - depending on the dose and route of administration - emerges within I h following treatment and lasts for a few hours [3, 18]. Similarly, Pfaff et al. [19] reported increases in firing of hippocampal neurons fol lowing systemic administration of ACTH which began within 3-10 min and lasted 25-50 min after injection. In humans, little attempts have been made to describe the time course of central nervous influences of ACTH-related peptides. This may have been due to a lack of assays sensitively and reliably indicating central nervous changes of ACTH-related peptides in humans. Endroczi et al. [20] reported on a suppression of stimulusevoked EEG synchronization to previously habituated stimuli following administration of ACTH 1—10 (I or 2 mg, i.v.) or ACTH 1-24 (0.5 mg, i.v.) which developed about 1 h after the injection and lasted for several days; i.e., these effects in hu
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/24/2019 12:15:14 PM
Abstract. Previous studies have demonstrated that the adrenocorticotropic hormone (ACTH) and its 4—10 fragment are potent modulators of attention in humans. In these studies the Nd component (‘negative displacement’) of the stimulus-evoked brain potential (event-related potential, ERP), which is a neurophysiological indicator of selective attention, proved most sensitive to effects of these peptides. The Nd decreased in amplitude linearly with logarithmically increasing doses of ACTH 4-10 applied. Here we report results complementing these previous findings by establishing a time course of the effects of ACTH 4-10 on human attention. In a double-blind cross-over study, attention performance on a dichotic listening task was tested in 18 healthy volunteers, after having received intravenously either placebo or 1 mg ACTH 4-10. Tests took place 0, 30. 90. 180, 330. 600 min, 24. 48 and 72 h after drug intake and took about 15 min. Each subject was tested on 4 of these occasions, selected according to a random schedule. During task performance ERPs to the different task stimuli were recorded. ERPs were used to determine the Nd (an indicator of controlled processing of stimuli which the subjects selectively attended to) and the mismatch negativity (MMN) reflecting automatic processing of stimulus deviance. ACTH 4-10 diminished the Nd significantly at 30 min after treatment ad ministration. On none of the other occasions significant changes in Nd occurred. MMN was not affected by the peptide. The results indicate a short-term action of ACTH 4-10 on selective attention, which takes about 30 min to develop and does not last longer than 90 min after treatment.
mans appeared to last much longer than those observed in ani mal studies. However, no placebo control was run in these ex periments. The present study aimed at describing the time course of central nervous influences of a single intravenous administra tion of ACTH 4-10 in humans. For this purpose, the Nd com ponent of the ERP was used as dependent variable which in an extensive series of foregoing studies (mentioned above) has been proved to be a reliable and sensitive indicator of brain actions of ACTH in humans.
Subjects and Methods Subjects. Design, and Procedure Eighteen male student volunteers (age between 19 and 30 years) participated in the experiments. The study was approved by the Com mittee on Research Involving Human Subjects of the University o f Ulm, and each subject gave written consent. The subjects were of normal hearing and free of medication at the time of the investigation. They were non smokers and had to abstain from alcoholic beverages for at least 12 h prior to the experimental sessions. In the morning on the days of the experiments subjects were not allowed to drink more than I cup of coffee or (black) tea. Each subject was tested following placebo and following admini stration of ACTH 4-10 (1 mg, diluted in 20 ml saline solution). Placebo and ACTH 4—10 conditions for a given subject were separated by an interval of at least 10 days. Treatments were given intravenously as short infusions (over 10 min) which started at 12.00 h. The order of treat ments was randomized (half of the subjects starting with placebo, the other half with infusion of ACTH 4-10) and the experiments were dou ble-blind. Attention tests were conducted at 0, 30, 90, 180, 330, 600 min, 24, 48, and 72 h after the infusion had been finished. The task took about 15 min. To avoid a strong decline o f motivation with repeated testing, on each of these occasions only 8 subjects were tested. Thus, each subject was tested on 4 of the 9 possible occasions, selected according to a random schedule. However, none of the subjects was tested on two consecutive occasions. Attention performance was tested in a dichotic listening paradigm [ 12] (fig. I). The task consisted o f four