Clinical Neurophysiology 113 (2002) 1894–1902
www.elsevier.com/locate/clinph
Dopamine modulates involuntary attention shifting and reorienting:
an electromagnetic study
Seppo Kähkönen a,b,c,*, Jyrki Ahveninen a,b,c, Eero Pekkonen a,b,d, Seppo Kaakkola d,
Juha Huttunen e, Risto J. Ilmoniemi b,c, Iiro P. Jääskeläinen f,g
a
Cognitive Brain Research Unit, Department of Psychology, University of Helsinki, Helsinki, Finland
BioMag Laboratory, Engineering Centre, Helsinki University Central Hospital, P.O. Box 340, Helsinki, FIN-00029 HUS, Finland
c
Helsinki Brain Research Center, P.O. Box, FIN-00014 University of Helsinki, Finland
d
Department of Neurology, Helsinki University Central Hospital, P.O. Box 340, Helsinki, FIN-00029 HUS, Finland
e
Department of Clinical Neurophysiology, Helsinki University Central Hospital, P.O. Box 340, Helsinki, FIN-00029 HUS, Finland
f
Massachusetts General Hospital – NMR Center, Harvard Medical School, Charlestown, MA, USA
g
Apperception & Cortical Dynamics Research Team, Department of Psychology, University of Helsinki, Helsinki, Finland
b
Accepted 9 September 2002
Abstract
Objective: Dopaminergic function has been closely associated with attentional performance, but its precise role has remained elusive.
Methods: Electrophysiological and behavioral methods were used to assess the effects of dopamine D2-receptor antagonist haloperidol on
involuntary attention shifting using a randomized, double-blind, placebo-controlled cross-over design. Eleven subjects were instructed to
discriminate equiprobable 200 and 400 ms tones in a forced-choice reaction-time (RT) task during simultaneous measurement of whole-head
magnetoencephalography and high-resolution electroencephalography.
Results: Occasional changes in task-irrelevant tone frequency (10% increase or decrease) caused marked distraction on behavioral
performance, as shown by significant RT increases to deviant stimuli and subsequent standard tones. Furthermore, while the standard
tones elicited distinct P1–N1–P2–N2–P3 waveforms, deviant tones elicited additional mismatch negativity (MMN), P3a, and reorienting
negativity (RON) responses, indexing brain events associated with involuntary attention shifting. While haloperidol did not affect the source
loci of the responses of magnetic N1 and MMN, the amplitude of the electric P3a and that of RON were significantly reduced and the latency
of magnetic RON were delayed following haloperidol administration.
Conclusions: The present results suggest that dopamine modulates involuntary attention shifting to task-irrelevant deviant events. It
appears that dopamine may disrupt the subsequent re-orienting efforts to the relevant task after distraction. q 2002 Elsevier Science Ireland
Ltd. All rights reserved.
Keywords: Attention; Auditory event-related responses; Dopamine; Electroencephalography; Haloperidol; Magnetoencephalography
1. Introduction
Involuntary attention shifting is a fundamental function
that helps one to orient to unexpected, potentially harmful
changes in the environment (Sokolov, 1975), but needs to be
controlled when concentrating on goal-directed functioning.
Impaired control of involuntary attention shifting can cause
pronounced distractibility and an inability to modify
responses to external stimuli.
The neural basis of involuntary attention shifting can be
studied non-invasively with high temporal resolution using
* Corresponding author. Tel.: 1358-9-4717-5542; fax: 1358-9-47175781.
E-mail address: [email protected] (S. Kähkönen).
event-related potentials (ERP) and event-related magnetic
fields (ERF), which are time-locked changes due to external
stimuli in the electroencephalogram (EEG) and magnetoencephalogram (MEG), respectively (Hari and Lounasmaa,
1989; Näätänen et al., 1994). MEG and EEG measure different aspects of electrical brain activity. The localization of
cerebral activity is usually simpler and more accurate with
MEG than with EEG. On the other hand, EEG shows the
activity from subcortical sources that may not be detected
with MEG (Hämäläinen et al., 1993). Simultaneous EEG
and MEG recording thus provides high spatial and temporal
resolution and make it possible to differentiate neural events
related to involuntary perceptual processes better than either
method alone.
