Preattentive dysfunction in bipolar disorder: A MEG study using auditory mismatch negativity

Background

Neuropsychological studies have demonstrated that cognitive dysfunction represents pathophysiological mechanisms underlying bipolar disorder. However, information processing deficits in bipolar disorder have not often been examined electrophysiologically. Here, we examined preattentive processing and sensory information processing using mismatch field (MMNm) and P1m components, respectively, using magnetoencephalography.

Methods

Ten patients with bipolar disorder and 20 healthy volunteers participated in the study. The participants were presented with auditory stimuli sequences comprising standard and deviant stimuli. MMNm was elicited in response to changes in duration and frequency of pure-tone stimuli and a vowel across-category change.

Results

The magnetic global field power of MMNm in the right hemisphere under the pure-tone condition was significantly delayed in patients with bipolar disorder compared to healthy volunteers, and that of P1m did not differ between the two groups. The MMNm dipole in the left hemisphere was located inferior in patients with bipolar disorder than in healthy volunteers. This finding did not correlate with clinical symptoms.

Conclusions

Information processing at the preattentive level is impaired in patients with bipolar disorder irrespective of clinical symptoms, and this dysfunction is not due to sensory level dysfunction. The quality of preattentive information processing impairment is different between patients with bipolar disorder and patients with major depressive disorder, as shown by the MMNm latency and power differences.     

Visual stimuli activate auditory cortex in deaf subjects: evidence from MEG

Studies using fMRI have demonstrated that visual stimuli activate auditory cortex in deaf subjects. Given the low temporal resolution of fMRI, it is uncertain whether this activation is associated with initial stimulus processing. Here, we used MEG in deaf and hearing subjects to evaluate whether auditory cortex, devoid of its normal input, comes to serve the visual modality early in the course of stimulus processing. In line with previous findings, visual activity was observed in the auditory cortex of deaf, but not hearing, subjects. This activity occurred within 100-400 ms of stimulus presentation and was primarily over the right hemisphere. These results add to the mounting evidence that removal of one sensory modality in humans leads to neural reorganization of the remaining modalities.     

Reproducibility of the hemodynamic response to auditory oddball stimuli: a six-week test-retest study

Determining the reliability and reproducibility of the hemodynamic response is important for the interpretation and understanding of the results of functional magnetic resonance imaging (fMRI) experiments. We describe a whole brain fMRI study designed to examine the reproducibility of the event-related hemodynamic response elicited by low-probability task-relevant target stimuli and low-probability task-irrelevant novel stimuli assessed 6 weeks apart. Reliable activation was observed during test and retest for processing of target stimuli in multiple frontal, temporal, parietal, cerebellar, and subcortical sites. Novel stimuli elicited reliable activation during test and retest in lateral frontal cortex, inferior parietal lobule, and lateral temporal cortex, though there was evidence of habituation at some cortical sites. The patterns of activation associated with target detection and novelty processing are consistent with the intracranial distribution of the neural sources generated during similar tasks and replicate the results of previous event-related fMRI studies. The observed pattern of results supports the hypothesis that the hemodynamic response to target and novel stimuli is highly reproducible over the 6-week test-retest period.     

Priority of repetitive adaptation to mismatch response following undiscriminable auditory stimulation: a magnetoencephalographic study

We analysed two different neural mechanisms related to the unconscious processing of auditory stimulation, neural adaptation and mismatch negativity (MMN), using magnetoencephalography in healthy non-musicians. Four kinds of conditioning stimulus (CS): white noise, a 675-Hz pure tone, and complex tones with six (CT6) and seven components (CT7), were used for analysing neural adaptation. The seven spectral components of CT7 were spaced by 1/7 octaves between 500 and 906 Hz on the logarithmic scale. The CT6 components contained the same spectral components as CT7, except for the center frequency, 675 kHz. Subjects could not distinguish CT6 from CT7 in a discrimination test. A test stimulus (TS), a 675-Hz tone, was presented after CS, and the effects of the presence of the same 675-Hz frequency in the CS on the magnetoencephalographic response elicited by TS was evaluated. The P2m component following CT7 was significantly smaller in current strength than that following CT6. The equivalent current dipole for P2m was located approximately 10 mm anterior to the preceding N1m. This result indicated that neural adaptation was taking place in the anterior part of the auditory cortex, even if the sound difference was subthreshold. By contrast, the magnetic counterpart of the MMN was not recorded when CT6 and CT7 were used as standard and deviant stimuli, respectively, being consistent with the discrimination test. In conclusion, neural adaptation is considered to be more sensitive than our consciousness or the MMN, or is caused by an independent mechanism.     

Automatic auditory off-response in humans: an MEG study

We recorded cortical activities in response to the onset and offset of a pure tone of long duration (LONG) and a train of brief pulses of a pure tone with an interstimulus interval of 50 ms (ISI–50 ms) or 100 ms (ISI–100 ms) by use of magnetoencephalograms in 11 healthy volunteers to clarify temporal and spatial profiles of the auditory on- and off-cortical response. Results showed that a region around the superior temporal gyrus (STG) of both hemispheres responded to both the onset and offset of the stimulus. The location of the source responsible for the main activity (N1m) was not significantly different between the on- and off-responses for any of the three tones. The peak latency of on-N1m was similar under the three conditions, while the peak latency of off-N1m was precisely determined by the ISI, which suggested that off-N1m is based on short-term memory of the stimulus frequency. In addition, there was a positive correlation of the N1m amplitude of N1m between the on- and off-responses among the subjects. The present results suggested that auditory on-N1m and off-N1m have similar physiological significance involved in responding to abrupt changes.     

