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NeuroImage 15, 153–158 (2002) doi:10.1006/nimg.2001.0956, available online at http://www.idealibrary.com on Aging and Cholinergic Modulation of the Transient Magnetic 40-Hz Auditory Response Jyrki Ahveninen,* ,† ,‡ ,1 Iiro P. Jääskeläinen,§ ,¶ Seppo Kaakkola,‡ Hannu Tiitinen,† ,¶ and Eero Pekkonen* ,† ,‡ *Cognitive Brain Research Unit and ¶Apperception & Cortical Dynamics Research Team, Department of Psychology, and ‡Department of Neurology, University of Helsinki, P.O. Box 13, FIN-00014 Helsinki, Finland; †BioMag Laboratory, Medical Engineering Centre, Helsinki University Central Hospital, Helsinki, Finland; and §Massachusetts General Hospital–NMR Center, Harvard Medical School, Charlestown, Massachusetts Received April 2, 2001 Cholinergic blockade by scopolamine, a central muscarinic receptor antagonist, may produce transient memory impairment in healthy subjects, and it has been used as a neurochemical model of cognitive degeneration in aged individuals. To observe the muscarinic modulation of memory and cortical auditory processing, nine cognitively intact elderly subjects (59 – 80 years) were studied using neuropsychological tests and 122channel magnetoencephalography (MEG) after an administration of scopolamine hydrobromide (0.3 mg, iv) or glycopyrrolate (0.2 mg, iv), a peripheral muscarinic antagonist. A double-blind randomized crossover design was used in two sessions separated by at least 1 week. Scopolamine, but not glycopyrrolate, produced a transient impairment of verbal memory performance in the elderly subjects. MEG indicated that the auditoryevoked 40-Hz magnetic response was significantly larger after scopolamine than after glycopyrrolate administration. Furthermore, reanalysis of our earlier results in younger subjects (20 –31 years), basically supporting the present MEG findings, tentatively suggests that the scopolamine effects on the 40-Hz response may be slightly pronounced with aging. In sum, the transient magnetic 40-Hz auditory response may be useful in studies on brain cholinergic deficits in elderly subjects. © 2002 Elsevier Science Key Words: 40-Hz response; acetylcholine; aging; Alzheimer’s disease; auditory event-related potentials; electroencephalography; magnetoencephalography; memory; muscarinic receptors; scopolamine. INTRODUCTION Scopolamine, an antagonist of muscarinic acetylcholine receptors, is capable of inducing transient memory 1 To whom correspondence should be addressed at the Cognitive Brain Res. Unit, Department of Psychology, P.O. Box 13, FIN-00014 University of Helsinki, Finland. Fax: ⫹358 9 191 22924. E-mail: [email protected]. impairment in normal subjects. Many researchers have thus attempted to model cholinergic disorders, for instance, the memory deficits associated with Alzheimer’s disease, by using scopolamine (Beatty et al., 1986; Broks et al., 1988). Furthermore, recent studies with magnetoencephalography (MEG), the functional brain-research method with a millisecond temporal resolution, suggest that scopolamine produces significant changes in the mass action of cerebral neurons in healthy young subjects (Ahveninen et al., 1999; Jääskeläinen et al., 1999; Pekkonen et al., 2001). Higher order cognitive processes may be based on rhythmic synchronization of neural discharges in the ␥ band (around 40 Hz) (Engel et al., 1992). An eventrelated 40-Hz rhythmic response, time- and phaselocked to auditory stimulation, can be detected with MEG and electroencephalography (EEG) (Pantev et al., 1991). MEG studies have associated 40-Hz oscillations, localized near the auditory cortex (Pantev et al., 1993), with temporal binding in auditory perception (Joliot et al., 1994). EEG studies in turn indicate that the transient component of 40-Hz auditory activity is enhanced by selective attention (Tiitinen et al., 1993) and gradually attenuated after long-term stimulation due to lessened vigilance (May et al., 1994). Thus, the 40-Hz auditory responses might represent essential components of cortical information processing that is presumed to be impaired in disorders associated with cholinergic deficits. Studies of cerebral mass action (Buchwald et al., 1991; Jääskeläinen et al., 1999) and cellular-level events (Aramakis et al., 1999; Cox et al., 1994; Metherate and Ashe, 1993) suggest that the acetylcholine system modulates sensory processing in the auditory cortex, where the 40-Hz responses originate (Pantev et al., 1993). Consistently, our previous study indicated that the 40-Hz response is enhanced after scopolamine challenge in healthy young human subjects (Ahveninen et al., 1999), suggesting that this response might be used as an index of cholinergic modulation of 153 © 1053-8119/02 $35.00 2002 Elsevier Science All rights reserved. 