1388-2457/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S13 88- 2457(02)0030 5-X
CLINPH 2002605
S. Kähkönen et al. / Clinical Neurophysiology 113 (2002) 1894–1902
Recently, a paradigm was developed that yields distinct
ERP and behavioral distraction effects with much smaller
deviances than in traditional study designs (Schröger and
Wolff, 1998a,b). In this paradigm, subjects have to discriminate between equiprobable long or short tones, which can
be of high-probability standard frequency or of low-probability deviant frequency. These task-irrelevant frequency
changes cause distraction on electrophysiological and behavioral level: they elicit a mismatch negativity (MMN)
followed by P3a, and they prolong reaction times (RT) in
the discrimination task. Moreover, task-irrelevant deviances
elicit an additional frontocentral negativity with a latency
around 400–600 ms (Schröger and Wolff, 1998a,b). This
effect, referred to as the reorienting negativity (RON)
(Schröger and Wolff, 1998a,b), has been proposed to reflect
neural processing in the context of reorienting of attention
following distraction.
The neurochemical regulation of involuntary attention
shifting is not yet fully known. However, previous studies
have shown that acute ethanol ingestion significantly
reduces behavioral distractibility (Jääskeläinen et al.,
1999), whereas the chronic effects have been documented
to be opposite (Ahveninen et al., 2000a). A recent study
indicated that a deficiency in the monoamine neurotransmitter serotonin induced by acute tryptophan depletion
decreases MMN and N2b elicited by task-irrelevant deviants. The EEG results were accompanied by an increase of
latencies of MMNm, the magnetic counterpart of MMN
(Ahveninen et al., 2002). These studies indicate that attention shifting may be regulated by gamma amino butyric acid
(GABA) and serotonin neurotransmitter systems.
The monoaminergic dopamine system may be associated
with this fundamental function (Coull, 1998); however, its
role has been scarcely studied. Attentional deficits were
observed in disorders with presumed dopamine dysfunction
such as in schizophrenia and Parkinson’s disease (Shelley et
al., 1991; Vieregge et al., 1994; Michie et al., 2000). Haloperidol is a dopamine D2-receptor antagonist that is widely
used for the treatment of schizophrenia. Acute administration of haloperidol changes dopaminergic activity in
animals (Lidsky and Banerjee, 1993), in healthy subjects
(Magliozzi et al., 1993), and in schizophrenic patients
(Davidson et al., 1987; Davidson and Davis, 1988). Our
previous studies have shown that haloperidol attenuates
the processing negativity, an ERP component elicited by
selectively attended standard tones, and it also increases
the amplitude of MMN elicited by deviants in the unattended stimulus channel (Kähkönen et al., 2001a). These
results, suggesting impaired selective attention, are
supported by another finding indicating that haloperidol
may also decrease the transient 40 Hz response to selectively attended tones (Ahveninen et al., 2000b). Our present
study was designed to investigate with simultaneous MEG
and EEG recordings whether changes in dopamine transmission induced by haloperidol affect involuntary attention
shifting in healthy subjects.
1895
2. Materials and methods
2.1. Subjects and design
A randomized, double-blind, placebo-controlled, crossover design was used with a 2 mg oral dose haloperidol
(Serenase w 1 mg tablet, Orion Pharma, Espoo, Finland) or
placebo. Drugs were given to 11 right-handed healthy
volunteers (aged 20–28 years; 6 females) after an institutional approval and an informed written consent were
obtained. Dosage was chosen in accordance with studies
showing that 2 mg of haloperidol affects cognitive performance without causing akathisia in healthy subjects (King,
1994). The drugs were administered 4 h before the measurements, because electrophysiological and positron emission
tomography (PET) data have shown that the effects peak
within 2–6 h after haloperidol administration in normal
subjects (Barlett et al., 1994; Leigh et al., 1992; McClelland
et al., 1990). The subjects were instructed to avoid alcohol
for at least 48 h, and caffeine and tobacco for 12 h, prior to
the recordings. The subjects reported having no history of
neurological or psychiatric disorders or having used any
drugs for 2 weeks before the study. None had been exposed
to any class of neuroleptics previously. The hearing levels
were confirmed by measuring the individual auditory
thresholds. All experimental sessions were carried out
between 8 and 12 a.m., and the sessions were separated by
1 week.
2.2. Stimuli and task
The stimuli were pure tones of either 200 or 400 ms in
duration (including 10 ms rise and fall times) with an
1110 ms offset-to-onset interstimulus interval (ISI). The
tone frequency, being 700 Hz for standard stimuli ðP ¼
0:88Þ and either 630 or 770 Hz for deviant stimuli
(P ¼ 0:06 for each), varied independently of the duration.
