I~Q. N-Psyf~hrumocd. bBld. Pq/chIat 1897. Vol. 21. pp.

761-771
Co&t 0 1997 Ehevkr .daux Inc.
Prlntcdinthcush Anrlghtar4!amd
027~6846/97 $32.00 + .CQ

ELSEVIER W 9027~5946(9~00077-8
THE TRANSIENT 40-Hz RESPONSE, MISMATCH NEGATIVITY, AND
ATTENTIONAL PROCESSES IN HUMANS
HANNUTIITINEN', PATRICK MAY' and RISTO N##T#NEN'

'Cognitive Brain Research Unit, Department of Psychology,

University of Helsinki, Finland
and
*Department of Mathematics, King's College London, London, UK

(Final form, February 1997)

Contents

Abstract
1. Introduction
2. Selective Attention and the Transient 40-Hz Response
3. Sustained Attention and the Transient 40-Hz Response
4. Stimulus Feature Detection and the Transient 40-Hz Response
5. Memory, Attention and Mismatch Negativity
6. Discussion
6.1. The 40-Hz Response and Attention
6.2. Mismatch Negativity and Attentive Processes
6.3. Stimulus Feature Detection and Integration
6.4. Clinical Applicability of the Responses
7. Conclusions
Acknowledgements
References

Abstract

Tiitinen, Hannu, Patrick May and Risto Naatanen: The Transient 40-Hz
Response, Mismatch Negativity, and Attentional Processes in Humans.
Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1997, =~1,.751_771.
(B1997E&vierscicrMXInc.

1. Recent experimental studies on the neurophysiological basis of

auditory selective attention and sensory memory forming the sensory-
data basis for tuning the selective-attention system in humans are
reviewed.
2. The results demonstrate that the transient 40-Hz response is
enhanced by selective attention, attenuated in the course of
long-term stimulation, but is not affected by changes in auditory
stimuli.

751
752 H. Tiitinen et al

3. Therefore, the 40-Hz response seems to be closely related to

selective and sustained attention, whereas it does not seem to be
associated with passive attention, as it does not reflect the
detection of changes in auditory stimuli.
4. Changes in auditory stimulation are registered by pre-attentive
sensory memory, indexed by the mismatch negativity (MMN), a change-
specific component of the event-related potentials (ERPs). By this
time, the transient 40-Hz response has already terminated. The
magnitude of stimulus change is reflected in MMN latency. These
latency changes predict changes in attentive reaction time (RT).
5. Thus, the pre-attentive memory mechanism seems to govern attentive
detection of changes in the auditory environment.
6. It is concluded that the transient 40-Hz response is related to
active attention and MMN is related to passive attention.

Keywords: attention, auditory, 40-Hz response, mismatch negativity,

sensory memory.

Abbreviations: electroencephalography (EEG), equivalent current dipole

(ECD), event-related potential (BRP), magnetoencephalography (MEG),
mismatch negativity (MMN), reaction time (RT).

1. Introduction

Selective attention refers to the ability to choose information from

a potentially vast amount of stimulus sources. Although it is an
obvious and essential capability, selective attention has remained
poorly understood. The question of the fate of the unattended
information, i.e., to what extent information is processed
independently of attentional involvement, has been central in theories
of selective attention (Broadbent 1958, Deutsch and Deutsch 1963,
Kahneman and Treisman 1984, Naatanen 1992). A closely related question
is that of the extent to which memory mechanisms serve, or are related
to, attentional mechanisms (Naatanen 1990). Some insight into these
topics is offered by recent advances in cognitive neuroscience,
especially in studies of the oscillatory gamma-band activity and of
mismatch negativity (MMN; Naatanen et al. 1978), an index of the
auditory sensory memory.

Oscillatory activity in the brain has recently received considerable

attention, and is thought to play an integral part in neural
 40-I-b x&match negativity. and attentional processes
response. 753

information processing. However, little agreement has been reached on

the specific role of this activity. Gamma-band activity has been
suggested to reflect early processing of stimulus information (Galambos
et al. 1981, Pantev et al. 1991), stimulus feature integration
("binding"; Eckhorn et al. 1988, Gray et al. 1989, Engel et al. 1992)
and cognition (Bressler 1990, Llinds and Pare 1991, Llinds and Ribary
1993).