154 AHVENINEN ET AL. auditory processing. Therefore, we compared the effects of scopolamine with those of glycopyrrolate, a peripheral muscarinic antagonist that does not penetrate the blood– brain barrier, in cognitively intact aged subjects by using 122-channel MEG and neuropsychological tests. Additionally, our previous data (Ahveninen et al., 1999) were reanalyzed to compare MEG results in elderly and young subjects. METHODS Nine healthy right-handed volunteers (59 – 80 years; six females) were administered either scopolamine hydrobromide (0.3 mg, iv) or glycopyrrolate (0.2 mg, iv) in a double-blind, randomized crossover design, 1 h before the measurements. The subjects were supervised for at least 8 h after the drug administration (either by a trained nurse, S.H., or by physicians S.K. or E.P.). The study was approved by the National Agency for Medicines, Finland, and the Ethics Committee of the Department of Clinical Neurosciences, Helsinki University Central Hospital. A written informed consent was obtained after the procedures had been fully explained to the subjects. The subjects reported having had no neurological or psychiatric disorders. Each subject scored over 27/30 points (six subjects scored 30/30) in the Mini Mental Status Examination, which was used for screening signs of age-related cognitive impairment or dementia. Two subjects had hypertension, one had coronary arteriosclerosis, one had Chrohn’s disease, one had peptic ulcers and diaphragmatic hernia. None of the subjects took drugs affecting the CNS. However, two subjects were taking medication for hypertension, two used nonsteroidal anti-inflammatory drugs, one used isosorbide mononitrate for coronary disease, one was treated with an anti-ulcer agent, and two female subjects used hormone replacement treatment because of menopause. The subjects were instructed to avoid alcohol for at least 48 h and caffeine and tobacco for 12 h before MEG and EEG recordings. All experimental sessions were carried out between 8 and 12 AM, and the sessions were separated by 1 week. Before the MEG measurement, a brief neuropsychological test battery was administered to the subjects to monitor the cognitive effects of drug administration. The battery included the Wechsler Memory Scale Revised (WMS-R) Digit Span (forward and backward) and Logical Memory. During each session, one of the two subtests of the WMS-R Logical Memory was used in a counterbalanced order. Delayed recall was tested after each MEG measurement, 30 – 40 min after the immediate recall. A “forgetting ratio” was calculated for each subject by dividing the delayed Logical Memory score with the immediate recall score. During the MEG recordings, the subject sat in a comfortable chair in a magnetically shielded room (Euroshield, Eura, Finland) with the head inside a helmet- shaped 122-channel whole-head MEG instrument (Neuromag Ltd., Helsinki). The subjects were presented with 700-Hz pure tones to the left ear at 60 dB over the individually determined subjective hearing threshold with a stimulus-onset asynchrony of 500 ms. The tones were either 50-ms standards (P ⫽ 0.8) or deviants (400, 600, or 670 Hz; P ⫽ 0.067 for each). The activity elicited by the deviant tones was not analyzed because of insufficient signal-to-noise ratio (smaller number of summations). For each stimulus, the rise and fall times were 5 ms. The subjects were instructed to ignore the stimulation and to concentrate on a silent video movie. Stimulus-locked transient 40-Hz responses were measured (pass-band 0.03–150 Hz, sampling rate 800 Hz) with a 122-channel planar gradiometer (Ahonen et al., 1993) and digitally band-pass filtered offline at 32– 48 Hz. The analysis period was 750 ms (including a 150-ms prestimulus baseline). Vertical and horizontal eye movements were recorded with an electro-oculogram (EOG). Epochs containing over 150-V peak-topeak EOG changes or over 3-pT/cm MEG changes, as well as the responses to the first