Placebo analgesia is not due to compliance or habituation: EEG and behavioural evidence

This study was designed to resolve whether experimental placebo responses are due to either increased compliance or habituation. We stimulated both forearms and recorded laser-evoked potentials from 18 healthy volunteers treated on one arm with a sham analgesic cream and an inactive cream on the other (treatment group), and 13 volunteers with an inactive cream on both arms (controls). The treatment group showed a significant reduction in the pain ratings and laser-evoked potentials with both the sham and inactive creams. The control group showed no evidence of habituation to the laser stimulus. The results indicate that the reduction in pain during experimental placebo response is unlikely to be due to sensory habituation or compliance with the experimental instructions.     

The anterior N1 component as an index of modality shifting

Processing of a given target is facilitated when it is defined within the same (e.g., visual-visual), compared to a different (e.g., tactile-visual), perceptual modality as on the previous trial [Spence, C., Nicholls, M., & Driver, J. The cost of expecting events in the wrong sensory modality. Perception & Psychophysics, 63, 330-336, 2001]. The present study was designed to identify electrocortical (EEG) correlates underlying this "modality shift effect." Participants had to discriminate (via foot pedal responses) the modality of the target stimulus, visual versus tactile (Experiment 1), or respond based on the target-defining features (Experiment 2). Thus, modality changes were associated with response changes in Experiment 1, but dissociated in Experiment 2. Both experiments confirmed previous behavioral findings with slower discrimination times for modality change, relative to repetition, trials. Independently of the target-defining modality, spatial stimulus characteristics, and the motor response, this effect was mirrored by enhanced amplitudes of the anterior N1 component. These findings are explained in terms of a generalized "modality-weighting" account, which extends the "dimension-weighting" account proposed by Found and Müller [Searching for unknown feature targets on more than one dimension: Investigating a "dimension-weighting" account. Perception & Psychophysics, 58, 88-101, 1996] for the visual modality. On this account, the anterior N1 enhancement is assumed to reflect the detection of a modality change and initiation of the readjustment of attentional weight-setting from the old to the new target-defining modality in order to optimize target detection.     

Cingulate cortex activation and competing responses: the role of preparedness for competition

Regional cerebral blood flow (rCBF) was studied in a task, where a preparatory stimulus (S1) cued for an imperative second stimulus (S2) which was associated with a response. Two preparatory stimuli cued unequivocally each for one response. In contrast, a third preparatory stimulus cued for two response alternatives which appeared for the same ratio (each in 50% of all trials) introducing response competition. In a first experimental condition, non-arbitrary, unambiguous stimuli were used as S1 to enable the subjects to prepare their responses. In a second and third scan, arbitrary preparatory stimuli were used during different stages of awareness for the S1-S2 association. Subjects performed this task "naive" without knowledge about the S1-S2 association and also in an experimental condition being aware of the S1-S2 association. Button presses after unambiguous, non-arbitrary preparatory stimuli activated the right middle frontal gyrus and inferior parietal lobe if S1 was associated with a definite response. When the subjects did not know the S1-S2 relation, left prefrontal cortex activation was associated with trials including definite responses. Performing the same S1-S2 response condition after subjects knew their relation right prefrontal and left parietal areas became additionally engaged. However, in the first experimental condition using unambiguous, non-arbitrary stimuli and in the third, "aware" experimental condition when S1 was coupled with two response alternatives, the anterior cingulate cortex was activated. As these experimental conditions have in common, that the preparatory stimulus shares information about the upcoming competing response alternatives they highlight the evaluative role of the anterior cingulate cortex for competing actions.     