Also, a relationship of 40-Hz activity to attention (Spydell et al.

1979, Sheer 1989, Murthy and Fetz 1992), arousal and motivation
(Kristeva-Feige et al. 1993), and alertness (Rougeul et al. 1979) has
been suggested. Evidence militating against the 40-Hz activity being
related to attention has also been obtained (Linden et al. 1987).
Generalizations about 40-Hz activity are hard to make, not only because
of this plethora of interpretations (at least partly attributable to
variations in experimental methodologies and setups), but also because
of fundamental differences between the human and animal 40-Hz responses
(Galambos 1992).

The transient 40-Hz response might, however, reflect the operation

of an attention-triggering mechanism, as has been suggested of the Nl
and MMN components (Naatanen 1992) of the human event-related
potentials (ERPs). According to this view, the role of the neural
mechanism underlying the transient 40-Hz response is merely to inform
of the occurrence of a stimulus event while being insensitive to
stimulus qualities (Naatanen 1992, Freeman 1992).

mN, elicited by changes in stimulus features such as frequency,

intensity, duration, spatial origin, phonemic and complex-tone
structure, has been suggested to reflect the operation of pre-attentive
sensory memory (N>inen1992), the earliest memory system in audition.
This memory system, resembling the "echoic" memory described by Neisser
(1967) builds traces of the acoustic environment against which new
stimuli can be compared (Naatanen 1992). Because MMN is elicited even
by stimuli which are not attended, it seems to provide a convenient and
754 H. Tfltinen et al.

easily obtainable physiological measure of the processing of the

unattended auditory sensory information. Besides indexing sensory
memory, MMN has also been suggested to be related to passive attention
by operating as an attention-triggering mechanism which sends an
interrupt signal to attentional mechanisms, thereby triggering a switch
of the attentional focus to stimulus change (Naatanen 1992).

Magnetoencephalographic (MEG) studies in humans suggest that MMNm

(the magnetic counterpart of MMN) arises from supratemporal auditory
cortex (Hari et al. 1984). The contribution of auditory-cortex activity
to MMN is also revealed by intracranial MMN recordings in humans
(Kropotov et al. 1995), cats (Csepe et al. 1987), and monkeys (Javitt
et al. 1992). In monkey, intracranial MMN recordings indicate that MMN
is associated with activation of pyramidal neurons in supragranular
laminae of auditory cortex (Javitt et al. 1995). This activation, as
well as the epidurally recorded MMN, were abolished by an injection of
a selective NMDA antagonist MK-801 (Javitt et al. 1995). These results
suggest that normal functioning of NMDA receptors is crucial for the
formation of the neural traces providing the informational basis for
the change detection process.

While it is relatively well established that the occurrence of MMN

is not affected by selective attention (see, however, Woldorff et al.
1991, Naatanen 1991, 1992), the dependence of selective attention on
pre-attentive sensory memory processes has remained elusive. Previous
studies (Sams et al. 1985, Lang et al. 1990, Novak et al. 1990, 1992,
Winkler et al. 1993) seem to suggest a relationship between MMN and
attentive processes. Furthermore, the evidence for MMN attenuation
during long-term stimulation (i.e., its relationship to sustained
attention; Parasuraman 1984) has remained inconclusive (Naatanen 1992).
Similarly, no experimental evidence exists for the 40-Hz oscillatory
activity reflecting sustained attention.

The present review tries to shed light on the physiological

foundations of selective and sustained attention via the results of
 40-I-b response. mismatch negativity, and attentional processes 755

four studies conducted in our laboratory. In this series of studies,

the behavior of the transient 40-Hz response and MMN were
systematically studied in the auditory domain in order to determine
their possible role in attentional processes. In the following, the
authors present their main findings.