sequences of about 400 tone pips (60 dB SPL, 60 ms duration), delivered through earphones to the subject’s right and left ear. Interstimulus intervals between any two pips ranged from 250 to 1,250 ms with an average of 550 ms. Each sequence contained 4 different types of tone pips: one ear received a series made up of standard 800-Hz tone pips and randomly inserted rare target tones of 840 Hz; the other ear received a similar series made up of standard tones of 1,200 Hz and rare target tones of 1,260 Hz. The pro bability of a target was p = 0 .1 for each ear. The subject was instructed to attend to all stimuli in one ear and to covertly count all targets occurring in this ear. Stimuli in the opposite ear were to be ignored. The ear to be attended was counterbalanced across and within subjects. Also, the headphones were reversed after two of the sequences, and half of the subjects began the experiment with reversed earphones, in order to con trol for effects of the different frequencies o f the pips in both ears. Be tween any two sequences a short break (about 10 s) was used to check for the subject’s count. Subjects were instructed to fixate their eyes on a centrally located dot during performance of the attention task. Heart
B om / Unseld/ Pietrowsky/ Bickel /V oigt/ Fehm
rate, systolic and diastolic blood pressure were measured immediately before performance of the attention task. Plasma cortisol w;is deter mined from blood samples collected after task performance. The plasma was immediately separated and stored at -2 0 °C until radioimmunological determination o f conisol. Recordings and Apparatus During performance of the attention task, recordings were obtained of EEGs (5 s time constant, 30 Hz/3 dB high-frequency roll off) from midline electrode locations (Fz, Cz, Pz) referenced to linked electrodes attached at the earlobes. The vertical EOG was monitored for artifact recognition. For all recordings nonpolarizable silver-silver chloride electrodes of 16 mm diameter (Beckman Instruments, USA) were used. EEG and EOG signals were amplified by a Beckman type R611 dynograph (with modified input couplers), digitized (sampling rate 385 Hz) and stored on magnetic tape (pulse code modulated) for off-line averag ing of ERPs. Heart rate and blood pressure were measured automatically by a BC 40 (Bosch und Sohn, FRG) simulating the Riva-Rocci procedure. Plasma cortisol was determined by radioimmunoassay (Biermann, FRG) with a sensitivity o f 4.7 nmol/l. Intra- and interassay coefficients of variation were below 3 and 10%, respectively, between 27.6 and 1.380 nmol/l. All samples from an individual were assessed in dupli cate in the same assay. Data Reduction and Analysis Individual ERPs were averaged separately according to the experi mental conditions: treatment (placebo vs. 1 mg ACTH 4-10), time since treatment (0, 30, 90, 180, 330, 600 min, 24, 48, and 72 h), sequence (1-4), tone pip (attended vs. unattended standard, and attended vs. unattended target) and topography (Fz, Cz, Pz). The averaging epoch covered a 40-ms baseline and a 600 ms poststimulus onset interval. Epochs were excluded from analysis by a computer program if they contained eyeblinks, gross eye movements or other potential artifacts. Data from 2 individual attention tests (48 and 72 h since treatment) had to be discarded, due to a technical failure and because 1 subject had caught a cold. The Nd and the MMN were extracted from ERP responses. The Nd indexing selective attention was determined as mean difference ampli tude between ERPs to standard tones when attended and when unat tended, in the latency interval 0-460 ms poststimulus. The long latency interval was used to provide continuity with previous studies [e.g., 10, 211. The MMN indexing the automatic processing of stimulus deviance [e.g., 13] was determined by subtracting the mean amplitude within 140 and 360 ms poststimulus o f ERPs to unattended standard tones from the mean amplitude (within the same latency range) of ERPs to the unattended target tones. The deviation of the target counts from the correct value was taken as a crude behavioral measure of attention. Statistical evaluation of ERP measures, counting accuracy, plasma cortisol and cardiovascular parameters based on analyses of variance (ANOVA). They contained the repeated measure factors: treatment (placebo vs. ACTH 4-10), time since treatment, and sequence (1-4). ANOVAs on ERP measures, in addition, contained a factor topography (Fz, Cz, Pz). Significant (p < 0.05) effects for the time factor were post hoc evaluated by Wilcoxon’s t tests performed separately on the data for each testing occasion since treatment. Effects of the treatments on the Nd and MMN were also evaluated separately for the recording site, at which they displayed their maximum amplitudes.