Median nerve somatosensory evoked potentials in migraine

In visual evoked potential studies, habituation during stimulus repetition with the same stimulus at a constant intensity has been found to be abnormal in migraineurs between attacks. The purpose of this study was to investigate habituation of somatosensory evoked potentials (SEPs) and the effects of migraine on them. Eighty-five subjects were included in the study: 30 healthy volunteers (HVs) and 55 migraineurs [30 with migraine without aura (MO), 25 with migraine with aura (MA)]. During continuous stimulation at 3 Hz, four blocks of 100 responses were sequentially averaged of Erb's point (N9), cervical (N13), and cortical (N20) median nerve SEPs. Mean amplitude changes in the second, third and fourth blocks are expressed as percentages of the first block. There was habituation to N13 and N20 in the second, third and fourth blocks in HVs. In the migraine groups, there was no habituation; on the contrary, potentiation was found. This potentiation was statistically significant only in the second blocks for N13 (MO P=0.007, MA P=0.01 versus HVs). However, in both migraineur groups, the rate of N20 potentiations was statistically significant versus that in HVs for all blocks (all P < 0.05). It is concluded that whilst physiological habituation occurs in HVs for cervical and cortical SEPs, in migraine patients there is an interictal deficit of habituation of this sensory modality.     

Dynamics of narrow-band EEG phase effects in the passive auditory oddball task

Evidence suggests that the component frequencies of the electroencephalogram (EEG) are dynamically adjusted to provide particular brain states at stimulus occurrence, and that these facilitate cortical processing of the stimulus. We examined relationships between stimulus intensity, the phase of narrow-band EEG activity at stimulus onset, and the resultant event-related potentials (ERPs) in a passive auditory oddball task, using a novel conceptualization of orthogonal phase effects (cortical negativity vs. positivity, negative driving vs. positive driving, waxing vs. waning). EEG responses to the standard stimuli (50 vs. 80 dB, varied between subjects) were analysed. Prestimulus narrow-band EEG activity (in 1-Hz bands from 1 to 13 Hz) at Cz was assessed for each trial by digital filtering. For each frequency, the cycle at stimulus onset was used to sort trials into four phases, for which ERPs were derived from both the filtered and unfiltered EEG activity at Fz, Cz and Pz. Preferred brain states at various frequencies were indicated by 16-34% differential occurrence within the orthogonal phase dimensions explored. The preferred states were associated with smaller N1, N2 and N3, larger P2 and P3, shorter N1, P2, N2 and P3 latencies, and some intensity effects. These effects reflected the operation of three separate phase-influenced mechanisms, involving anticipatory potentials and prestimulus/poststimulus amplitudes in various EEG frequencies. Results indicate that, even in paradigms with a slightly varying interstimulus interval, brain dynamics provide preferred brain states at the moment of stimulus presentation, which differentially affect the EEG correlates of stimulus processing.     

Effects of selective attention on the late components of evoked potentials in man.

Vertex and specific evoked potentials to visual and cutaneous stimuli were recorded in 6 subjects. The delivery of roughly equal numbers of flashes and shocks was paced by the subjects themselves. They also had to choose which stimulus they would be given next; 9 times out of 10 the stimulus matched the subject's expectation and stimuli from the unexpected modality were given randomly 1 time out of 10 on the average. No task was required after the stimulus occurrence. Cortical evoked potentials (CEPs) to unexpected stimuli were averaged and compared with CEPs the major difference consisted in large N2 and P3 waves in response to unexpected stimuli; no difference was observed in the amplitude of the N1 wave. In specific CEPs unexpected stimuli also elicited N2 and P3 waves; in addition N1 showed a slight tendency to be higher in CEPs to unexpected stimuli,     

Lack of habituation of nociceptive evoked responses and pain sensitivity during migraine attack.

OBJECTIVE: The aim of the present study was to investigate the habituation of subjective pain sensation to CO(2) laser stimulus, in relation to the amplitude modifications of the cortical evoked responses (LEPs), during both the migraine attack and the not symptomatic phase. METHODS: Fourteen migraine patients were selected and compared with 10 healthy controls. Eight patients were evaluated during both the pain-free and the attack phases. Three following series of 20 averaged LEPs were recorded, stimulating the hands and the supraorbital zones: during the attack, two consecutive series of 20 averaged LEPs were carried out. The subjective sensation was requested for each laser stimulus, using a 0-10 points Verbal Rating Scale (VRS). RESULTS: In normal subjects the N2-P2 waves amplitude showed habituation across the three repetitions, which correlated with the habituation of the subjective rating of the stimulus. During the not symptomatic phase, patients showed a lack of habituation of the N2-P2 amplitude when the hand and the face was stimulated, with a pattern of increase of the pain rating across the three repetitions; in addition there was a lack of correlation between the LEPs amplitude and the subjective sensation. During the attack, the LEPs amplitude and the pain rating were increased when the face was stimulated, but they did not habituate across the two repetitions, likely the pain-free condition. The percent LEPs amplitude variation across the three repetitions correlated with the main indices of migraine severity, mainly when the supraorbital zone was stimulated. CONCLUSIONS: The abnormal cortical excitability in migraine could condition an anomalous behavior of nociceptive cortex during the interictal phase of migraine: it persists during the acute phase, and correlates with the frequency and duration of migraine. SIGNIFICANCE: The reduced habituation of the nociceptive cortex may concur with the onset and evolution of headache.     