The tones were randomly presented to left ear at 60 dB
above the individually determined subjective hearing
threshold. The subject was instructed to press as rapidly as
possible a button with his left thumb to the 200 ms tones and
another button with his right thumb to the 400 ms tones, and
to ignore occasional frequency changes in the same tones.
The stimuli were presented in two blocks to avoid fatigue,
with resting periods of about 60 s between the blocks. RT
and hit rates (HR) were measured to standards (excluding
the first standard after a deviant), to deviants and to standards after deviant.
2.3. Data acquisition
During the MEG and EEG recordings, each subject sat in
a comfortable chair in a magnetically and electrically
shielded room (Euroshield Ltd, Finland). The ERF and
ERP were recorded with a 122-channel whole-head MEG
(4-D Neuroimaging Oy, Finland; Ahonen et al., 1993) and
64-channel EEG. Each two-channel sensor unit in MEG
1896
S. Kähkönen et al. / Clinical Neurophysiology 113 (2002) 1894–1902
measured two independent magnetic field gradient components 2Bz =2x and 2Bz =2y, the z-axis being normal to the
scalp. The position of the subject’s head relative to the
recording instrument was determined by measuring the
magnetic fields produced by marker coils in relation to
cardinal points of the head (nasion, left and right pre-auricular points) that were located before the experiment using
an Isotrak 3D-digitizer (Polhemus, Colchester, VT, USA;
Ahlfors and Ilmoniemi, 1989). ERPs were recorded with an
electrode cap (Virtanen et al., 1996) and an amplifier (Virtanen et al., 1997) specifically designed and built for simultaneous EEG and MEG measurements. The nose electrode
was used as a reference. Vertical and horizontal electrooculograms (EOG) were recorded. The locations of the
EEG electrodes and the marker coils in relation to the cardinal points on the head were determined with the digitizer.
The recording passband was 0.03–100 Hz for EEG and
MEG and 0.5–30 Hz for EOG. The sampling rate was
394 Hz. Digital band-pass filtering was performed off-line
at 1–30 Hz for N1/N1m and MMN/MMNm and 0.5–30 Hz
for P3a/P3am and RON/RONm. The analysis period for
averaged epochs was 750 ms (including a 100 ms pre-stimulus baseline). The first 20 responses and all the epochs coinciding with EOG, EEG, or MEG changes exceeding
100 mV, 150 mV, or 3000 fT/cm, respectively, were omitted
from averaging. At least 100 responses (25 for each deviant
subset) for the deviants were averaged.
The ERP/ERF peaks were obtained from the latency
ranges of 80–150 ms for N1/N1m, 130–250 ms for MMN/
MMNm, 250–500 ms for P3a and P3am, and 480–550 ms
for RONm. The time window from 450 to 550 ms was used
for RON. The responses were judged significant when their
peak amplitudes were larger than two times the standard
deviations (SD) of the pre-stimulus noise.
2.4. Data analysis
ERPs and ERFs were averaged separately for standard
and deviant stimuli. The deviance-related ERPs and ERFs
were measured from subtraction curves (the pooled deviantstimulus response minus standard-stimulus response). The
ERF peak latencies and amplitudes were measured from the
channel pair showing the highest amplitude over the left and
right temporal areas. Left monaural stimulation is known to
elicit an MEG signal over both the right and left auditory
cortices (Pekkonen et al., 1995). The amplitudes and
sources of N1m and MMNm were estimated with single
equivalent current dipoles (ECD), determined by a leastsquares fit for a fixed subset of 34 channels separately
over each hemisphere from the orthogonal sensor pair
ð½2Bz =2x2 1 ½2Bz =2y2 Þ1=2 . Dipole fits with at most 30%
residual variance were considered successful. A spherical
head model was used for source modeling. The N1, MMN,
P3a, and RON peak amplitudes were measured manually
from the channels: F1, Fz, F2, FC1, FCz, FC2, C1, Cz,
C2, P1, Pz, and P2. Latencies were measured at the FCz
electrode location for MMN, P3a, and RON and at the Cz
for N1. Weighted mean amplitudes were used for analysis.
The EEG data of two subjects was rejected because of technical reasons.
The effects of haloperidol on N1m, MMNm, P3am, and
RONm amplitudes were tested by two-way (drug by hemisphere) repeated measures analyses of variance (ANOVAs).