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/24/2019 12:15:14 PM
170
ACTH and Human Allention
Cz
Pz
Fig. I. The middle panel Illustrates the dichotic listening paradigm: subjects were presented with series of tone pips in both ears at once. In each ear rate target tone pips (indicated by longer strokes) were inter spersed among frequent standard pips. Target pips in one ear were to be counted, while all pips in the opposite ear were to be ignored. Upper panels: ERPs to standard pips when attended (the respective upper lines) and when unattended (lower lines) recorded at Fz, Cz, and Pz electrode locations during the testing 30 min following placebo treat ment. (Vertex negative is upward.) Bottom panels: Nd components (at Fz, Cz, and Pz) constructed by subtracting ERP responses to unattend ed standard tones from ERPs to attended standard to n es.----- = Pla cebo;------ = A C T H 4-10(I mgi.v.). Recordings were obtained 30 min following administration of the treatments.
Results
Event-Related Potentials
For both treatment conditions and for all attention tests ERPs to attended standard stimuli were shifted towards in creased negativity, as compared to the ERP responses to the same stimuli when unattended. The mean amplitude difference within 0-460 ms poststimulus (Nd) was larger at frontal and central than at parietal electrode sites (mean ± SEM, during
Fig. 2. Amplitudes of Nd (a) and MMN(b) at Fz obtained at differ ent times following treatment administration, which took place between 12.00 and 12.10 h . ----- = Placebo;------ = ACTH 4-10 (1 mg i.v.). **p < 0.05, for the differences between the effects of the treatments.
placebo sessions - Fz: 1.22 ± 0.15 ¡TV, Cz: 1.00 ± 0.16 pV, Pz: 0.54 ± 0 .1 3 pV; main effect for topography: p < 0.001, fig. 1). MMN, which is the mean difference amplitude between ERPs to unattended target tones and unattended standard tones 140-360 ms poststimulus also displayed maximum am plitudes at anterior recording sites (mean ± SEM during pla cebo sessions - Fz: 1.76 ± 0.29 pV, Cz: 1.44 ± 0.29 pV, Pz: 0.79 ± 0.24 uV; main effect topography: p < 0.001). MMN, in general, was more variable than Nd amplitude.
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/24/2019 12:15:14 PM
Fz
171
Bom/Unseld/Pietrowsky/Bickel/Voigt/Fehm
172
a C o r tis o l l o g / i l l
b s y s BP (mmHg)
0
0.5
15
3.0
55
10
24
48
72 (10
0
05
15
30
55
tO
24
48
72
(h |
Fig. 3. Plasma cortisol (a) heart rate (HR, c), systolic (b). and diastolic blood pressure (d) measured at different times following treatment administration, which took place between 12.00 and 12.10 h . ----- = Placebo;-------= ACTH 4-10 (1 mg i.v). There was a tendency towards an increased heart rate following ACTH 4-10, 3 h after treatment administration (Wicoxon’s t test; p < 0.10).