Modulation of P2 auditory-evoked responses by the spectral complexity of musical sounds

We investigated whether N1 and P2 auditory-evoked responses are modulated by the spectral complexity of musical sounds in pianists and non-musicians. Study participants were presented with three variants of a C4 piano tone equated for temporal envelope but differing in the number of harmonics contained in the stimulus. A fourth tone was a pure tone matched to the fundamental frequency of the piano tones. A simultaneous electroencephalographic/magnetoencephalographic recording was made. P2 amplitude was larger in musicians and increased with spectral complexity preferentially in this group, but N1 did not. The results suggest that P2 reflects the specific features of acoustic stimuli experienced during musical practice and point to functional differences in P2 and N1 that relate to their underlying mechanisms.     

Contribution of attentional and cognitive factors to laser evoked brain potentialsModulation attentionnelle et cognitive des réponses évoquées par laser

Painful stimuli delivered by infrared laser stimulators elicit laser-evoked potentials (LEP) or magnetic fields in respective electroencephalogram (EEG) and magnetoencephalogram (MEG). Evidence is reviewed that LEP represent a series of event-related potentials (ERP) that depend on vigilance and arousal, selective spatial attention and contextual task variables. Paradigms adopted from other stimulus modalities in the assessment of attention and cognition in ERP and applied to LEP allow the view that middle-latency (N1) and long latency (N2-P2) components of LEP can be overlapped or supplemented by endogenous components such as the processing negativity and distinct members (P3a and P3b) of the "P300" activities, each of which is considered in detail in this review. This composite entity needs to be considered when LEP are experimentally or clinically used in the assessment of sensory and cognitive phenomena and abnormalities of pain sensation.     

Intracranial identification of an electric frontal-cortex response to auditory stimulus change: a case study

The aim of the present study was to clarify whether ERPs recorded directly from the human frontal cortex contributed to the auditory N1 and mismatch negativity (MMN) elicited by changes in non-phonetic and phonetic sounds. We examined the role of prefrontal cortex in the processing of stimulus repetition and change in a 6-year-old child undergoing presurgical evaluation for epilepsy. EEG was recorded from three bilateral sub-dural electrode strips located over lateral prefrontal areas during unattended auditory stimulation. EEG epochs were averaged to obtain event-related potentials (ERPs) to repeating (standard) tones and to infrequent (deviant) shorter duration tones and complex sounds (telephone buzz). In another condition, ERPs were recorded to standard and deviant syllables, /ba/ and /da/, respectively. ERPs to vibration stimuli delivered to the fingertips were not observed at any of the sub-dural electrodes, confirming modality specificity of the auditory responses. Focal auditory ERPs consisting of P100 and N150 deflections were recorded to both tones and phonemes over the right lateral prefrontal cortex. These responses were insensitive to the serial position of the repeating sound in the stimulus train. Deviant tones evoked an MMN peaking at around 128 ms. Deviant complex sounds evoked ERPs with a similar onset latency and morphology but with an approximately two-fold increase in peak-to-peak amplitude. We conclude that right lateral prefrontal cortex (Brodmann's area 45) is involved in early stages of processing repeating sounds and sound changes.     

