P300 and contingent negative variation in migraine

Abstract

We reviewed P300 and contingent negative variation (CNV) studies performed in migraine in order to identify their relevance in migraine and the role of neurophysiology in migraine. Publications available to us were completed by a Medline search. There is experimental and clinical evidence for loss of cognitive habituation in migraine which may serve as a specific diagnostic tool; therefore, we reviewed studies on migraine that analyzed habituation and lack of habituation by P300 and CNV, performing short-term habituation (STH) and long-term habituation (LTH). Finally, we described the two components of P300 (a and b) and of CNV (early and late wave) and the two abnormalities reported from the majority of studies on event-related potential in migraine: increased amplitude of average event-related potential and lack of habituation. These abnormalities are especially related to the early component characterizing orienting activity.

J Headache Pain (2004) 5:S51S58

DOI 10.1007/s10194-004-0108-3Michele Feleppa

Walter Di Iorio

Donato M.T. SaracinoP300 and contingent negative variation in

migraineReceived: Accepted in revised form: M. Feleppa () W. Di Iorio

Department of Neuroscience,

Hospital G. Rummo,

Via dellAngelo, I-82100 Benevento, Italy

e-mail: [email protected]

Tel.: [phone]/57465

Fax: [phone]D.M.T. SaracinoDepartment of Medical Up-Grading,

Hospital G. Rummo, Benevento, ItalyAbstract We reviewed P300 and

contingent negative variation

(CNV) studies performed in

migraine in order to identify their

relevance in migraine and the role

of neurophysiology in migraine.

Publications available to us were

completed by a Medline search.

There is experimental and clinical

evidence for loss of cognitive habituation in migraine which may serve

as a specific diagnostic tool; therefore, we reviewed studies on

migraine that analyzed habituation

and lack of habituation by P300 and

CNV, performing short-term habituation (STH) and long-term habituation (LTH). Finally, we described

the two components of P300 (a andb) and of CNV (early and late

wave) and the two abnormalities

reported from the majority of studies on event-related potential in

migraine: increased amplitude of

average event-related potential and

lack of habituation. These abnormalities are especially related to the

early component characterizing orienting activity.Key words Migraine P300 CNV

HabituationThe event-related potential (ERP) component P300 is considered a cognitive neuroelectrical indicator of central

nervous system activity [1] involved with the processing

of new information when attention is engaged to update

memory representations [2]. P300 latency can be regarded

as a measure of the relative timing of the stimulus evaluation process, indicating an upper limit on categorization

and stimulus evaluation time [3], or the time taken to allocate resources and engage memory updating [4]. P300

amplitude is held to index attentional resource allocation

when memory updating is engaged [2]. The P300 component in many event-related brain potential (ERP) studies is

obtained using the so-called odd-ball paradigm, in which

two stimuli are presented in random order, with one occurring more frequently than the other [5]. The subject is

required to discriminate the infrequent or rare stimulus

(target stimulus) from the frequent or standard stimulus

(nontarget) by noting the occurrence of the target typically by pressing a button or mental counting [6, 7]. A

modification of the oddball paradigm has been developed

in which infrequent-nontarget stimuli are inserted into the

sequence of target and standard stimuli. When novel

stimuli (e.g., dog barks, color forms, etc.) are presented as

the infrequent nontargets in the series of more typical

targets and standard stimuli (e.g., tones, letters of the

alphabet, etc.), a P300 component that is large over the

frontal/central areas is produced. This component has

been dubbed the P3a, whereas the infrequent-target

stimulus elicits a parietal maximum P300 or P3b [8, 9].

Because this novel P300 exhibits an anterior/central scalp

distribution, short peak latency, and rapid habituation, it

has been interpreted as reflecting frontal lobe functionS52[10, 11]. In the 1960s, electrophysiologists described a

slow negative wave, called the contingent negative variation (CNV), that can be recorded on the brain cortical surface between two defined and contingent external stimuli[12]. The first stimulus serves as a warning (S1); it

announces an imperative stimulus (S2) which can be

directly acted upon by pressing a key. When the interval

between S1 and S2 is longer than 2 s, two CNV components can be distinguished: (1) an early component,

which has its greatest amplitude between 550 and 750 ms

after S1, and (2) a late component, which shows a maximum amplitude in the 200 ms preceding S2. The negativity is not seen in the raw EEG and can only be detected

with averaging [13]. The CNV amplitude is associated

with expectation, attention, preparation, motivation, and

readiness [12, 14, 15]. The expectation of stimuli can

selectively reduce brain activation [16], while the anticipatory state itself may be associated with increased blood

flow in the anterior cingulated cortex [17]. The early component is observed predominantly frontally and related to

the attention to stimulus; the late component has a more

central distribution and is associated with motor readiness[18]. The late CNV may consist of motor preparation and

stimulus preceding negativity, or SPN [19]. There is evidence for multiple sources of CNV [20]. The anterior cingulated gyrus, caudate nucleus, thalamus, and reticular

formation may be critical for the generation of the early

phase of CNV, and the dorsolateral prefrontal cortex may

be involved in the generation of the late phase [21]. The

early CNV may also originate in the frontal lobes [22].