2. Selective Attention and the Transient 40-Hz Response

The first experiment (Tiitinen et al. 1993) addressed the question

of whether the transient 40-Hz response reflects selective attention.
The 40-Hz activity was studied in a dichotic-listening paradigm in 8
subjects. The subject was instructed to attend to stimuli presented to
a designated ear and to press a response key every time he/she detected
an occasional deviant tone among the standard tones in that ear and to
ignore concurrent stimuli in the opposite ear. In a separate, control
condition, subjects were reading a book while the same auditory
stimulus sequences were presented. Thus, for identical stimuli,
responses were obtained when stimuli were attended, unattended (the
subject attended to stimuli in the opposite ear), or when the subject
was reading (the subject ignored all auditory stimuli).

Scalp-recorded 40-Hz responses were averaged and, as described

elsewhere (Sinkkonen et al. 1995), the averaged EEG was digitally
convoluted by a Gabor filter. This method provides a continuous measure
of frequency-specific amplitude over time, i.e., the amplitude envelope
of the oscillation around 40 Hz.

Figure 1 presents the grand-averaged 40-Hz responses. The 40-Hz

response peaked at around 25 ms from stimulus onset and lasted for
about 100 ms. Selective attention clearly affected the response.
Responses to attended stimuli were enhanced, especially in the frontal
sites, when compared with responses to unattended stimuli and to those
elicited while the subject was reading. This response, as well as the
attention effect, was most prominent at the frontal and central
electrodes (Fz, Cz) .
756 H. Tiltlnen et al.

Left Ear Stimuli Right Ear Stimuli

-0.25 Time (ms)

0 100 200

I -0.24 -0.25
0 100 200 0 100 200

Fig. 1. Selective attention enhances the auditory 40-Hz response. The

scalp distribution and the attention effect of the 40-Hz response.
Gabor-filtered grand-average 40-Hz responses measured from the scalp
at E'pz, Fz, and Cz to left- (1000 Hz) and right-ear (500 Hz) standard
stimuli when attended (thick line), when stimuli in the opposite ear
were attended (medium line), or when the subject was reading a book
(thin line). Stimulus onset at 0 ms. The power of a limited frequency
band cannot be measured without temporal spreading of the response that
gives rise to an apparent response before stimulus onset. (Data from
Tiitinen et al. 1993).

3. Sustained Attention and the Transient 40-Hz Response

The effect of long-term stimulation on the 40-Hz response was studied

in order to determine whether this response might reflect sustained
attention (May et al. 1994). Subjects (N=lO) were reading a book while
auditory stimuli consisting of standard and deviant tones were
presented to the left ear. The 5-hour experimental session were divided
into 4 subsessions separated from one another by lo-minute breaks.
Thus, the effect of long-term stimulation on the 40-Hz response and its
 response.mismatch
40-I-k negaWty.andattentionalprocesses 757

relationship to sustained attention could be determined. For the 40-Hz

responses, the EEG was digitally convoluted by a Gabor filter
(Sinkkonen et al. 1995). The Nl and MMN responses were also analyzed.

It was found that the very prominent 40-Hz response, peaking at about
30 ms from stimulus onset, significantly attenuated in amplitude at the
frontal (Fpz, Fz) electrodes during the experimental session (Fig. 2,
left column). Furthermore, there was a secondary peak in the response
at around 100 ms, which also attenuated in amplitude. Thus, it seems
that the transient 40-Hz response might reflect sustained attention.

Fig. 2. Long-term stimulation attenuates the transient 40-Hz response.

The 40-Hz (left column), Nl (middle column), and MMN (right column)
responses from electrodes Fpz, Fz, and Cz. Thick and thin lines
represent the responses from the first and last subsession, dashed and
dotted lines from the second and third subsession, respectively.
Stimulus onset at 0 ms. The 40-Hz responses were collapsed into two
classes in order to enhance the S/N ratio. Stimuli were presented via
earphones to the subject's left ear. Each block consisted of a random
sequence of standard (p=O.80) lOOO-Hz and deviant (p=O.20) 1200-Hz
tones (85 dB SPL, duration 55 ms, rise and fall times 5 ms each). The
IS1 was 1000 ms.(Data from May et al. 1994)
758 H.Tfltinen et a&

The Nl response amplitudes significantly attenuated during the 4

subsessions (Fig. 2, center column), whereas that of the MMN response
did not (Fig. 2, right column). As the 40-Hz responses, the responses
obtained in 4 subsessions were also collapsed into 2 classes and
reanalyzed. The outcome of the analyses remained the same.