The pattern and habituation of the orienting response in man and rats

Autonomic and central nervous indices of the orienting response (OR) were investigated in awake human subjects and sleeping rats. Ten acoustic stimuli of 60 dB and two stimuli of 80 dB were presented for 10 s each with a constant interstimulus interval of 50 s. Responses were averaged across subjects for each single trial. An exponential fit to scores of each physiological variable was used to compare OR, habituation and dishabituation between samples and variables. An OR to the first stimulus, habituation of response amplitude, and dishabituation in response to the change in stimulus intensity were observed for event-related EEG desynchronization, a negative-positive evoked potential complex in humans and rats, as well as for skin conductance in humans. While heart rate did not show systematic changes across the 60 dB tones in both samples, a deceleration was observed in response to the first 80 dB tone. Results suggest comparable patterns of orienting to acoustic stimuli and habituation of the OR in the awake human and the sleeping rat, suggesting the possibility of OR as a unitary response. Species differed with respect to speed of habituation but not with respect to sensitivity towards stimulus change.     

Effects of the critical band on auditory-evoked magnetic fields

Changes in the bandwidth affect the perceived loudness of a stimulus even when the level of the stimulus remains fixed. If the bandwidth of a sound is varied while maintaining the overall intensity, the loudness remains constant as long as the bandwidth is less than the critical bandwidth. If the bandwidth is increased beyond the critical bandwidth, the loudness increases with increasing bandwidth. Human cortical responses as a function of stimulus bandwidth were examined by recording auditory-evoked magnetic fields. The results showed that the N1m magnitudes, that is, the estimated equivalent current dipole moments, increased with increasing bandwidth when the bandwidth was increased beyond the critical bandwidth.     

Anticipation and execution of a simple reading task enhance corticospinal excitability.

OBJECTIVE: Electromyographic responses (EMG) evoked in the right hand by transcranial magnetic stimulation (TMS) of the left motor cortex are enhanced during continuous reading. This enhancement is the result of increased excitability of the motor cortex. We proposed that anticipation and reading of single words would also enhance corticospinal excitability. We studied the temporal course of corticospinal excitability changes following left and right hemisphere TMS. METHODS: Ten normal volunteers were studied. A warning stimulus (S1) was followed by an imperative stimulus (S2) whereupon a word was presented. Subjects responded by reading the word aloud or reading it silently. In other conditions, no word was displayed and the subjects responded to S2 by saying the word 'Cat', pursing their lips, or doing nothing. EMG was recorded over the contralateral hand following a TMS pulse over the motor cortex during and after the S1-S2 period. RESULTS: Enhancement of EMG amplitudes was significantly greater following left hemisphere TMS. The enhancement in the S1-S2 period and that following S2 had a time course similar to several event-related brain potentials. CONCLUSIONS: There may be a common mechanism underlying both corticospinal excitability and the contingent negative variation, readiness potential and N400.     

Event-related potentials in the auditory oddball as a function of EEG alpha phase at stimulus onset.

OBJECTIVE: We aimed to examine the relation between the phase of electroencephalogram (EEG) alpha activity at stimulus onset and event-related potentials (ERPs) in a fixed-inter-stimulus interval auditory 'oddball' task, using a novel conceptualisation of orthogonal phase effects (cortical negativity versus positivity, negative driving versus positive driving, waxing versus waning). METHODS: EEG responses to button-press targets, from 14 subjects presented with 4 blocks of 150 stimuli (50% target probability), were examined. Pre-stimulus alpha activity (8-13 Hz) at Pz was assessed for each trial by digital filtering of the EEG. The alpha cycle at Pz, starting from a negative-going zero crossing, was used to sort trials into 4 phases, for which ERPs were derived from both the filtered and unfiltered EEG activity at Fz, Cz, and Pz. RESULTS: Preferred brain states in this paradigm were indicated by an 8% greater occurrence of negative driving than positive driving, and a 33% greater occurrence of waxing than waning phases. Negative driving phases were associated with increased N1 latencies and decreased N2 amplitudes. Latencies of N1 and P2 were reduced in waxing phases. These reflected systematic changes in alpha frequency and amplitude at stimulus onset. CONCLUSIONS: In a fixed-inter-stimulus interval paradigm, component frequencies of the EEG are dynamically adjusted in order to provide brain states at the moment of stimulus presentation which differentially affect the EEG correlates of stimulus processing. SIGNIFICANCE: The results add to our understanding of the genesis of the ERP, indicating the importance of the dynamic interplay between instantaneous EEG activity and stimulus processing reflected in the ERP.     