few stimuli of the sequence, were automatically rejected. At least 1600 responses were recorded and averaged for the standard stimulus. Each two-channel MEG sensor unit measures two independent magnetic-field gradient components, B z/x and B z/y, the z axis being normal to the local helmet surface. The precise position of the subject’s head relative to the MEG instrument was determined by measuring magnetic fields produced by three marker coils attached to the scalp. Before the measurement, the locations of the marker coils in relation to cardinal points of the head (nasion, left, and right preauricular points) were determined using an Isotrak 3D digitizer (Polhemus, Colchester, VT). The cutoff point for the reliability of the individual 40-Hz responses was taken to be 2 times the standard deviation (SD) of the prestimulus (⫺100 . . . 0 ms) noise level. The waveforms were rectified and the 40-Hz response amplitudes were quantified as the mean amplitude during the latency range of 20 –70 ms. Over the left and right temporal areas, the response amplitude was determined from a subset of 12 gradiometers (six orthogonal pairs) located approximately over the auditory cortex. For each channel pair, the square root of the sum of squares of the longitudinal and latitudinal field gradient was calculated. To dissociate the signal from the noise at the individual level, the spatial distribution of the 40-Hz response was estimated from the grand-averaged 40-Hz response in the placebo (glycopyrrolate) condition. This estimate was used for calculation of a weighted-average amplitude of the six channel pairs for each subject, after both scopolamine and glycopyrrolate conditions. AGING AND CHOLINERGIC MODULATION OF 40-HZ RESPONSE To compare the brain function in the elderly and young subjects, we reanalyzed our previous data (Ahveninen et al., 1999) by using the same procedures as described above. These 13 healthy right-handed volunteers (20 –31 years; 6 females) had been administered similar doses of each drug using the identical design. The dipole modeling, providing an estimate of the “center of gravity” of the cortical activation, was based on a coordinate system in which the x axis points from the left to the right preauricular point, the y axis is perpendicular to the x axis and passes through the nasion, and the z axis points upward. The center of symmetry in the head model was at {x, y, z} ⫽ {0, 0, 45 mm}. Equivalent current dipoles (ECD) were fitted for right auditory cortices using a subset of 20 channels (contralateral to the ear stimulated). The ECD parameters were determined to explain the measured data optimally in the least-squares sense. ECDs were determined for consecutive peaks (of either polarity, separated by approximately 12.5 ms). The best-fitting ECD during the 20- to 70-ms poststimulus period was selected for the within-pairs comparisons of drug effects. A drug-by-hemisphere analysis of variance (ANOVA) with contrasts was used to test the drug effects in the square-root transformed waveform amplitudes. The drug-induced differences in the Logical Memory were analyzed by using a drug-by-recall-point (immediate or delayed) two-way ANOVA. Other neuropsychological test scores were analyzed using one-way ANOVA. ECD source locations and dipole moments (the least-squares fitting) were analyzed by using one-way ANOVAs (within subject). The differences between the elderly and the young subjects’ 40-Hz responses were statistically analyzed by using a three-way ANOVA (agegroup by drug by hemisphere). Furthermore, two contrasts were calculated from the three-way ANOVA to analyze the age-related differences in the 40-Hz response within both drug conditions. RESULTS Neuropsychological Tests The neuropsychological results are presented in Table 1. ANOVA indicated a significant drug-by-recalldelay interaction (F(1,8) ⫽ 5.58, P ⬍ 0.05), suggesting that scopolamine impaired particularly the delayed recall of WMS-R Logical Memory task. This was supported by a significant decrease in the delayed-to-immediate recall ratio by scopolamine (F(1,8) ⫽ 5.81, P ⬍ 0.05). No significant drug effects were observed in other neuropsychological test parameters. MEG Waveforms A reliable transient 40-Hz magnetic auditory response (⬎2 times baseline SD) was observed in eight of 155 TABLE 1 Means ⫾ SD of the Neuropsychological Results after