The frontal cortex is known to be a crucial structure for

working memory, as confirmed in functional magnetic

resonance imaging, positron emission tomography (PET)

imaging, and direct neuronal recordings, and it may be

functionally specialized [23]. Loveless and Sanford [24]

called the two components of the CNV O-wave (or orienting wave following the warning signal) and E-wave

(or expectancy wave anticipating the imperative signal) in

order to denote their hypothesized functional significance.

According to Rohrbaugh et al. [25], the early CNV

observed in S1S2 paradigms with long interstimulus

intervals (3 s or more) is identical to the negative afterwave or slow negative wave (SNW) elicited by unpaired

stimuli. Both early CNV and SNW are sensitive to task

requirements enhancing the signal value of the stimuli[26]. For example, very much in the way the early CNV

responds to the signal value of the warning stimulus, the

amplitude of the SNW increases when a simple counting

task is imposed or discrimination of various stimuli is

required [27]. The increase seems to depend on the difficulty of the task [28]. The extent, however, to which these

waves may be held to be a manifestation of orienting

activity is, according to Rohrbaugh and Gaillard [29], an

important but largely unexplored problem. At least two

O-wave components were described [24, 27, 28]. The first

component peaking at about 500 ms or a little later is followed by a second broadly distributed wave. While the

first is negative at frontal scalp sites (slow negative wave

1, SNW1) and usually positive parietally (slow positive

wave, SPW), the later component of the O-wave (SNW2)

is uniformly negative at all sites, but tends to be strong

predominantly at frontal or central sites. Results of more

recent investigations suggest that the anterior negative

and the posterior positive aspects of the O-wave are independent and can be dissociated [10, 24]. Support for

assumptions relating the O-wave to orienting activity

comes from different lines of evidence. First, it is suggested by the bilateral distribution of the O-wave.

Particularly the late, SNW2, component appears to be

more pronounced over the right hemisphere [27]. This laterality agrees with hypotheses linking orienting and attention with functions of the right hemisphere [30].

Furthermore, the anterior-posterior gradient of the O-

wave is in accordance with neuropsychological and neurophysiological literature relating the frontal cortex to

attentional processes incorporated in orienting [31]. Also,

the effects of different experimental manipulations on

elicitation and magnitude of the O-wave seem to confirm

its relationship to orienting and attention [27]. The amplitude of the O-wave, for example, appears to depend on

manipulations affecting task relevance and stimulus significance [24, 27, 29]. In healthy subjects, the amplitude of evoked cortical

responses normally decreases with repetitive presentation

of a stimulus. This phenomenon is commonly referred to

as habituation [32], and one of its metabolic advantages

could be protection against overexcitation and lactate

accumulation in sensory cortices [33].Migraine patients, unlike healthy control subjects,

show a dissimilar electrophysiological behavior, as shown

for visual-evoked potentials (VEPs), which fail to habituate to repeated stimuli and sometimes even potentiate [34,35]. This also holds true for ERPs [36]. It has been

hypothesized that the simultaneous occurrence of this

deficit of habituation and a reduced mitochondrial energy

reserve might lead to the activation of the trigeminovascular system, culminating in the migraine attack [37].

Extensive research on EP habituation described two main

kinds of physiological phenomena: short-term habituation

(STH) and long-term habituation (LTH) [38]. The STH

occurs when individual stimuli are repeated at short interstimulus intervals and is often attributed to a refractory

period [39] or sensory gating [40]. It has been proposed

that, if the stimuli are presented in pairs, the first stimulus

activates excitatory inputs that cause a neuronal response

as well as inhibitory pathways that induce a suppressionS53of neuronal activity on the following stimulus. These

processes result in STH [41]. This form of habituation is

independent of stimulus intensity, psychological characteristics of the stimulus, and attentional demands, and is

possibly under strong genetic control [4042]. In particular, the STH of the P50 (P1), a positive peak occurring

about 4090 ms after stimulus onset, has been intensively

investigated because of its relevance in a number of psychiatric and neurological disorders [40, 42, 43]. The LTH

occurs across blocks of stimuli lasting minutes and is

often explained with the dual-process theory of

Thompson and Spencer [32] or the comparator theory of

Sokolov [44]. It has been suggested that the habituation of

a neuronal response occurs when the external events of

the environment and the internal neural model are

matched and no longer produce an orienting response of

attentional focus [32, 39, 44, 45]. This habituation

depends on the intensity, psychological significance of the

stimulus, and attentional resources [38, 39, 45, 46]. The

LTH was investigated most often for the P300 wave in the

odd-ball paradigm and requires allocation of attentional

resources [43, 47]. In summary, the STH is more probably

related to the preattentive screening out of irrelevant stimuli [3941], while the LTH is attributed to the attentive