The effect of haloperidol was analyzed on weighted mean
amplitudes of N1, MMN, P3a, and RON by two-way (drug
by electrodes) repeated measures ANOVAs. RTs were
correlated with latencies of P3a and RON using Spearman
correlation. Paired and unpaired t tests were also used when
appropriate.
3. Results
3.1. Behavioral data
Under placebo, deviants produced a significant prolongation of RT compared with standard sounds (t ¼ 25:5,
P ¼ 0:0004) and standards after deviants (t ¼ 24:0,
P ¼ 0:002). Haloperidol prolonged RT to standards, to
deviants and standards after deviants compared to placebo
but these differences were not significant (t ¼ 20:98,
P . 0:05; t ¼ 20:20, P . 0:05; t ¼ 20:35, P . 0:05,
respectively). No differences were found in HR to standards
and deviants after haloperidol and placebo conditions
(Table 1).
3.2. MEG results
Fig. 1 shows the MEG responses of one representative
subject. Results are summarized in Table 2. ANOVA
revealed that haloperidol had a significant drug-by-hemisphere interaction [Fð1; 10Þ ¼ 8:2, P ¼ 0:04] on RONm
latency. Other main effects were insignificant. Haloperidol
had no significant effects for dipole moments of N1m or
MMNm over both hemispheres. Nor did it affect the locations of N1m and MMNm (Table 3).
Table 1
Reaction times and hit rates after haloperidol and placebo admimistrations
RT (ms)
Standards
Deviants
Standards after deviants
RT lag (ms) to standards
after deviants
HR (%)
Standards
Deviants
Standards after deviants
Haloperidol
(mean ^ SD)
Placebo
(mean ^ SD)
624 ^ 22
655 ^ 22
642 ^ 24
613 ^ 15
652 ^ 19
637 ^ 17
31 ^ 9
39 ^ 7
94 ^ 1
94 ^ 1
94 ^ 2
95 ^ 1
94 ^ 2
95 ^ 2
S. Kähkönen et al. / Clinical Neurophysiology 113 (2002) 1894–1902
1897
Fig. 1. MEG response (subtraction curves) in one subject measured during haloperidol (solid lines) and placebo (dotted lines) administration. The stimuli were
delivered to the left ear. The enlarged response on the right is from the channel showing largest responses over the right temporal area (contralateral to the ear
stimulated). On the bottom, the arrows depict the orientation and loci of single ECD of the MMNm response.
1898
S. Kähkönen et al. / Clinical Neurophysiology 113 (2002) 1894–1902
Table 2
N1m, MMNm, P3am, and RONm amplitudes and latencies after haloperidol and placebo administrations
Component
N1m
N1m
MMNm
MMNm
P3am
P3am
RONm
RONm
Hemisphere
Amplitude (fT/cm)
Contralateral
Ipsilateral
Contralateral
Ipsilateral
Contralateral
Ipsilateral
Contralateral
Ipsilateral
Latency (ms)
Haloperidol
Placebo
Haloperidol
Placebo
66 ^ 14
37 ^ 4
66 ^ 23
49 ^ 22
45 ^ 21
40 ^ 22
32 ^ 15
35 ^ 19
59 ^ 63
34 ^ 4
66 ^ 26
46 ^ 18
39 ^ 13
35 ^ 16
38 ^ 42
33 ^ 6
99 ^ 2
111 ^ 4
191 ^ 44
196 ^ 58
325 ^ 73
300 ^ 60
533 ^ 71
503 ^ 89
110 ^ 3
110 ^ 4
184 ^ 43
169 ^ 35
341 ^ 81
278 ^ 48
540 ^ 90
444 ^ 68
3.3. EEG results
The standard tones elicited distinct P1–N1–P2–N2–P3
waveforms and deviant tones elicited additional MMN,
P3a, and RON responses (Figs. 2 and 3). EEG results are
summarized in Table 4. A significant main effect was found
in the RON amplitudes [Fð1; 8Þ ¼ 10:0, P ¼ 0:01]. The
ANOVA showed a significant drug-by-electrode interaction
Fð1; 8Þ ¼ 5:0, P ¼ 0:05] on RON amplitudes and a significant drug-by-electrode interaction [Fð1; 8Þ ¼ 13:2,
P ¼ 0:007] on P3a amplitudes. The post-hoc paired t test
showed that haloperidol significantly decreased the P3a
amplitudes at parietal electrodes (t ¼ 3:6, P ¼ 0:007).