Plasma Cortisol, Cardiovascular Parameters and Counting Performance
Cortisol concentrations obtained after performance on the attention task are shown in figure 3. Cortisol concentrations strongly depended on the time of day, with lowest values at 22.00 h (corresponding to 600 min since treatment). ACTH 4-10 did not influence adrenal cortical secretory activity. There were also no systematic effects of ACTH 4-10 on heart rate, systolic and diastolic blood pressure (fig. 3). Average deviations of the counts from the correct value (across all testings since treatment administration) were for the placebo condition 1.58 ± 0.31 and for the ACTH 4-10 condi tion 1.52 ± 0.26. Differences between the effects of the treat ments did not reach statistical significance for any of the testings performed after treatment administration. This may have been due to the fact that counting performance is only a rather crude
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/24/2019 12:15:14 PM
Figure 2 shows mean Nd amplitudes (at Fz) obtained at dif ferent times following administration of placebo or ACTH 4-10. Compared to the placebo treatment, ACTH 4-10 signifi cantly decreased frontal Nd amplitude during the testing 30 min following treatment administration. This effect was sta tistically confirmed by ANOVA [treatment • time since treat ment • topography, F( 16,120) = 2.17, p< 0.0!5, Greenhouse Geisser Probability] and post hoc t tests for the difference be tween the effects of the treatments for this testing occasion (at Fz: two-sided Wilcoxon’s t test: p
Neuroendocrinology 1990; 52: 169-174
Time Course of ACTH 4-10 Effects on Human Attention Jan Borna. Ulrike Unseld\ Reinhard Pietrowskya. Ulrich Bickelh. Karlheinz Voigtc, Horst L Fehrn■' ‘■Angewandte Physiologie, Innere Medizin I, Universität Ulm, FRG; o Institut für Klinische Pharmakologie, Freie Universität Berlin, Berlin; cInstitut für Normale und Pathologische Physiologie, Universität Marburg, FRG
KeyWords. ACTH • ACTH 4-10 • Attention • Event-related potentials • Time course
The adrenocorticotropic hormone (ACTH) is one of several hypophyseal hormones released in response to stressful stimuli into the blood stream. A number of studies have provided evi dence that this hormone feeds back to the brain to modify be havior [1-4], Structure activity studies showed that the 4-10 fragment of ACTH is essential for the behavioral potency of ACTH [5, 6]. ACTH 4-10 lacks any corticotropic action. In a series of studies in humans, we have shown that ACTH as well as its 4-10 fragment affect auditory event-related poten tial (ERP) indicators of attention [7-10]. In these studies effects of ACTH on basically two different ERP components were in vestigated; these were the Nd ('negative displacement', some times termed processing negativity), which is a sign of 'con trolled' or selective attention, and the mismatch negativity (MMN) reflecting the 'automatic' processing of stimulus de viance [11-17]. The Nd, in these studies, appeared to be most sensitive to the peptides' central nervous actions. Its amplitude
Received: November 6, 1989 Accepted after revision: January 17, 1990
linearly decreased with logarithmically increasing doses (0.1, 1, 10 mg) of ACTH 4-10, indicating that the peptide impairs se lective attention [7], The MMN, on the other hand, was not af fected by ACTH and related peptides. Presently, little is known of the time course of central ner vous effects of ACTH or ACTH 4-10 in humans. In rats, effects of fragments of ACTH on retention of avoidance behavior ap peared to be of a short-term nature which - depending on the dose and route of administration - emerges within I h following treatment and lasts for a few hours [3, 18]. Similarly, Pfaff et al. [19] reported increases in firing of hippocampal neurons fol lowing systemic administration of ACTH which began within 3-10 min and lasted 25-50 min after injection. In humans, little attempts have been made to describe the time course of central nervous influences of ACTH-related peptides. This may have been due to a lack of assays sensitively and reliably indicating central nervous changes of ACTH-related peptides in humans. Endroczi et al. [20] reported on a suppression of stimulusevoked EEG synchronization to previously habituated stimuli following administration of ACTH 1—10 (I or 2 mg, i.v.) or ACTH 1-24 (0.5 mg, i.v.) which developed about 1 h after the injection and lasted for several days; i.e., these effects in hu