processes of the orienting response [32, 43, 44, 47]. Migraine patients are also distinguished by a higher

dependence of their auditory-evoked cortical responses on

stimulus intensity than healthy volunteers [48, 49]. This

increased intensity dependence of auditory potentials

(IDAP) is, like sensitization, only detectable interictally[50]. The middle latency auditory potentials are complex

neuronal phenomena that depend on thalamo-cortico-thalamic activities and various state-setting subcortico-cortical

pathways; there is, nonetheless, indirect evidence that IDAP

is inversely correlated with central serotonergic transmission [51]. If deficient, the latter may lead to a decreased cortical preactivation level and possibly be the basis for the

observed lack of habituation in migraineurs [52].It has been hypothesized hat the strong IDAP found in

migraineurs might be due to a deficit of habituation to

high-intensity stimuli [53], and thus these two distinct

phenomena may in fact be expressions of the same dysfunction in habituation. Migraine patients are characterized as having attacks caused by a deficit of habituation,

or even potentiation, of cortical-evoked and ERPs.

Another interictal electrophysiological abnormality found

in migraineurs is a marked dependence on the intensity of

auditory-evoked cortical potentials. In contrast to habituation which is measured during repetition of a stimulus at

the same intensity, IDAP is obtained after stimulations of

increasing intensities. These two electrophysiological

phenomena are thought to reflect different aspects of cortical information processing, and their impairment in

migraine may be directly or indirectly related to decreased

activity in the state-setting monoaminergic projections to

the sensory cortices [54]. Habituation, i.e., amplitude

reduction of a cortical response to a sustained stimulus of

equal intensity, is considered to reflect an adaptive cortical mechanism protecting from sensory overstimulation[55] and lactate accumulation [33]. In the Aplysia gillwithdrawal reflex, habituation is controlled by serotonergic neurons [56]. Although habituation of long latency

cortical-evoked responses in the human brain is likely to

have more complex underlying molecular mechanisms,

there are some arguments suggesting that it might be

inversely related to serotonin activity. Evers et al. [57]

have shown in migraineurs that habituation, assessed by a

latency increase of the event-related visual P300 response,

varies inversely with platelet serotonin content; in particular, it arguments, i.e., normalizes, during the attack in

parallel with a decrease in platelet serotonin.

Normalization of amplitude habituation during the attack

was also found for VEPs [58] and CNV [59]. In a recent

study, Siniatchkin et al. [43] demonstrate that migraine

patients are characterized by two kinds of habituation

deficits compared with healthy subjects: (a) the sensory

gating deficit or reduced STH of the P50 wave, independent of attentional demands to the stimulation, and (b) the

LTH of the P300 wave under circumstances of increased

cortical processing and enhanced mobilization of attentional resources. These habituation deficits represent

abnormalities of different levels of information processing

in migraine. The reduced P50 STH possibly represents the

impairment of an early stage of the automatic screening

out of stimuli, whereas the P300 LTH deficit results from

disturbed cognitive processing. According to the authors,

how the STH and LTH are related, and which mechanisms

underlie these abnormalities, needs to be investigated in

further studies.The majority of studies on evoked and event-related

potentials in migraine have shown two abnormalities:

increased amplitudes of averages of large numbers of trials and lack of habituation in successive trial blocks [60].

At first sight, increased amplitudes of cortical-evoked

responses would favor the hypothesis of cortical hyperexcitability in migraine between attacks [61]. However, it is

useful to remember that evoked responses are averaged

over a large number of stimulations and that for low numbers of trials amplitudes were lower, not higher, than in

healthy volunteers [60]. The suggestion has been made

therefore that the increase of EP amplitude found in some

studies was not due to cortical hyperexcitability, but merely to the lack of habituation of the responses during sustained stimulation [34]. In the strict physiological sense,

hyperexcitability indeed indicates that the threshold to

obtain a response is decreased and/or that a greaterS54response is induced by a given suprathreshold stimulus[54]. Although habituation is a complex neurobiological

phenomenon, it might uniquely depend, for corticalevoked activation, on the preactivation excitability level.