Potentiation of amygdaloid and hippocampal auditory-evoked potentials in a discriminatory fear-conditioning task in mice as a function of tone pattern and context

According to the local memory storage hypothesis, information about the tone-shock association in an auditory fear-conditioning paradigm is stored in synapses within the lateral amygdala. Thus, fear-conditioning-induced potentiation of auditory-evoked potentials in response to a conditioned stimulus (CS+, a series of short lasting tones; patterned tone) has been interpreted as an in vivo correlate of amygdaloid synaptic plasticity. Here, we re-examine the specificity of potentiation of auditory-evoked potentials in terms of (i) local confinement to the lateral amygdala, (ii) parameters of CS+ and (iii) influence of context, using a discriminatory fear-conditioning paradigm. Adult male C57BL/6J mice were implanted with recording electrodes aimed at the lateral amygdala, the CA1 region of the hippocampus and the neck muscles for simultaneous recordings of auditory-evoked potentials and startle responses. In a neutral context, auditory-evoked potentials within lateral amygdala and CA1 as well as startle and freezing responses to the CS+ were significantly potentiated following conditioning, as compared with pre-conditioning values and responses to a neutral stimulus (CSn; tone of different frequency). Potentiation was only evident if CS+ was presented as a uniform series but not if presented mixed with CSn. Accordingly, mice failed to show intensified freezing to a patterned tone if a single lasting tone of the same frequency served as CS+. Both CA1 and lateral amygdala auditory-evoked potentials were potentiated in response to CSn if presented in the conditioning context. These findings demonstrate that (i) potentiation of auditory-evoked potentials is not restricted to the lateral amygdala, (ii) both tone frequency and pattern of tone presentation are essential for proper CS+ recognition and (iii) contextual memory leads to a general potentiation of auditory-evoked potentials.     

Auditory input to the pedunculopontine nucleus: II. Unit responses

The pedunculopontine nucleus (PPN) has been implicated in sleep-wake control, arousal responses, and motor functions. The PPN also has been implicated in the generation of the P1 middle-latency auditory-evoked potential. The present study was undertaken to determine the nature of the responsiveness of single neurons in and around the PPN following auditory stimulation. Somatosensory responsiveness also was tested in some cells. These results demonstrate a) the presence of a significant proportion of PPN neurons that respond to auditory click stimuli; b) two populations of neurons showing either low threshold/short latency/low habituation or high threshold/ longer latency/thigh habituation; c) the responses of longer latency neurons precede the onset and peak of depth- and vertex-recorded middle-latency auditory-evoked potentials; d) thresholds of longer latency neurons similar to the threshold for wave A in the intact cat, the P13 potential in the intact rat, or the startle reflex; and e) convergent somatosensory and auditory responses at a similar latency in a number of PPN neurons. These findings suggest that neurons in and around the PPN may participate in auditory and somatosensory information processing related to arousal, and may contribute to the manifestation of the P1 auditory middle-latency evoked potential.     

The influence of extrinsic motivation on competition-based selection

The biased competition approach to visuo-spatial attention proposes that the selection of competing information is effected by the saliency of the stimulus as well as by an intention-based bias of attention towards behavioural goals. Wascher and Beste (2010) [32] showed that the detection of relevant information depends on its relative saliency compared to irrelevant conflicting stimuli. Furthermore the N1pc, N2pc and N2 of the EEG varied with the strength of the conflict. However, this system could also be modulated by rather global mechanisms like attentional effort. The present study investigates such modulations by testing the influence of extrinsic motivation on the selection of competing stimuli. Participants had to detect a luminance change in various conditions among others against an irrelevant orientation change. Half of the participants were motivated to maximize their performance by the announcement of a monetary reward for correct responses. Participants who were motivated had lower error rates than participants who were not motivated. The event-related lateralizations of the EEG showed no motivation-related effect on the N1pc, which reflects the initial saliency driven orientation of attention towards the more salient stimulus. The subsequent N2pc was enhanced in the motivation condition. Extrinsic motivation was also accompanied by enhanced fronto-central negativities. Thus, the data provide evidence that the improvement of selection performance when participants were extrinsically motivated by announcing a reward was not due to changes in the initial saliency based processing of information but was foremost mediated by improved higher-level mechanisms.     