Scopolamine and Glycopyrrolate Administration WMS-R logical memory Immediate recall Delayed recall Forgetting rate WMS-R digit span Forward Backward Total score Scopolamine Glycopyrrolate 7.3 ⫾ 3.8 5.1 ⫾ 4.7 0.6 ⫾ 0.4 9.0 ⫾ 2.4 9.3 ⫾ 2.5 1.1 ⫾ 0.2* 5.6 ⫾ 0.7 4.4 ⫾ 0.9 12.4 ⫾ 2.5 6.1 ⫾ 0.9 4.4 ⫾ 0.9 13.3 ⫾ 3.7 * P ⬍ 0.05. the nine subjects. Data from a representative subject in both conditions are presented in Fig. 1. The main effect of the drug-by-hemisphere ANOVA (F(1,7) ⫽ 5.63, P ⬍ 0.05) suggested that the 40-Hz response was significantly larger after scopolamine than after glycopyrrolate administration. The a priori contrasts, further, indicated that this enhancement was significant (F(1,7) ⫽ 6.58, P ⬍ 0.05) over the right temporal areas, i.e., in the hemisphere contralateral to the ear stimulated (Fig. 1), whereas the enhancement of the 40-Hz magnetic response did not reach statistical significance over the left hemisphere. The waveform data are presented in Table 2. MEG Dipole Modeling ECD could be modeled reliably (goodness of fit 67– 97%) in seven subjects in the right, contralateral hemisphere. There were no significant differences in the ECD source locations between the two drug conditions. As indicated in Table 3, the best ECD of the transient magnetic 40-Hz response during the 20- to 70-ms poststimulus period was located near the temporal lobes, wherein the primary auditory cortex is located. Supporting the waveform results, the dipole moments were significantly larger after scopolamine administration than in the glycopyrrolate condition (F(1,6) ⫽ 6.35, P ⬍ 0.05). Comparisons between the Aged and the Young Subjects The reanalyzed 40-Hz response amplitudes in the young subjects are presented in Table 2. The main effects of the three-way ANOVA indicated that scopolamine enhanced the magnetic 40-Hz response in the combined subject group (F(1,19) ⫽ 14.3, P ⬍ 0.01). Moreover, the contrasts indicated that after the scopolamine administration, the 40-Hz response was significantly larger in the aged than in the young subjects (F(1,19) ⫽ 10.7, P ⬍ 0.01). However, no significant age-related differences were found after glycopyrrolate administration. Finally, the enhancement of the 40-Hz 156 AHVENINEN ET AL. FIG. 1. The transient magnetic 40-Hz auditory response measured with the Neuromag 122-channel MEG device after scopolamine and glycopyrrolate administration in a representative elderly subject. The stimuli were delivered to the left ear. Two gradiometer pairs from each hemisphere with the largest responses are enlarged. response by scopolamine in the 20- to 70-ms period was statistically significant in the young subjects (F(1,12) ⫽ 8.95, P ⬍ 0.05). DISCUSSION The effect of cholinergic modulation on early auditory processing and memory function was studied by comparing the effects of scopolamine and glycopyrrolate, central and peripheral antagonists of muscarinic acetylcholine receptors, respectively. The main finding was the significant enhancement of the transient 40-Hz auditory magnetic response after scopolamine administration in cognitively intact elderly subjects. On the group level, 40-Hz response amplitude averaged during the 20- to 70-ms poststimulus period, was enhanced by approximately 40% in the elderly sub- jects, as measured from the 12 contralateral gradiometers. This is in line with previous observations in healthy young subjects (Ahveninen et al., 1999). Our earlier results (Ahveninen et al., 1999) were reanalyzed to study the magnitude of scopolamine effects in aged versus young subjects. Interestingly, the 40-Hz response appeared to be significantly larger in the aged than in the young subjects after scopolamine administration, but no significant age-related differences were found in the glycopyrrolate condition. Thus, the scopolamine effects on the magnetic 40-Hz response might be pronounced with aging, which generally agrees with previous neuropsychological results (Flicker et al., 1992; Tariot et al., 1996). However, as regards comparisons between aged and young subjects, the results should be considered tentative, because the amount of averaged epochs was increased for the TABLE 2 Means ⫾ SD Amplitudes (fT/cm) of the 40-Hz Response Obtained from the MEG Waveforms in the Elderly Subjects and in the Young Subjects from Our Previous Study (Ahveninen et al., 1999) Elderly subjects Right hemisphere Left hemisphere Young subjects Scopolamine Glycopyrrolate Scopolamine Glycopyrrolate 2.4 ⫾ 1.1 1.7 ⫾ 0.5 1.7 ⫾ 0.9* 1.4 ⫾ 0.8† 1.5 ⫾ 0.3 1.1 ⫾ 0.5 1.2 ⫾ 0.4† 0.9 ⫾ 0.2 * P ⬍ 0.05 and † P ⬍ 0.10 in scopolamine vs glycopyrrolate condition. 