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NeuroImage 15, 153–158 (2002)
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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
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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
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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
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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.
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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.
Nevertheless, the transient 40-Hz response may provide a tool for investigating cholinergic deficits in the
aged human brain.
ACKNOWLEDGMENTS
This work was supported by the Helsinki University Central Hospital Research Funds, the Ella and Georg Ehrnrooth’s Foundation,
and the Academy of Finland. We thank Ms. Suvi Heikkilä for her
assistance in carrying out the experiments.
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