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/24/2019 12:15:14 PM
Abstract. Previous studies have demonstrated that the adrenocorticotropic hormone (ACTH) and its 4—10 fragment are potent modulators of attention in humans. In these studies the Nd component (‘negative displacement’) of the stimulus-evoked brain potential (event-related potential, ERP), which is a neurophysiological indicator of selective attention, proved most sensitive to effects of these peptides. The Nd decreased in amplitude linearly with logarithmically increasing doses of ACTH 4-10 applied. Here we report results complementing these previous findings by establishing a time course of the effects of ACTH 4-10 on human attention. In a double-blind cross-over study, attention performance on a dichotic listening task was tested in 18 healthy volunteers, after having received intravenously either placebo or 1 mg ACTH 4-10. Tests took place 0, 30. 90. 180, 330. 600 min, 24. 48 and 72 h after drug intake and took about 15 min. Each subject was tested on 4 of these occasions, selected according to a random schedule. During task performance ERPs to the different task stimuli were recorded. ERPs were used to determine the Nd (an indicator of controlled processing of stimuli which the subjects selectively attended to) and the mismatch negativity (MMN) reflecting automatic processing of stimulus deviance. ACTH 4-10 diminished the Nd significantly at 30 min after treatment ad ministration. On none of the other occasions significant changes in Nd occurred. MMN was not affected by the peptide. The results indicate a short-term action of ACTH 4-10 on selective attention, which takes about 30 min to develop and does not last longer than 90 min after treatment.
mans appeared to last much longer than those observed in ani mal studies. However, no placebo control was run in these ex periments. The present study aimed at describing the time course of central nervous influences of a single intravenous administra tion of ACTH 4-10 in humans. For this purpose, the Nd com ponent of the ERP was used as dependent variable which in an extensive series of foregoing studies (mentioned above) has been proved to be a reliable and sensitive indicator of brain actions of ACTH in humans.
Subjects and Methods Subjects. Design, and Procedure Eighteen male student volunteers (age between 19 and 30 years) participated in the experiments. The study was approved by the Com mittee on Research Involving Human Subjects of the University o f Ulm, and each subject gave written consent. The subjects were of normal hearing and free of medication at the time of the investigation. They were non smokers and had to abstain from alcoholic beverages for at least 12 h prior to the experimental sessions. In the morning on the days of the experiments subjects were not allowed to drink more than I cup of coffee or (black) tea. Each subject was tested following placebo and following admini stration of ACTH 4-10 (1 mg, diluted in 20 ml saline solution). Placebo and ACTH 4—10 conditions for a given subject were separated by an interval of at least 10 days. Treatments were given intravenously as short infusions (over 10 min) which started at 12.00 h. The order of treat ments was randomized (half of the subjects starting with placebo, the other half with infusion of ACTH 4-10) and the experiments were dou ble-blind. Attention tests were conducted at 0, 30, 90, 180, 330, 600 min, 24, 48, and 72 h after the infusion had been finished. The task took about 15 min. To avoid a strong decline o f motivation with repeated testing, on each of these occasions only 8 subjects were tested. Thus, each subject was tested on 4 of the 9 possible occasions, selected according to a random schedule. However, none of the subjects was tested on two consecutive occasions. Attention performance was tested in a dichotic listening paradigm [ 12] (fig. I). The task consisted o f four sequences of about 400 tone pips (60 dB SPL, 60 ms duration), delivered through earphones to the subject’s right and left ear. Interstimulus intervals between any two pips ranged from 250 to 1,250 ms with an average of 550 ms. Each sequence contained 4 different types of tone pips: one ear received a series made up of standard 800-Hz tone pips and randomly inserted rare target tones of 840 Hz; the other