Haloperidol significantly decreased the RON amplitudes
at frontocentral and central electrodes (t ¼ 2:5, P ¼ 0:03
and t ¼ 3:1, P ¼ 0:01, respectively). Haloperidol did not
affect the latencies of N1, MMN, P3a, and RON. The RT
to deviant tones correlated positively with the latencies of
P3a in the haloperidol condition (s ¼ 0:67, P ¼ 0:05), but
not in the placebo condition. No significant correlations
between the RT and the latencies of RON were observed.
4. Discussion
The present data suggest a specific pattern of changes by
haloperidol in ERP and ERF components elicited by taskirrelevant deviant events. The single dose of (2 mg) of this
dopamine antagonist did not significantly affect the behavioral accuracy of the subjects. One of the most profound
effects was the RON amplitude decrement, which was
accompanied by the peak-latency delay in RONm. RON,
being maximal at frontocentral EEG electrodes, is elicited
by task-irrelevant deviances and is suggested to be generated by multiple generators in frontal and centroparietal
brain regions (Schröger et al., 2000). Its physiological role
is not yet well characterized, but earlier EEG studies with
the present distraction paradigm suggest that RON reflects
neural processing related to attention reorienting following
distraction (Schröger and Wolff, 1998a,b; Schröger et al.,
2000). The RON/RONm findings thus suggest that the
modulation of dopamine transmission by haloperidol may
impair the switching of attention back to the relevant task
after distraction. However, haloperidol is known to bind
with high affinity to sigma receptors (Weisman et al.,
1988). Therefore it is possible that some of the observed
effects in dopamine D2-poor areas reflect direct binding at
non-dopaminergic sites.
The present study also indicated a significant reduction of
P3a amplitude by haloperidol. This ERP component, being
usually maximal over the central and frontal scalp areas, is
presumed to reflect attention switching to irrelevant tones
(Sams et al., 1985; Grillon et al., 1990, Woods, 1992; Escera
et al., 1998). It has been proposed that P3a has two main
sources: the source responsible for the early part of P3a
would be located in the superior temporal cortex (Alho et
al., 1998) and the later part would be generated in the prefrontal cortex (Baudena et al., 1996). In the present study,
haloperidol effects on P3a amplitude were, however, mainly
observed in the parietal areas. This suggests that haloperidol
Table 3
Dipole locations (x, y, z), strength (Q), goodness-of-fit (g), and number of subject modeled (N) of N1m and MMNm after haloperidol and placebo administrations
Variable Hemisphere
N1m
N1m
MMNm
MMNm
Contralateral
Ipsilateral
Contralateral
Ipsilateral
x (mm)
y (mm)
z (mm)
Q (nAm)
g (%)
Haloperidol Placebo
Haloperidol Placebo
Haloperidol Placebo
Haloperidol Placebo
Haloperidol Placebo
59 ^ 6
59 ^ 10
61 ^ 8
53 ^ 14
26 ^ 25
10 ^ 20
24 ^ 18
38 ^ 31
94
91
86
83
54 ^ 6
2 51 ^ 8
50 ^ 10
2 43 ^ 12
52 ^ 5 10 ^ 12
2 56 ^ 7 2 ^ 12
48 ^ 7 20 ^ 20
2 44 ^ 7 3 ^ 18
11 ^ 8
6 ^ 11
16 ^ 15
9 ^ 12
58 ^ 6
58 ^ 8
56 ^ 12
61 ^ 15
20 ^ 8
10 ^ 5
25 ^ 14
26 ^ 17
N
95
91
85
82
11/11
11/11
11/10
9/10
S. Kähkönen et al. / Clinical Neurophysiology 113 (2002) 1894–1902
1899
Fig. 2. Grand-averaged ERPs after haloperidol and placebo administration. Negativity is upward.
effects may have been mediated by other than frontal or
supratemporal P3a sources, localized at the parietal, parahippocampal, and anterior cingulate regions by intracranial
recordings (Alain et al., 1989; Baudena et al., 1996; Halgren
et al., 1995; Kropotov et al., 1995).