4. Stimulus Feature Detection and the Transient 40-Hz Response

In the third experiment (Tiitinen et al. 1994a), the relation of the

40-Hz response to the suggested attention-triggering (NUtWen 1992)
and the memory-related processes creating the informational basis for
attention triggering was studied. Subjects (N=lO) were reading while
sequences of 1000 Hz standard tones randomly interspersed with deviant
1200 Hz tones were presented to the left ear. Thus, it was possible to
determine whether the 40-Hz response reflected the processing of
changes in stimulus features and was in this way associated with the
passive form of attention in audition. Gabor filtering (Sinkkonen et
al. 1995) was used.

In Fig. 3, the standard- and deviant-tone responses from Fz-electrode

are presented together with the scalp distribution of the 40-Hz
responses. Shortly after stimulus onset, there was prominent activity
peaking at around 30 ms from stimulus onset and lasting for about 100
ms, with the largest amplitudes observed in the frontal and central
electrodes.

This activity, however, was very similar for the standard and deviant
stimuli, there being no significant amplitude differences. Thus, the
transient 40-Hz response appears to be insensitive to changes in
stimulus features.

As Fig. 3 shows, no 40-Hz activity was elicited during the time MMN,
peaking at around 125 ms and lasting for about 150 ms, was observed.
 40-Hz response. mismatch negativity. and attentional processes 759

40-I& responses
Fz oz

0 LILIzI 1-
0 1002OOms
Event-related potentials
~p-q--q

Mismatch negativity

Fig. 3. The auditory 40-Hz response is insensitive to changes in

auditory stimulation. Top row: The 40-Hz responses elicited by standard
(thick line) and deviant (thin line) stimuli, middle row: the
respective ERPs, bottom row: the respective MMN responses. Stimulus
onset at 0 ms. The 40-Hz responses commenced at stimulus onset, and
were most prominent at the frontal and central electrodes. There were
no differences in the responses to standard and deviant stimuli,
indicating that the 40-Hz response is not associated with change
detection. (Data from Tiitinen et al. 1994a)

5. Memory, Attention, and Mismatch Negativity

In a subsequent experiment (Tiitinen et al. 1994b), 10 subjects were

presented with lOOO-Hz standard tones randomly interspersed with
deviant tones differing in frequency. The magnitude of frequency
deviance was varied from 5 to 320 Hz in eight steps. In the first part
of the experiment, MMN was measured while the subject was reading a
book and ignoring auditory stimuli. In the second part, the subject's
ability to detect changes in stimulation was tested. The subject was
instructed to attend to the same stimuli as those presented in the ERP
sessions and to respond to the deviating tones by pressing a response
780 H.TfltinenetaL

key. Thus, the deviant stimuli were subject to both pre-attentive and
attentive change detection.

The MMN responses measured from the frontal electrode Fz (a) and the
right mastoid (b) are presented in Fig. 4. The standard tones, depicted
in the inserts, elicited minute, invariant responses. The polarity
reversal of the nose-referenced MMN between the frontal and mastoid
electrodes suggested that the response originated in the vicinity of
the auditory cortex. This was confirmed by 122-channel whole-head MEG
(Knuutila et al. 1993) measurements, where the sources of the activity
for the 8 frequency deviations were found to be highly localized in an
area approximately 2 cm below the scalp and 3 cm above the preauricular
point (Tiitinen et al. 199413).