ear received a similar series made up of standard tones of 1,200 Hz and rare target tones of 1,260 Hz. The pro bability of a target was p = 0 .1 for each ear. The subject was instructed to attend to all stimuli in one ear and to covertly count all targets occurring in this ear. Stimuli in the opposite ear were to be ignored. The ear to be attended was counterbalanced across and within subjects. Also, the headphones were reversed after two of the sequences, and half of the subjects began the experiment with reversed earphones, in order to con trol for effects of the different frequencies o f the pips in both ears. Be tween any two sequences a short break (about 10 s) was used to check for the subject’s count. Subjects were instructed to fixate their eyes on a centrally located dot during performance of the attention task. Heart
B om / Unseld/ Pietrowsky/ Bickel /V oigt/ Fehm
rate, systolic and diastolic blood pressure were measured immediately before performance of the attention task. Plasma cortisol w;is deter mined from blood samples collected after task performance. The plasma was immediately separated and stored at -2 0 °C until radioimmunological determination o f conisol. Recordings and Apparatus During performance of the attention task, recordings were obtained of EEGs (5 s time constant, 30 Hz/3 dB high-frequency roll off) from midline electrode locations (Fz, Cz, Pz) referenced to linked electrodes attached at the earlobes. The vertical EOG was monitored for artifact recognition. For all recordings nonpolarizable silver-silver chloride electrodes of 16 mm diameter (Beckman Instruments, USA) were used. EEG and EOG signals were amplified by a Beckman type R611 dynograph (with modified input couplers), digitized (sampling rate 385 Hz) and stored on magnetic tape (pulse code modulated) for off-line averag ing of ERPs. Heart rate and blood pressure were measured automatically by a BC 40 (Bosch und Sohn, FRG) simulating the Riva-Rocci procedure. Plasma cortisol was determined by radioimmunoassay (Biermann, FRG) with a sensitivity o f 4.7 nmol/l. Intra- and interassay coefficients of variation were below 3 and 10%, respectively, between 27.6 and 1.380 nmol/l. All samples from an individual were assessed in dupli cate in the same assay. Data Reduction and Analysis Individual ERPs were averaged separately according to the experi mental conditions: treatment (placebo vs. 1 mg ACTH 4-10), time since treatment (0, 30, 90, 180, 330, 600 min, 24, 48, and 72 h), sequence (1-4), tone pip (attended vs. unattended standard, and attended vs. unattended target) and topography (Fz, Cz, Pz). The averaging epoch covered a 40-ms baseline and a 600 ms poststimulus onset interval. Epochs were excluded from analysis by a computer program if they contained eyeblinks, gross eye movements or other potential artifacts. Data from 2 individual attention tests (48 and 72 h since treatment) had to be discarded, due to a technical failure and because 1 subject had caught a cold. The Nd and the MMN were extracted from ERP responses. The Nd indexing selective attention was determined as mean difference ampli tude between ERPs to standard tones when attended and when unat tended, in the latency interval 0-460 ms poststimulus. The long latency interval was used to provide continuity with previous studies [e.g., 10, 211. The MMN indexing the automatic processing of stimulus deviance [e.g., 13] was determined by subtracting the mean amplitude within 140 and 360 ms poststimulus o f ERPs to unattended standard tones from the mean amplitude (within the same latency range) of ERPs to the unattended target tones. The deviation of the target counts from the correct value was taken as a crude behavioral measure of attention. Statistical evaluation of ERP measures, counting accuracy, plasma cortisol and cardiovascular parameters based on analyses of variance (ANOVA). They contained the repeated measure factors: treatment (placebo vs. ACTH 4-10), time since treatment, and sequence (1-4). ANOVAs on ERP measures, in addition, contained a factor topography (Fz, Cz, Pz). Significant (p < 0.05) effects for the time factor were post hoc evaluated by Wilcoxon’s t tests performed separately on the data for each testing occasion since treatment. Effects of the treatments on the Nd and MMN were also evaluated separately for the recording site, at which they displayed their maximum amplitudes.