According to the ceiling theory [62], which is most

often applied to explain the occurrence of an augmenting or reducing response to increasing stimulation

intensities, a low preactivation level of sensory cortices

allows a wider range of suprathreshold activation before

reaching the ceiling and initiating a reducing response,i.e., habituation. This theory, applied to EP findings in

migraineurs, would explain both the low first-block

amplitude for most EPs and the lack of habituation on trial

repetition [54]. There is evidence that the preactivation

level of cortical excitability depends on the so-called

state-setting, chemically addressed connections that originate in the brain stem and involve serotonin and noradrenaline as transmitters [63, 64]. Low interictal activity

of these systems, especially of the raphe-cortical serotoninergic pathway, could indeed be responsible for the

observed electrophysiological abnormalities in

migraineurs [65]. If this hypothesis is correct, one would

expect that decreasing cortical activation would produce

lack of habituation in healthy volunteers, and vice versa,

that increasing activation in migraineurs would normalize

their habituation patterns [54]. This was indeed recently

demonstrated by using repetitive transcranial magnetic

stimulation (rTMS). High-frequency rTMS of the occipital cortex, known to activate the underlying cortex, was

followed by a normalization of VEP habituation in

migraineurs, while low-frequency rTMS, which has an

inhibitory effect, induced a VEP habituation deficit in normal control subjects [66]. The precise relationship

between interictal abnormal cortical information processing and migraine pathogenesis remains to be determined.

The possibility that dysfunctional monoaminergic nuclei

in the brain stem may play a causative role in migraine

attacks [67], and may be responsible independently for

interictal lack of habituation of evoked potentials as an

epiphenomenon, cannot be excluded. We know that cortical habituation is also a protective mechanism against

overstimulation [33] and that the mitochondrial phosphorylation potential as studied by magnetic resonance spectroscopy is reduced interictally in the brain of migraineurs

[6870]. Lack of habituation may favor, under certain circumstances, a metabolic disequilibrium, which would

lead to activation of the major pain-signaling system of

the brain, the trigeminovascular system [71]. The ictal

normalization of EP amplitudes and habituation suggests

that there is, in close temporal proximity to the migraine

attack, an increase in the cortical preactivation level,

probably due to enhanced activity in raphe-cortical serotoninergic pathways [54]. Interestingly, the ictal normalization of visual-evoked P3 habituation is accompanied by

a decrease in platelet serotonin content [57], and two PET

studies have shown brain stem activation during the

migraine attack [67, 72]. According to the biobehavioral

theory of migraine [73], this ictal normalization of electrophysiological findings could be part of a homeostatic

process. Various studies have demonstrated a more negative bCNV in patients with migraine during foreperiods

that are shorter than 2 s [74]. Studies employing longer

foreperiods predominantly report a higher early wave

amplitude in migraine without aura [7577], but higher

late wave amplitudes have also been reported [75]. The

higher CNV amplitudes are believed to emerge as a result

of the slow habituations over trials [74, 76, 78]. Research

in cortical electrophysiology such as that embracing the

thalamic gating model [77] or the threshold regulation

theory [79] has linked the CNV to cortical negative brain

potentials, such as the CNV, reflecting the task-related

tuning of cortical areas. The threshold regulation theory

postulates that preparation is achieved by lowering neuronal firing thresholds in the appropriate cortical neuronal

networks and by selectively increasing cortical excitability. This is ultimately reflected in an enhanced negativity

in these particular cortical areas. In agreement with these

ideas, migraine researchers have generally attributed these

CNV findings to a hyperactivity of central catecholaminergic systems [80, 81]. High catecholaminergic activity is

thought to induce a state of cortical hyperexcitability and

arousal that presents normal habituation [82]. The early

wave increases even more during the days before an attack

but decreases to the level of healthy control subjects during the attack [82]. Along with this normalization of CNV

early wave amplitude, the impaired habituation also

resolves during the attack [77]. In the 23 days following

the attack, the CNV remains at this normal level after

which it gradually deteriorates again [83]. This normalization during an attack has been suggested to be related

to the depletion of noradrenaline activity combined with

an increased serotoninergic transmission [84]. During the

postattack period, Mulder et al. [82] demonstrated lower

CNV early and late wave amplitudes over the frontal cortex in migraineurs without aura compared with control

subjects, suggesting postattack hypoexcitability of the

frontal cortex. Concordant studies from different laboratories have shown that CNV amplitude is increased in

migraineurs between attacks, mainly in those suffering

from migraine without aura [75, 76, 78, 85, 86]. This

increase was more pronounced for the early component in

comparison with healthy volunteers or tension-type

headache patients [76], which can be interpreted as disturbed attention and possibly reflect an excess of excitatory versus inhibitory processes. When taking into account

age as a variable [87], decrease in early CNV amplitudeS55with aging was found in healthy volunteers but not in

migraineurs, which the authors interpreted as a disturbance of cerebral maturation. Disease duration also had an

effect on CNV abnormalities in migraineurs [88]. A strong

familial influence on CNV parameters was reported by

Siniatchkin et al. [89], who found abnormalities not only

in migraineurs but also in healthy subjects with a positive

family history for migraine [90]. The sensitivity of CNV

to different prophylactic agents used in migraine and the

relative specificity of the difference between headache

forms suggest that CNV is a useful method for studying

headaches [91]. Siniatchkin et al. [92] found differences

in habituation of the early component of CNV in migraine

and chronic daily headache (CDH); however, in the latter,

these differences have been related to lower baseline

amplitudes, and the authors conclude that CNV may be

considered a predictive variable for transformed migraine.