Finally, no significant haloperidol effects were observed
1900
S. Kähkönen et al. / Clinical Neurophysiology 113 (2002) 1894–1902
Fig. 3. Grand-averaged substraction waveforms after haloperidol and placebo administration. Negativity is upward.
in MMN/MMNm, which is surprising in the light of our
earlier findings (Kähkönen et al., 2001a). This discrepancy
may, however, be caused by the fact that, the stimulation
and task parameters were different. No effects were indicated in N1/N1m responses generated mainly near the
primary auditory cortices (Hari et al., 1980), which basically
S. Kähkönen et al. / Clinical Neurophysiology 113 (2002) 1894–1902
1901
Table 4
N1, MMN, P3a, and RON indices following haloperidol and placebo administration a
ERP deflection
N1
N1
N1
N1
MMN
MMN
MMN
MMN
P3a
P3a
P3a
P3a
RON
RON
RON
RON
a
Electrode
Fz
FCz
Cz
Pz
Fz
FCz
Cz
Pz
Fz
FCz
Cz
Pz
Fz
FCz
Cz
Pz
Amplitude (mV)
Latency (ms)
Haloperidol
Placebo
Haloperidol
Placebo
22.6 ^ 1.4
22.9 ^ 1.7
23.0 ^ 1.9
22.8 ^ 1.9
22.7 ^ 1.2
22.7 ^ 1.8
22.4 ^ 2.0
22.1 ^ 2.3
3.7 ^ 1.8
4.3 ^ 2.2
4.1 ^ 2.5
3.2 ^ 2.1
20.2 ^ 1.8
20.3 ^ 1.9
20.7 ^ 2.6
21.0 ^ 3.2
22.7 ^ 1.2
23.0 ^ 1.4
23.2 ^ 1.6
22.8 ^ 1.4
22.6 ^ 1.0
22.5 ^ 1.2
21.8 ^ 1.3
21.5 ^ 1.6
3.9 ^ 1.7
4.8 ^ 2.2
5.3 ^ 2.4
4.9 ^ 2.2**
20.6 ^ 2.4
20.9 ^ 2.9*
20.6 ^ 2.9**
20.6 ^ 3.0
106 ^ 19
100 ^ 7
155 ^ 26
152 ^ 33
317 ^ 76
311 ^ 38
522 ^ 56
488 ^ 48
Paired t test between haloperidol and placebo conditions; *P , 0:05, **P , 0:01.
supports earlier observations that the role of the central
dopamine system is not crucial in the early auditory-cortical
stimulus processing (e.g. Kähkönen et al., 2001b).
PET studies have shown that haloperidol alters metabolic
activity in subcortical and cortical areas. Barlett et al. (1994)
showed with PET that 5 mg of haloperidol reduces glucose
utilization in frontal, occipital, and anterior cingulate cortex,
whereas the effect is the opposite in the putamen and cerebellum. They suggested that haloperidol produces the effects
in the striatum and other D2-rich areas. This could lead to
increased inhibition of the thalamus through increased activity in GABA projections to globus pallidus and thalamus.
Reduced activity from the thalamus could contribute to
reduced neocortical activity. Notably, these brain regions
that indicate the most profound metabolic changes by haloperidol are also suggested to be crucial for attention and
executive cognitive functions. Tentatively, the present
reductions in P3a and RON/RONm, suggesting impairments
in neural processes underlying involuntary attention shifting
and reorienting, may thus be mediated by haloperidol effects
on the above-mentioned neuronal networks connecting the
basal ganglia and pre-frontal brain regions.
In conclusion, our combined MEG and EEG results,
demonstrating haloperidol-induced modulation of auditory
evoked responses, suggest that dopamine modulates involuntary attention shifting and reorienting. The findings might
also be associated with deficits observed in psychiatric and
neurological disorders with dopamine abnormalities.
Acknowledgements
This work was supported by Helsinki University Central
Hospital Research Funds and the Academy of Finland. We
thank Mrs Suvi Heikkilä and Mr Teemu Peltonen for their
excellent technical assistance.
References
Ahlfors S, Ilmoniemi RJ. Magnetometer position indicator for multichannel
MEG. In: Williamson SJ, Hoke M, Romani GL, editors. Advances in
biomagnetism, New York, NY: Plenum Press, 1989. pp. 673–676.
Ahonen AI, Hämäläinen MS, Kajola MJ, Knuutila JE, Laine PP, Lounasmaa OV, Parkkonen LT, Simola JT, Tesche CD. 122-channel SQUID
instrument for investigating the magnetic signals from the human brain.
Physica Scripta 1993;T49:198–205.