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/24/2019 12:15:14 PM
170
ACTH and Human Allention
Cz
Pz
Fig. I. The middle panel Illustrates the dichotic listening paradigm: subjects were presented with series of tone pips in both ears at once. In each ear rate target tone pips (indicated by longer strokes) were inter spersed among frequent standard pips. Target pips in one ear were to be counted, while all pips in the opposite ear were to be ignored. Upper panels: ERPs to standard pips when attended (the respective upper lines) and when unattended (lower lines) recorded at Fz, Cz, and Pz electrode locations during the testing 30 min following placebo treat ment. (Vertex negative is upward.) Bottom panels: Nd components (at Fz, Cz, and Pz) constructed by subtracting ERP responses to unattend ed standard tones from ERPs to attended standard to n es.----- = Pla cebo;------ = A C T H 4-10(I mgi.v.). Recordings were obtained 30 min following administration of the treatments.
Results
Event-Related Potentials
For both treatment conditions and for all attention tests ERPs to attended standard stimuli were shifted towards in creased negativity, as compared to the ERP responses to the same stimuli when unattended. The mean amplitude difference within 0-460 ms poststimulus (Nd) was larger at frontal and central than at parietal electrode sites (mean ± SEM, during
Fig. 2. Amplitudes of Nd (a) and MMN(b) at Fz obtained at differ ent times following treatment administration, which took place between 12.00 and 12.10 h . ----- = Placebo;------ = ACTH 4-10 (1 mg i.v.). **p < 0.05, for the differences between the effects of the treatments.
placebo sessions - Fz: 1.22 ± 0.15 ¡TV, Cz: 1.00 ± 0.16 pV, Pz: 0.54 ± 0 .1 3 pV; main effect for topography: p < 0.001, fig. 1). MMN, which is the mean difference amplitude between ERPs to unattended target tones and unattended standard tones 140-360 ms poststimulus also displayed maximum am plitudes at anterior recording sites (mean ± SEM during pla cebo sessions - Fz: 1.76 ± 0.29 pV, Cz: 1.44 ± 0.29 pV, Pz: 0.79 ± 0.24 uV; main effect topography: p < 0.001). MMN, in general, was more variable than Nd amplitude.
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/24/2019 12:15:14 PM
Fz
171
Bom/Unseld/Pietrowsky/Bickel/Voigt/Fehm
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24
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72
(h |
Fig. 3. Plasma cortisol (a) heart rate (HR, c), systolic (b). and diastolic blood pressure (d) measured at different times following treatment administration, which took place between 12.00 and 12.10 h . ----- = Placebo;-------= ACTH 4-10 (1 mg i.v). There was a tendency towards an increased heart rate following ACTH 4-10, 3 h after treatment administration (Wicoxon’s t test; p < 0.10).
Plasma Cortisol, Cardiovascular Parameters and Counting Performance
Cortisol concentrations obtained after performance on the attention task are shown in figure 3. Cortisol concentrations strongly depended on the time of day, with lowest values at 22.00 h (corresponding to 600 min since treatment). ACTH 4-10 did not influence adrenal cortical secretory activity. There were also no systematic effects of ACTH 4-10 on heart rate, systolic and diastolic blood pressure (fig. 3). Average deviations of the counts from the correct value (across all testings since treatment administration) were for the placebo condition 1.58 ± 0.31 and for the ACTH 4-10 condi tion 1.52 ± 0.26. Differences between the effects of the treat ments did not reach statistical significance for any of the testings performed after treatment administration. This may have been due to the fact that counting performance is only a rather crude
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/24/2019 12:15:14 PM
Figure 2 shows mean Nd amplitudes (at Fz) obtained at dif ferent times following administration of placebo or ACTH 4-10. Compared to the placebo treatment, ACTH 4-10 signifi cantly decreased frontal Nd amplitude during the testing 30 min following treatment administration. This effect was sta tistically confirmed by ANOVA [treatment • time since treat ment • topography, F( 16,120) = 2.17, p< 0.0!5, Greenhouse Geisser Probability] and post hoc t tests for the difference be tween the effects of the treatments for this testing occasion (at Fz: two-sided Wilcoxon’s t test: p