According to Aurora [93], depression may also have

played a role in the CNV difference in CDH, and also

comorbidity (i.e., depression and analgesic overuse) may

alter CNV.Studies of the P300 component of the classic odd-ball

paradigm of ERPs in migraine gave conflicting results. A

reduced P300 amplitude and a prolonged latency were

found when an auditory stimulus was used [94, 95], except

in one study [96]. In a paradigm with visual stimuli, however, there were no differences in P300 amplitude, but prolonged P300 latency in migraine without aura [36, 57, 97].

In the passive odd-ball paradigm, latency and amplitude of

the P3a component, which reflects automatic processing

of a novel stimulus, were on average normal interictally in migraine [98].References1. Regan D (1989) Human brain electrophysiology. Evoked potentials and

evoked magnetic fields in science and

medicine. Elsevier, New York2. Polich J (1996) Meta-analysis of P300

normative aging studies.

Psychophysiology 33:3343533. Coles MGH, Smid HGOM, Scheffers

MK, Otten LJ (1995) Mental chronometry and the study of human information processing. In: Rugg MD, Coles

MGH (eds) Electrophysiology of mind.

Oxford University Press, New York, pp

861314. Fjell AM, Walhovd KB (2001) P300

and Neuropsychological tests as measures of aging: scalp topography and

cognitive changes. Brain Topogr

14:25405. Demiralp T, Ademoglu A, Comerchero

M, Polich J (2001) Wavelet analysis of

P3a and P3b. Brain Topogr 13:252676. Picton TW (1992) The P300 wave of

the human event-related potential. J

Clin Neurophysiol 9:4564797. Polich J (1999) P300 in clinical applications: meaning, methods and measurements. In: Niedermeyer E, Lopes

da Silva FH (eds)

Electroencephalography: basic principles, clinical applications, and related

fields. William & Wilkins, Baltimore,

pp 107910918. Courchesne E, Hillyard SA, Galambos

R (1975) Stimulus novelty, task relevance and the visual evoked potential

in man. Electroencephalogr Clin

Neurophysiol 39:1311439. Squires N, Squires K, Hillyard S

(1975) Two varieties of long-latency

positive waves evoked by unpredictable auditory stimuli in man.

Electroencephalogr Clin Neurophysiol

38:38740110. Friedman D, Simpson GV (1994) ERP

amplitude and scalp distribution to target and novel events: effects of temporal order in young, middle-aged and

older adults. Cog Brain Res 2:496311. Knight R (1996) Contribution of

human hippocampal region to novelty

detection. Nature 383:25625912. Walter WG, Cooper R, Aldrige VJ,

McCallum WC, Winter AL (1964)

Contingent negative variation: an electric sign of sensory-motor association

and expectancy in the human brain.

Nature 203:38038413. Kropp P, Gerber WD (1995)

Contingent negative variation during

migraine attack and interval: evidence

for normalization of slow cortical

potentials during the attack.

Cephalalgia 15:12312814. Rizzo PA, Amabile G, Caporali M,

Spadaro M, Zanasi M, Morocuti CA

(1978) CNV study in a group of

patients with traumatic head injuries.

Electroencephalogr Clin Neurophysiol

45:28115. Rockstroh B, Elbert T, Birbaumer N,

Lutzenberger W (1982) Slow brain

potentials and behavior. Urban &

Schwarzenberg, Munich16. Drevets WC, Burton H, Videen TO,

Snyder AZ, Simpson JR, Raichle ME

(1995) Blood flow changes in human

somatosensory cortex during anticipated stimulation. Nature 373:24925217. Murtha S, Chertkow H, Beauregard M,

Dixon R, Evans A (1996) Anticipation

caused increased blood flow to the

anterior cingulated cortex. Hum Brain

Mapp 4:10311218. Mnatsakanian EV, Tarkka IM (2002)

Task-specific expectation is revealed in

scalp recorded slow potentials. Brain

Topogr 15:879419. Brunia CH (1988) Movement and stimulus preceding negativity. Biol Psychol

26:16517820. Hamano T, Luder HO, Ikeda A,

Coldura TF, Comair YG, Shibasaki H

(1997) The cortical generators of the

contingent negative variations in

humans: a study with subdural electrodes. Electroencephalogr Clin

Neurophysiol 104:257268S5621. Rosahl SK, Knight RT (1995) Role of

prefrontal cortex in generation of the

CNV. Cereb Cortex 2:12312422. Cui RQ, Egkher A, Huter D, Lang W,

Lindinger G, Deecke L (2000) High

resolution spatiotemporal analysis of

the contingent negative variation in

simple or complex motor tasks and a

non motor task. Clin Neurophysiol

111:1847185923. Fletcher PC, Henson RNA (2001)

Frontal lobes and human memory.