Ahveninen J, Jääskeläinen IP, Pekkonen E, Hallberg A, Hietanen M, Näätänen R, Schröger E, Sillanaukee P. Increased distractibility by task-irrelevant sound changes in abstinent alcoholics. Alcohol Clin Exp Res
2000a;24:1850–1854.
Ahveninen J, Kähkönen S, Tiitinen H, Pekkonen E, Huttunen J, Ilmoniemi
RJ, Jääskeläinen IP. Suppression of transient 40-Hz auditory response
by haloperidol suggests modulation of human selective attention by
dopamine D2 receptors. Neurosci Lett 2000b;292:29–32.
Ahveninen J, Kähkönen S, Pennanen S, Liesivuori J, Ilmoniemi RJ, Jääskeläinen IP. EEG and MEG measurements after tryptophan depletion
suggest serotonergic modulation of auditory involuntary attention.
Neuroimage 2002;16:1052–1061.
Alain C, Richer F, Achim A, Saint Hilaire JM. Human intracerebral potentials associated with target, novel, and omitted auditory stimuli. Brain
Topogr 1989;1:237–245.
Alho K, Winkler I, Escera C, Huotilainen M, Virtanen J, Jääskeläinen IP,
Pekkonen E, Ilmoniemi RJ. Processing of novel sounds and frequency
changes in the human auditory cortex: magnetoencephalographic
recordings. Psychophysiology 1998;35:211–224.
Barlett EJ, Brodie JD, Simkowitz P, Dewey SL, Rusinek H, Wolf A, Fowler
JS, Volkow ND, Smith G, Wolkin A, Cancro R. Effects of haloperidol
challenge on regional cerebral glucose utilization in normal human
subjects. Am J Psychiatry 1994;151:681–686.
Baudena P, Halgren E, Heit G, Clarke JM. Intracerebral potentials to rare
target and distractor auditory and visual stimuli. III. Frontal cortex.
Electroenceph clin Neurophysiol 1996;94:251–264.
Coull JT. Neural correlates of attention and arousal: insights from electro-
1902
S. Kähkönen et al. / Clinical Neurophysiology 113 (2002) 1894–1902
physiology, functional neuroimaging and psychopharmacology. Prog
Neurobiol 1998;55:343–361.
Davidson M, Davis KL. A comparison of plasma homovanillic acid
concentrations in schizophrenic patients and normal controls. Arch
Gen Psychiatry 1988;45:561–563.
Davidson M, Giordani AB, Mohs RC, Horvath TB, Davis BM, Powchik P,
Davis KL. Short-term haloperidol administration acutely elevates
human plasma homovanillic acid concentrations. Arch Gen Psychiatry
1987;44:189–190.
Escera C, Alho K, Winkler I, Näätänen R. Neural mechanisms of involuntary attention to acoustic novelty and change. J Cogn Neurosci
1998;10:590–604.
Grillon C, Courchesne E, Ameli R, Geyer MA, Braff DL. Increased
distractibility in schizophrenic patients. Electrophysiologic and behavioral evidence. Arch Gen Psychiatry 1990;47:171–179.
Halgren E, Baudena P, Clarke JM, Heit G, Marinkovic K, Devaux B,
Vignal JP, Biraben A. Intracerebral potentials to rare target and distractor auditory and visual stimuli. II. Medial, lateral and posterior temporal
lobe. Electroenceph clin Neurophysiol 1995;94:229–250.
Hämäläinen M, Hari R, Ilmoniemi RJ, Knuutila J, Lounasmaa OV. Magnetoencephalography – theory, instrumentation, and applications to
noninvasive studies of the working human brain. Rev Mod Phys
1993;65:413–497.
Hari R, Lounasmaa OV. Recording and interpretation of cerebral magnetic
fields. Science 1989;244:432–436.
Hari R, Aittoniemi K, Järvinen ML, Katila T, Varpula T. Auditory evoked
transient and sustained magnetic fields of the human brain. Localization
of neural generators. Exp Brain Res 1980;40:237–240.
Jääskeläinen IP, Schröger E, Näätänen R. Electrophysiological indices of
acute effects of ethanol on involuntary attention shifting. Psychopharmacology 1999;141:16–21.
Kähkönen S, Ahveninen J, Jääskeläinen IP, Kaakkola S, Näätänen R,
Huttunen J, Pekkonen E. Effects of haloperidol on selective attention:
a combined whole-head MEG and high-resolution EEG study. Neuropsychopharmacology 2001a;25:498–504.