Fig. 4. MMN as a function of the magnitude of frequency deviation. MMN

from electrodes Fz (a) and the right mastoid (b) for deviance values
5 - 320 Hz. Stimulus blocks consisting of standard (1000 Hz, 65 dB SPL,
duration 60 ms, p=O.95) and deviant stimuli (p=O.O5) were presented in
random order through earphones to the subject's left ear. The frequency
of the deviant stimulus in a block was either 1005 (thin line), 1010,
1020, 1040, 1080, 1127, 1202, or 1320 (thick line) Hz. The IS1 was 200
ms. Stimulus onset at 0 ms. MMN was obtained by subtracting the
response to the standard tone from that to the corresponding deviant
tone. The MMN amplitude grew and its latency decreased with increasing
frequency deviance. The invariant responses to the standard tones
measured from the Fz and right-mastoid electrodes are depicted in the
inserts. (Data from Tiitinen et al. 199433)

Subjects were then tested for attentive processing of changes in the

auditory environment. Figure 5a shows that both the subject's reaction
time (RT) and the MMN peak latency monotonically decreased as a
 40-Hz response,mismatchnegativity.andattentionalprocesses 761

function of the magnitude of the frequency deviation. The RT changed

at the same rate as the MMN latency, the two measures correlating
highly with each other (Figs. 5a & 5b). The peak amplitude of MMN at
Fz linearly increased up to 3.5 uV as a function of the logarithm of
the frequency difference (see Fig. SC). MMN was most prominent in the
frontal and central scalp areas, and it was reliably elicited by
frequency differences at and above 2%. Also, the hit rate strongly
correlated with the MMN duration, which increased and reached a plateau
of 100 ms at around 4% frequency difference (Fig. 5d). The subject's
ability to detect changes in auditory stimuli, as reflected by the hit
rate, also improved until it reached a plateau at around 4% frequency
difference (Fig. 5e).

Deviance (Hz) Deviance (Hz) Deviance (Hz)

Fig. 5. Pre-attentive sensory memory governs attentive processing of

changes in auditory stimulation. The subject was presented with two
stimulus blocks per deviation (i.e., about 75 presentations per
deviation) and requested to respond quickly and accurately to deviant
tones by pressing a response key. In (a) both the behavioral RT and the
MMN peak latency monotonically decreased as a function of the magnitude
of change in tone frequency (the bars indicating the standard error of
the mean). In (b), the MMN peak latency has been subtracted from the
RT, demonstrating that the difference was constant. The MMN peak
amplitude (c) linearly increased as a function of the logarithm of the
magnitude of the frequency deviance (the bars indicate the standard
error of the mean). With increasing magnitude of deviation, both the
MMN duration from Fz (d) and the hit rate (e) increased until they
reached a plateau. The durations of the responses to 5- and lo-Hz
deviances are denoted by open circles, with the former arbitrarily
defined as zero. (Data from Tiitinen et al. 1994b)
762 H. Tlitinen et al.

6. Discussion

This series of experiments conducted in our laboratory demonstrate

that the transient 40-Hz response, occurring almost immediately after
stimulus onset, is related to both selective and, possibly, sustained
attention, but is insensitive to changes in stimulus features,
suggesting that this response is not related to passive attention. The
processing of changes becomes observable at about 100 ms from stimulus
onset, in the form of the MMN response. MMN is elicited without
accompanying 40-Hz activity. In the present studies we found that MMN,
suggested as reflecting change detection based on pre-attentive sensory
memory, governed attentive detection of changes in the auditory
environment. These findings will now be discussed in more detail.

6.1. The 40-Hz Response and Attention

The finding that the transient 40-Hz response is related to selective

and, possibly, sustained attention is somewhat surprising in the light
of the common assumption that early, stimulus-onset attention effects
in this frequency range do not exist (Regan 1989). The relationship to
selective attention was especially strong: this effect was reliably
observed even with single subjects. Further, because the unattended-
stimulus responses were of equal amplitudes to those obtained while the
subject was reading (Fig. 11, either the attentional mechanism
reflected by the 40-Hz response does not supress, for example, by
gating or filtering, the processing of unattended stimuli, or this
suppression extends beyond modality borders. Our findings relating the
transient 40-Hz response to attentional mechanisms seem to be
consistent with earlier observations applying different methods (single
cell measurements vs. mass action), subjects (animals vs. humans), and
stimulation (steady-state vs. transient; Rougeul et al. 1979, Spydell
et al. 1979, Sheer 1989, Murthy and Fetz 1992).