Insights from functional neuroimaging.

Brain 124:84988124. Loveless NE, Sanford AJ (1974)

Effects of age on the contingent negative variation and preparatory set in a

reaction-time task. J Gerontol

29:526325. Rohrbaugh JW, Syndulko K, Lindsley

DB (1976) Brain wave components of

the contingent negative variation in

humans. Science 191:1055105726. Zimmer H, Demmel R (2000)

Habituation and laterality of orienting

processes as reflected by slow negative

waves. Biol Psych 53:1617627. Rohrbaugh JW (1984) The orienting

reflex: performance and central nervous system manifestations. In:

Parasuraman R, Davies R (eds)

Varieties of attention. Academic Press,

Orlando, Fl, pp 32337328. Rohrbaugh JW, Syndulko K, Lindsley

DB (1978) Cortical slow negative

waves following non-paired stimuli:

effects of task factors.

Electroencephalogr Clin Neurophysiol

45:55156729. Rorbaugh JW, Gaillard AWK (1983)

Sensory and motor aspects of the contingent negative variation. In: Gaillard

AWK, Ritter W (eds) Tutorials in

Event related potential research:

endogenous components. North-

Holland Publishing, Amsterdam, pp

26931030. Heilman KM, Van den Abell T (1980)

Right hemisphere dominance for attention: the mechanism underlying hemispheric asymmetrics of inattention

(neglect). Neurology 30:32733031. Giard M-H, Perrin F, Pernier J,

Bouchet P (1990) Brain generators

implicated in the processing of auditory stimulus deviance: a topographic

event related potential study.

Psychophysiol 27:62764032. Thompson R, Spencer WA (1966)

Habituation. A model phenomenon for

the study of neuronal substrates of

behaviour. Psychol Rev 22:164333. Sappey-Marinier D, Galabrese G, Fein

G, Hugg JW, Biggins C, Weiner MW

(1992) Effect of photic stimulation on

human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood F

Met 22:58459234. Schoenen J, Wang W, Albert A,

Delwaide PJ (1995) Potentiation

instead of habituation characterizes

visual evoked potentials in migraine

patients between attacks. Eur J Neurol

22:11512235. Afra J, Cecchini AP, De Pasqua V,

Albert A, Schoenen J (1998) Visual

evoked potentials during long periods

of pattern-reversal stimulation in

migraine. Brain 121:23324136. Evers S, Bauer B, Suhr B, Husstedt

IW, Grotemeyer KH (1997) Cognitive

processing in primary headache: a

study on event-related potentials.

Neurology 48:10811337. Schoenen J (1996) Deficient habituation of evoked cortical potentials in

migraine: a link between brain biology,

behavior and trigeminovascular activation. Biomed Pharmacother 22:717838. Woods DL, Elmasian R (1986) The

habituation of event-related potentials

to speech sounds and tones.

Electroencephal Clin Neurophysiol

65:44745939. Roemer RA, Shagass C, Teyler TJ

(1984) Do human evoked potentials

habituate? In: Peeke HV, Petrinovich L

(eds) Habituation, sensitization, and

behaviour. Academic Press, New York,

pp 32534640. Adler LE, Freedman R, Ross RG,

Olincy A, Waldo MC (1999)

Elementary phenotypes in the neurobiological and genetic study of schizophrenia. Biol Psych 46:81841. Freedman R, Waldo M, Bickford-

Wimer P, Nagamoto H (1991)

Elementary neuronal dysfunction in

schizophrenia. Schizophr Res

4:23324342. Schwarzkopf SB, Lamberti S, Smith

DA (1993) Concurrent assessment of

acoustic startle and auditory P50

evoked potential measures of sensory

inhibition. Biol Psych 33:8152843. Siniatchkin M, Kropp P, Gerber W-D

(2003) What kind of habituation is

impaired in migraine patients?

Cephalalgia 23:51151844. Sokolov E (1963) Perception and the

conditioned reflex. Pergamon, Oxford45. Loveless N (1983) The orienting

response and evoked potentials in man.

In: Siddle D (ed) Orienting and habituation: perspectives in human research.

John Wiley, New York, pp 7110846. Woods DL, Elmasian R (1986) The

habituation of event-related potentials

to speech sounds and tones.

Electroencephal Clin Neurophysiol

65:44745947. Polich J, McIsaac HK (1994)

Comparison of auditory P300 habituation from active and passive conditions. Int J Psychophysiol 17:253448. Wang W, Timsit-Berthier M, Schoenen

J (1996) Intensity dependence of auditory evoked potentials is pronounced in

migraine: an indication of cortical

potentiation and low serotoninergic

neurotransmission. Neurology

22:1404140949. Siniatchkin M, Kropp P, Neumann M,

Gerber W, Stephani U (2000) Intensity

dependence of auditory evoked cortical

potentials in migraine families. Pain

22:2475450. fra J, Sandor PS, Schoenen J (2000)

Habituation of visual and intensity

dependence of auditory evoked cortical

potentials tends to normalize just

before and during the migraine attack.