Kähkönen S, Ahveninen J, Pekkonen E, Kaakkola S, Huttunen J, Peltonen
T, Ilmoniemi RJ, Jääskeläinen IP. Early cortical auditory processing
appears to be independent of dopamine D2 receptor modulation as
measured by whole-head magnetoencephalography. Psychiatry Res
Neuroimaging 2001b;107:117–123.
King DJ. Psychomotor impairment and cognitive disturbances induced by
neuroleptics. Acta Psychol Scand 1994;380:53–58.
Kropotov JD, Näätänen R, Sevostianov AV, Alho K, Reinikainen K,
Kropotova OV. Mismatch negativity to auditory stimulus change
recorded directly from the human temporal cortex. Psychophysiology
1995;32:418–422.
Leigh TJ, Link CGG, Fell GL. Effects of granisetron and haloperidol, alone
and in combination, on psychometric performance and the EEG. Br J
Clin Pharmacol 1992;34:65–70.
Lidsky TI, Banerjee SP. Acute administration of haloperidol enhances
dopaminergic transmission. J Pharmacol Exp Ther 1993;265:1193–
1198.
Magliozzi JR, Doran AR, Gietzen DW, Olson AM, Maclin EL, Tuason VB.
Effects of single dose haloperidol administration on plasma homovanillic acid levels in normal subjects. Psychiatry Res 1993;47:141–149.
McClelland GR, Cooper SM, Pilgrim AJ. A comparison of the central
nervous system effects of haloperidol, chlopromazine and sulpride in
normal volunteers. Br J Clin Pharmacol 1990;30:795–803.
Michie PT, Budd TW, Todd J, Rock D, Wichmann H, Box J, Jablensky AV.
Duration and frequency mismatch negativity in schizophrenia. Clin
Neurophysiolol 2000;111:1054–1065.
Näätänen R, Ilmoniemi R, Alho K. Magnetoencephalography in studies of
human cognitive brain function. Trends Neurosci 1994;17:389–395.
Pekkonen E, Huotilainen M, Virtanen J, Sinkkonen J, Rinne T, Ilmoniemi
RJ, Näätänen R. Age-related functional differences between auditory
cortices: a whole-head MEG study. NeuroReport 1995;6:1803–1806.
Sams M, Paavilainen P, Alho K, Näätänen R. Auditory frequency discrimination and event-related potentials. Electroenceph clin Neurophysiol
1985;62:437–448.
Schröger E, Wolff C. Attentional orienting and reorienting is indicated by
human event-related brain potentials. NeuroReport 1998a;9:3355–
3358.
Schröger E, Wolff C. Behavioral and electrophysiological effects of taskirrelevant sound change: a new distraction paradigm. Cogn Brain Res
1998b;7:71–87.
Schröger E, Giard MH, Wolff C. Auditory distraction: event-related potential and behavioral indices. Clin Neurophysiol 2000;111:1450–1460.
Shelley AM, Ward P, Catts SV, Michie PT, Andrews S, McConaghy N.
Mismatch negativity: an index of a preattentive deficit in schizophrenia.
Biol psychiatry 1991;30:1059–1062.
Sokolov EN. The neural mechanisms of the orienting reflex. In: Sokolov
EN, Vinogradova OS, editors. Neuronal mechanisms of the orienting
reflex, Hillsdale, NJ: Erlbaum, 1975. pp. 217–338.
Vieregge P, Verleger R, Wascher E, Stuven F, Kompf D. Auditory selective
attention is impaired in Parkinson’s disease – event-related evidence
from EEG potentials. Brain Res Cogn Brain Res 1994;2:117–129.
Virtanen J, Rinne T, Ilmoniemi RJ, Näätänen R. MEG-compatible multichannel EEG electrode array. Electroenceph clin Neurophysiol
1996;99:568–570.
Virtanen J, Parkkonen L, Ilmoniemi RJ, Pekkonen E, Näätänen R. Biopotential amplifier for simultaneous operation with biomagnetic instruments. Med Biol Eng Comput 1997;35:402–408.
Weisman AD, Su TP, Hedreen JC, London ED. Sigma receptors in postmortem human brains. J Pharmacol Exp Ther 1988;247:29–33.
Woods DL. Auditory selective attention in middle-aged and elderly
subjects: an event-related brain potential study. Electroenceph clin
Neurophysiol 1992;84:456–468.