157 AGING AND CHOLINERGIC MODULATION OF 40-HZ RESPONSE TABLE 3 Means ⫾ SD of the ECD Results after Scopolamine and Glycopyrrolate Administration Scopolamine Glycopyrrolate Latency (ms) x (mm) y (mm) z (mm) Q (nAm) Goodness of fit (%) 46 ⫾ 16.9 44 ⫾ 17.6 48 ⫾ 5.3 52 ⫾ 5.0 12 ⫾ 16.6 11 ⫾ 10.6 55 ⫾ 22.2 51 ⫾ 11.3 2.0 ⫾ 1.0* 1.3 ⫾ 0.9 87 ⫾ 10.1 88 ⫾ 10.9 * P ⬍ 0.05. present study, which may have slightly improved the signal-to-noise ratio in the elderly subjects in relation to the young ones. Supporting previous well-documented observations (Beatty et al., 1986; Broks et al., 1988), the cholinergic blockade by scopolamine impaired memory performance, as characterized by increased forgetting of verbal material in the elderly subjects. However, the short-term memory or immediate recall was not significantly affected. The memory impairment produced by scopolamine thus resembled the clinical presentation of qualitative memory deficits in early or preclinical Alzheimer’s disease, in which increased forgetting may precede impairments in short-term and immediate memory (Christensen et al., 1998). However, it has to be noted that as for a neuropsychological study, the number of subjects was relatively small; moreover, the brief test battery was mainly designed for monitoring the behavioral drug effects. The present results on the 40-Hz response appear to differ from scopolamine effects on the late cognitive ERP components. For example, P3 is abolished by central anticholinergic drugs (Hammond et al., 1987; Meador et al., 1989) and by lesions in subcortical cholinergic nuclei innervating the cortex (Wang et al., 1997). However, rat studies (Brett et al., 1996) indicate that MAEP or spontaneous auditory-cortical 40-Hz oscillations are not affected by ablation of the major cortical cholinergic projections, suggesting that the auditorycortical neural networks may oscillate independent of cholinergic input. Nevertheless, these networks, generating MAEP/MAEF and 40-Hz oscillations, may still be modulated by cholinergic inputs as suggested by their enhancement by anticholinergic drugs (Ahveninen et al., 1999; Buchwald et al., 1991; Jääskeläinen et al., 1999). This idea is clearly supported by the present findings. The enhancement of the 40-Hz response by scopolamine in the elderly subjects might be surprising against the background of cellular-level neuropharmacological studies as well, suggesting that muscarinic activation produces mainly excitatory effects in the auditory cortex (Aramakis et al., 1999; Cox et al., 1994; Metherate and Ashe, 1993). However, it has to be noted that both excitatory and inhibitory subtypes of muscarinic receptors have been cloned (Durieux, 1996), and the acetylcholine effects are known to depend on the type of postsynaptic neuron (Pirch, 1995). Enhancement of glutamatergic excitability by muscarinic activation at the auditory cortex may, further, rely on the strength of simultaneous postsynaptic inhibition; it has been proposed that cholinergic modulation might suppress weak input activation and enhance strong input activation (Aramakis et al., 1999). Alternatively, one might speculate that the present effect represents disinhibition of early cortical auditory processing, given that scopolamine effects are reportedly most profound in the frontal lobes (Prohovnik et al., 1997), which are suggested to regulate evoked-potential generation at sensory cortices (Skinner and Yingling, 1977; Yingling and Skinner, 1976). However, further studies are clearly needed to verify these interpretations. CONCLUSION The present results suggest that transient magnetic 40-Hz auditory-evoked responses may be modulated by muscarinic acetylcholine receptors. Scopolamine doses that produced amnesic symptoms appeared to result in disinhibition of early auditory processing in cognitively intact elderly subjects. Tentatively, the scopolamine effects on the transient 40-Hz response might be slightly pronounced with aging. Further studies are needed to unravel the mechanisms that determine how the scopolamine effects on this response are mediated. 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