Developmental changes of N400 event related potential of a semantic category decision task and modality specific findings in patients with developmental dyslexia

We investigated modality-specific changes in N400 event related potential using a semantic category decision task in 38 control subjects and 8 patients with developmental dyslexia. In control children under 10 years old, auditory N400 showed a negative deflection over the fronto-centro-parietal areas with substantial amplitude. Control children over 10 years old showed a similar pattern of N400 waves in a visual and an auditory-visual modality, suggesting that the visual modality becomes dominant in the late teens. Dyslexic children showed more errors on a visual than auditory modality task with poorer N400 waves for visual stimuli. However, peak latencies of N400 in an auditory-visual modality were almost the same for auditory stimuli in control children. Differences in the N400 pattern in children might reflect the fragility and reversibility of the semantic processes through stimulus modalities.     

Effects of interstimulus interval on cortical responses to painful laser stimulation.

Short laser pulses applied to the skin are used increasingly in both clinical and basic assessment of nociceptive brain mechanisms. The authors aimed to characterize further the cortical responses to noxious laser stimuli and to define the interstimulus interval (ISI) for the optimum signal-to-noise ratio during a fixed measurement time. Three hundred six-channel whole-scalp magnetoencephalographic (MEG) and midline EEG signals were recorded from nine healthy adults during painful thulium laser stimulation. The stimuli were delivered on the dorsum of the left hand at ISIs of 0.5, 1, 2, 4, 8, and 16 seconds. The MEG responses peaked at 160 to 195 msec around the contralateral primary somatosensory (SI) cortex, at 150 to 190 msec in the contralateral secondary somatosensory (SII) cortex, and at 160 to 205 msec in the ipsilateral SII cortex. The simultaneously measured electrical vertex potentials peaked at 190 to 230 msec and 310 to 330 msec (N200-P300). All these responses showed rather similar refractory times: The amplitudes increased strongly from 0.5 to 4-second ISIs and thereafter saturated at ISIs of 8 to 16 seconds. On the basis of the time constants of the recovery cycles, the optimum ISI for obtaining the best signal-to-noise ratio for laser-evoked MEG and EEG responses during a fixed measurement interval is 4 to 5 seconds.     

How response inhibition modulates nociceptive and non-nociceptive somatosensory brain-evoked potentials.

OBJECTIVE: To examine and compare the modulation of nociceptive somatosensory laser-evoked potentials (LEPs) and non-nociceptive somatosensory electrically-evoked potentials (SEPs) by brain processes related to response inhibition. METHODS: A warning auditory tone was followed by either an electrical or a laser stimulus. Subjects performed a Go/Nogo task in which they were instructed to respond to the laser stimulus and refrain from responding to the electrical stimulus in half of the runs. In the other half, they performed the opposite. The paradigm allowed a direct, within-subject comparison of the electrophysiological correlates of brain processes related to the Go/Nogo task in both somatosensory submodalities. RESULTS: In the Nogo-condition, SEPs displayed an enhanced N120 (early Nogo-response), a reduced vertex P240 and enhanced frontal P3 (late Nogo-responses). In contrast, LEPs only displayed late Nogo-related responses (reduced vertex P350 and enhanced frontal P3). CONCLUSIONS: The early Nogo-related enhancement of SEPs may reflect brain processes specific to the processing of non-nociceptive somatosensory stimuli. Later components of the Nogo-response may reflect cortical activity common to the processing of both nociceptive and non-nociceptive somatosensory stimuli. SIGNIFICANCE: Response inhibition significantly modulates both LEPs and SEPs. Part of these activities may be specific of the eliciting stimulus modality.