Cephalalgia 22:71471951. Hegerl U, Juckel G (1993) Intensity

dependence of auditory evoked potentials as an indicator of central serotoninergic neurotransmission: a new

hypothesis. Biol Psychiatry

22:17318752. Schoenen J (1996) Deficient habituation of evoked cortical potentials in

migraine: a link between brain biology,

behavior and trigeminovascular activation. Biomed Pharmacother 22:717853. Wang W, Timsit-Berthier M, Schoenen

J (1996) Intensity dependence of auditory evoked potentials is pronounced in

migraine: an indication of cortical

potentiation and low serotonergic neurotransmission. Neurology

22:14041409S5754. Ambrosini A, Rossi P, De Pasqua V,

Pierelli F, Schoenen J (2003) Lack of

habituation causes high intensity

dependence of auditory evoked cortical

potentials in migraine. Brain

126:2009201555. Thompson RF, Berry SD, Rinaldi PC,

Berger TW (1979) Habituation and orienting reflex: the dual-process theory

revised. In: Kimmel HD, van Olst EH,

Orlebeke JF (eds) The orienting reflex

in humans. Lawrence Erlbaum,

Hillsdale, NJ, pp 216056. Kandel ER (1991) Cellular mechanisms of learning and biological basis

of individuality. In: Kandel ER,

Schwartz JH, Jessell TM (eds)

Principles of neural science, 3rd edn.

Elsevier, New York, pp 1009103157. Evers S, Quibeldey F, Grotemeyer KH,

Suhr B, Husstedt IW (1999) Dynamic

changes of cognitive habituation and

serotonin metabolism during the

migraine interval. Cephalalgia

19:4859158. Judit A, Sndor P, Schoenen J (2000)

Habituation of visual and intensity

dependence of auditory evoked cortical

potentials tends to normalize just

before and during the migraine attack.

Echolalia 20:71471959. Kropp P, Gerber WD (1995)

Contingent negative variation during

migraine attack and interval: evidence

for normalization of slow cortical

potentials during the attack.

Cephalalgia 15:123860. Ambrosini A, de Noordhout A, Sndor

PS, Schoenen J (2003)

Electrophysiological studies in

migraine: a comprehensive review of

their interest and limitations.

Cephalalgia 23:133161. Welch KMA, DAndrea G, Tepley N,

Barkley G, Ramadan NM (1990) The

concept of migraine as a state of central neuronal hyperexcitability. Neurol

Clin 8:81782862. Knott JR, Irwin DA (1973) Anxiety,

stress and the contingent negative variation. Arch Gen Psychiatry

29:53854163. Hegerl U, Juckel G (1993) Intensity

dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis. Biol Psychiatry 33:17318764. Mesulam MM (1990) Large-scale neurocognitive networks and distributed

processing for attention, language and

memory. Ann Neurol 28:59761365. Schoenen J (1996) Abnormal cortical

information processing between

migraine attacks. In: Sandler M,

Ferrari M, Harnett S (eds) Migraine

pharmacology and genetics. Altman,

London, pp 23325366. Bohotin V, Fumal A, Vandenheede M,

Grard P, Bohotin C, Maertens de

Noordhout A et al (2002) Effects of

repetitive transcranial magnetic stimulation on visual evoked potentials in

migraine. Brain 125:11167. Weiller C, May A, Limmroth V, Juptner

M, Kaube H, Schayck RV et al (1995)

Brain stem activation in spontaneous

migraine attacks. Nature Med 1:65866068. Welch KMA, Levine SR, DAndrea G,

Schultz L, Helpern JA (1989)

Preliminary observations on brain

energy metabolism in migraine studied

by in vivo 31-phosphorus NMR spectroscopy. Neurology 39:53854169. Barbiroli B, Montagna P, Cortelli P,

Funicello R, Iotti S et al (1992)

Abnormal brain and muscle energy

metabolism shown by 31P magnetic

resonance spectroscopy in patients

affected by migraine with aura.

Neurology 42:1209121470. Montagna P, Cortelli P, Monari L,

Pierangeli G, Parchi P et al (1994)

31P-Magnetic resonance spectroscopy

in migraine without aura. Neurology

44:66666871. Schoenen J (1994) Pathogenesis of

migraine: the biobehavioural and

hypoxia theories reconciled. Acta

Neurol Belg 94:798672. Sndor PS, Dydak U, Schoenen J,

Crelier G, Kollias S et al (2000)

Functional magnetic resonance spectroscopic imaging (fMRSI) shows cortical lactate changes during prolonged

visual stimulation in migraine with

aura: the metabolic equivalent of electrophysiological dyshabituation?