The evidence for the relationship of the 40-Hz response to sustained

attention was provided by the observation that this response attenuated
 40-Hzresponse.mismatch
negatfvity.andattentionalprocesses 763

during long-term stimulation. Attenuation was also evident for the

secondary peak, which possibly signifies a stimulus offset response.
The Nl amplitude was also found to attenuate. As this attenuation is
known to reflect a decrease in sustained attention (Parasuraman 1984),
the 40-Hz response might also be associated with sustained attention.
To demonstrate this conclusively, however, a simultaneous demonstration
both of this attenuation effect and a performance decrement in a
behavioral signal-detection task would be required.

6.2. Mismatch Negativity and Attentive Processes

The detection of changes in auditory stimuli was reflected in MMN,

after the 40-Hz oscillation had terminated. The fact that MMN was not
accompanied by the transient 40-Hz response implies that the proposed
attention-triggering function of MMN (NaBtanen 1992) does not
necessarily require the activation of the mechanism underlying the
40-Hz response. In addition, as the MMN amplitude did not show
systematic change during long-term stimulation, it does not seem to
reflect sustained attention.

The authors found that the MMN peak latency predicted the behavioral
RT extremely well. This result demonstrates how RT changes are mainly
governed by pre-attentive sensory memory processes, which therefore
seem to play a fundamental role in determining attentive discrimination
performance and the speed of the associated motor response in humans.
Changes in task difficulty (in this case, frequency difference) are
directly reflected as changes in sensory memory processing time, which
seem to be linearly transferred to perceptual, attentive, and motor
processes. This implies that the problem of change detection is tackled
already in the very early stage of processing which takes place in the
vicinity of the primary sensory cortices. Previous observations,
applying smaller frequency differences (Sams et al. 1985, Lang et al.
1990, Winkler et a1.1993) and a limited number of frequency steps
(Novak et al. 1990, 1992), give further support to this finding.
764 H.Tfltinen
etal.

Furthermore, both the MMN duration and the hit rate as a function of
the magnitude of frequency change rapidly reached a plateau. This
result might suggest that the temporal length of the neural signal
generated by the sensory-memory mechanism determines whether conscious
detection of stimulus change takes place. However, in low
discriminability conditions, the MMN levelled off slightly later,
implying that some other mechanism enhanced the hit rate (Sams et al.
1985).

MMN was reliably elicited by deviances at and above 28, and its
amplitude was directly proportional to the logarithm of the frequency
difference. Since this relationship between frequency difference and
the response amplitude parallels the well-known, behaviorally observed
relationship between sound frequency difference and the perceived pitch
difference (Stevens and Davis 1966), the perception of pitch
differences might be reflected in the physiological measure of the MMN
amplitude. Evidence for the proposed relationship, demonstrating that
objective stimulus frequency is transformed into subjective pitch
representation was, indeed, recently obtained (Winkler et al. 1995).

6.3. Stimulus Feature Detection and Integration

Gamma-band activity has been suggested to reflect binding, or

spatiotemporal feature integration (Eckhorn et al. 1988, Gray et al.
1989, Llinas and Pare 1991, Engel et al. 1992), whereby a stimulus,
which is a conjunction of separate features, is perceived as a coherent
whole. According to this view, the unitary nature of a stimulus is
signalled by the synchronization of gamma-band activity across the
separate areas activated by the separate stimulus features. As the EEG
measures the spatially averaged activity of neurons, an observed
increase in the oscillation amplitude can be caused, besides by an
increase in the oscillation amplitude of individual oscillators, by an
increase in the number of oscillators in synchrony. The latter could
be achieved by improving the synchronization of a fixed number of
assemblies always responding to a stimulus, by increasing the number
 40-Hz response, mtsmatch negattvity. and attentions1 processes 765

of permanently synchronous assemblies responding to a stimulus, or by

a combination of these two. In all these instances the observed
increase in oscillation ampiitude would be explained by the number of
assemblies in synchrony increasing. Provided that synchronization of
a neural assembly's oscillatory activity with that of others indicates
that the assembly's activity is being integrated with that of the
others, and that this integration leads to, or is equivalent to, the
building up of the stimulus representation, an observed increase in the
40-Hz oscillation amplitude would imply that more cell assemblies are
contributing to the stimulus representation. Thus, the present results
suggest that the effect of attention could be to increase the number
of cell assemblies contributing to the stimulus representation (without
necessarily changing the number of cells responding to the stimulus).
It seems then that already at stimulus onset, attentional mechanisms
contribute to the processing of the stimulus.

While this would contradict theories of attention relying purely on

the concept of late selection (Deutsch and Deutsch 1963), the early
increase in stimulus analysis brought about by selective attention
would seem to have little effect on automatic processes such as MMN,
whose underlying change detection mechanism is able to operate with or
without attention. Therefore attention would not seem to affect the
temporal integration of the output of feature detectors necessary for
the formation of the kinds of auditory environment representations that
the elicitation of MMN would seem to require. This reliance of MMN on
temporal integration (as opposed to spatiotemporal integration, as has
been suggested of gamma-band activity) lasting roughly 200 ms, is
suggested by experiments where MMN was obtained to changes in temporal
stimulus features, such as when a series of tone pairs was followed by
a reversed tone pair (Tervaniemi et al. 1994), and even in more
'abstract' stimulus features, such as when the only constant feature
in stimulation against which a change occurred was that the tones were
either 'rising' or 'falling' stimulus sequences (Paavilainen et al.
1995).

The authors found no evidence that the 40-Hz response reflects

766 H.Tit&en et al.

differential processing, or detection of changes in stimulus features,

as does the MMN. On the contrary, it seems that the 40-Hz response was
insensitive to stimulus features and to the temporal context of the
stimulus, as indicated by the responses to standard and deviant stimuli
being identical. The mechanism underlying the 40-Hz response therefore
does not seem to be affected by the memory trace of past stimulation
upon which the MMN relies. Rather, the transient 40-Hz response seems
to reflect a neuronal level detection of stimulus occurrence without
reflecting the processing of stimulus context.

There are also interesting findings demonstrating that as the IS1

between two closely presented stimuli is increased beyond 12-15 ms, two
separate stimulus events are consciously perceived and two separate 40-
Hz responses are obtained (Joliot et al. 1994). Contrasting this
observation with the MMN results on temporal integration of auditory
stimulus events (Tervaniemi et al. 1994, Paavilainen et al. 1995), it
seems that while auditory stimuli are segregated on a rapid lo-ms
timescale, separate stimuli are also being integrated within a time
window of about 200 ms.

6.4. Clinical Applicability of the Responses

On several occasions, it has been discussed that changes in the

amplitude, as well as the presence/absence of the 40-Hz transient and
steady state responses could be used for diagnostic purposes (Ribary
et al. 1989, Llinas and Pare 1991, Engel et al. 1992, Plourde 1993).
As the attentional enhancement of the transient 40-Hz response was
reliably observed even at the single-subject level (Tiitinen et al.
1993), it might serve as a diagnostic tool for studying attentional
disorders in clinical groups such as schizophrenics and patients with
Alzheimer's disease.

The most convincing case for the clinical applicability of MMN are
studies of coma patients, where MMN was found to be an effective
predictor of recovery from coma (Kane et al. 1993). Also, there are
 40-Hz response.mismatchnegatM~.andattentionalprccesses 767

data showing that MMN amplitude is attenuated in patients with

Alzheimer's disease (Verleger et al. 1992, Pekkonen et al. 1994) and
schizophrenia (Shelley et al. 1991, Javitt et al. 1995). Experiments
are currently proceeding along several lines in order to further
determine to what extent these brain responses can be applied for
diagnostic and prognostic purposes.

7. Conclusions

The amplitude changes in the transient 40-Hz response reflect

selective attention and, possibly, sustained attention. Changes in
attentive reaction times can be predicted by non-invasively measuring
the latency of mismatch negativity (MMN). A highly useful task of
future research would be to relate these non-invasive mass-action level
observations to invasive measurements.

Acknowledgements

The support of the Academy of Finland, the Emil Aaltonen Foundation,

and the British Council is gratefully acknowledged.

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