Cephalalgia 20:27773. Welch KMA (1986) Migraine: a biobehavioural disorder. Cephalalgia

[Suppl. 4]:10311074. Schoenen J, Maertens de Noordhout A,

Timsit-Berthier M, Timsit M (1986)

Contingent negative variation and efficacy of beta-blocking agents in

migraine. Cephalalgia 6:22923375. Bcker KB, Timsit-Berthier M,

Schoenen J, Brunia CH (1990)

Contingent negative variation in

migraine. Headache 30:60460976. Kropp P, Gerber WD (1993) Is

increased amplitude of contingent negative variation in migraine due to cortical hyperactivity or to reduced habituation? Cephalalgia 13:374177. Kropp P, Gerber WD (1995)

Contingent negative variation during

migraine attack and interval: evidence

for normalization of slow cortical

potentials during the attack.

Cephalalgia 15:12312878. Maertens de Noordhout A, Timsit-

Berthier M, Timsit M, Schoenen J

(1986) Contingent negative variation in

headache. Ann Neurol 19:788079. Rockstroh B, Elbert T, Canavan A,

LutzenbergerW, Birbaumer N (1989)

Slow cortical potentials and behavior.

Urban & Schwarzenberg, Baltimore80. Timsit-Berthier M, Mantanus H,

Poncelet M, Marissiaux P, Legros JJ

(1986) Contingent negative variation as

a new method to assess the catecholaminergic systems. In: Gallai V

(ed) Maturation of the CNS and evoked

potentials. Elsevier, New York, pp

26026881. Nagel-Leiby S, Welch KM, Dandrea

G, Grunfeld S, Brown E (1990) Eventrelated slow potentials and associated

catecholamine function in migraine.

Cephalalgia 10:31732982. Mulder EJCM, Linssen WHJP,

Passchier J, de Geus EJC (2001)

Interictal and postictal contingent negative variation in migraine without aura.

Headache 41:727883. Kropp P, Gerber WD (1998) Prediction

of migraine attacks using a slow cortical potential, the contingent negative

variation. Neurosci Lett 257:737684. Gerber WD, Schoenen J (1998)

Biobehavioral correlates in migraine:

the role of hypersensitivity and information-processing dysfunction.

Cephalalgia 18[Suppl 21]:51185. Schoenen J, Maertens A, Timsit-

Berthier, Timsit M (1985) Contingent

negative variation (CNV) as a diagnostic and physiopathologic tool in

headache patients. In: Rose FC (ed)

Migraine. Clinical and research

advances. Karger, Basel, pp 1725S5886. Schoenen J, Timsit-Berthier M, Timsit

M (1985) Correlations between contingent negative variation and plasma levels of catecholamines in headache

patients. Cephalalgia 5 [Suppl 1]:48087. Kropp P, Kirbach U, Detlefsen JO,

Siniatchkin M, Gerber WD, Stephani

U (1999) Slow cortical potentials in

migraine: a comparison of adults and

children. Cephalalgia 19[Suppl25]:606488. Kropp P, Siniatchkin M, Gerber WD

(2000) Contingent negative variation

as indicator of duration of migraine

disease. Funct Neurol 15[Suppl3]:788189. Siniatchkin M, Kirsch E, Kropp P,

Stephani U, Gerber WD (2000) Slow

cortical potentials in migraine families.

Cephalalgia 20:88189290. Siniatchkin M, Kropp P, Gerber WD

(2001) Contingent negative variation

in subjects at risk for migraine without

aura. Pain 94:15916791. Maertens de Noordhout A, Timsit-

Berthier M, Timsit M, Schoenen J

(1987) Effects of beta blockade on

contingent negative variation in

migraine. Ann Neurol 21:1111292. Siniatchkin M, Gerber W-D, Kropp P,

Vein A (1998) Contingent negative

variation in patients with chronic daily

headache. Cephalalgia 18:56556993. Aurora SK (1998) CNV in CDH.

Editorial commentary. Cephalalgia

18:53194. Drake ME, Pakalnis A, Padamadan H

(1989) Long-latency auditory event

related potentials in migraine.

Headache 29:23924195. Wang W, Schoenen J, Timsit-Berthier

M (1995). Cognitive functions in

migraine without aura between attacks:

a psychophysiological approach using

the oddball paradigm. Neurophysiol

Clin 25:31196. Mazzotta G, Alberti A, Cantucci A,

Gallai V (1995) The event-related

potential P300 during headache-free

period and spontaneous attack in adult

headache sufferers. Headache

35:21021597. Evers S, Bauer B, Grotemeyer KH,

Kurlemann G, Husstedt IW (1998)

Event-related potentials (P300) in primary headache in childhood and adolescence. J Child Neurol 13:32232698. Wang W, Schoenen J (1998) Interictal

potentiation of passive oddball auditory event-related potentials in

migraine. Cephalalgia 18:261265