Event-related potentials in response to 3-D auditory stimuli

To evaluate auditory spatial cognitive function, age correlations for event-related potentials (ERPs) in response to auditory stimuli with a Doppler effect were studied in normal children. A sound with a Doppler effect is perceived as a moving audio image. A total of 99 normal subjects (age range, 4–21 years) were tested. In the task-relevant oddball paradigm, P300 and key-press reaction time were elicited using auditory stimuli (1000 Hz fixed and enlarged tones with a Doppler effect). From the age of 4 years, the P300 latency for the enlarged tone with a Doppler effect shortened more rapidly with age than did the P300 latency for tone-pips, and the latencies for the different conditions became similar towards the late teens. The P300 of auditory stimuli with a Doppler effect may be used to evaluate auditory spatial cognitive function in children.     

Memory-based comparison process not attenuated by haloperidol: a combined MEG and EEG study

Auditory P50 and N100 responses reflect preattentive processing, whereas subsequent mismatch negativity (MMN) response indexes memory-based comparison process. Divergent ERP responses have been found in schizophrenia and in Parkinson's disease (PD), which have abnormalities in cerebral dopamine activity. We used simultaneously magnetoencephalography and electroencephalography to investigate, whether a single dose of haloperidol, a dopamine D2-receptor antagonist, modulates preattentive auditory processing using a randomized, double-blind, placebo-controlled crossover design. Our results showed that haloperidol did not alter MMN to frequency and duration changes, whereas the magnetic MMN to frequency change was significantly accelerated. The amplitude and latency changes of the electric and magnetic P50 and N100 were insignificant. Our results indicate that memory-based sound comparison and preceding cortical processing underlying stimulus detection are not attenuated by haloperidol, whereas haloperidol appears to accelerate preattentive sound comparison.     

Auditory cortex accesses phonological categories: an MEG mismatch study

The studies presented here use an adapted oddball paradigm to show evidence that representations of discrete phonological categories are available to the human auditory cortex. Brain activity was recorded using a 37-channel biomagnetometer while eight subjects listened passively to synthetic speech sounds. In the phonological condition, which contrasted stimuli from an acoustic /dae/-/tae/ continuum, a magnetic mismatch field (MMF) was elicited in a sequence of stimuli in which phonological categories occurred in a many-to-one ratio, but no acoustic many-to-one ratio was present. In order to isolate the contribution of phonological categories to the MMF responses, the acoustic parameter of voice onset time, which distinguished standard and deviant stimuli, was also varied within the standard and deviant categories. No MMF was elicited in the acoustic condition, in which the acoustic distribution of stimuli was identical to the first experiment, but the many-to-one distribution of phonological categories was removed. The design of these studies makes it possible to demonstrate the all-or-nothing property of phonological category membership. This approach contrasts with a number of previous studies of phonetic perception using the mismatch paradigm, which have demonstrated the graded property of enhanced acoustic discrimination at or near phonetic category boundaries.     

Distinct pre-attentive responses to non-scale notes: An auditory mismatch negativity (MMN) study

Objective: The aim of the present study was to examine patterns of neural activity in response to variations in scale notes and alterations from a scale note to a non-scale note.Methods: Event-related potentials (ERPs) were recorded in response to scale and non-scale violin notes using an odd-ball mismatch negativity (MMN) paradigm. Standard stimuli were set to the scale note A4 (440 Hz). Deviant stimuli included two scale notes (scale-B, B4 = 494 Hz; scale-C, C5 = 523 Hz) and a non-scale note halfway between them (non-scale, B4 + 42¢ = 506 Hz).Results: MMN amplitude elicited by the non-scale was significantly larger than that elicited by the scale-B and scale-C, which did not differ significantly from one another.Conclusion: The current results suggest that the human brain may possess pre-attentive mechanisms for extracting relational aspects among sounds of the musical scale.Significance: The results indicate that non-scale notes may be processed in a different way even in the pre-attentive stage than scale notes.     

The time course of the BOLD response in the human auditory cortex to acoustic stimuli of different duration.

The relationship between activity within the human auditory cortices and the duration of heard tones was investigated by measuring the hemodynamic response with functional magnetic resonance imaging. We demonstrate that there is no significant influence of stimulus duration as used here on the intensity and spatial extent of the hemodynamic response in the auditory cortices. We found however, that the time course of the hemodynamic response to the repeated stimulus presentation exhibited a characteristic decline after the first stimulus exposure during the activation period. The possible reasons for this time course are currently unknown, however, several factors may be involved, including top-down mechanisms and/or the interplay of tissue perfusion and oxygen consumption.     

Hemisphere differences in response time to simple auditory stimuli.

Ten right-handed and ten left-handed matched groups of normal males were tested on a bi-lateral response task to simple unilateral auditory stimuli presented in a random sequence to the right and left ears. Significantly shorter reaction times were recorded for right ear presentations in the right-handed subjects but not in the left-handers and similar differentially significant effects were found between the presumed neural pathways of response in favour of the intra-hemispheric route. The findings are discussed in terms of the functional differences between the cerebral hemispheres.     

Refractoriness, habituation, and mismatch effects in the auditory event-related potential to alternating stimuli

Amplitude enhancement in the N1 component of auditory event-related potentials (ERPs) to alternately presented sounds has been referred as a typical example for the effect of release from neural refractoriness. We tested this hypothesis to see whether some other effects also contribute to this phenomenon. Two tones of different frequencies were presented singly or in pairs, and ERPs were recorded using monotonous (mnt) and alternating (alt) sequences of these stimuli. Comparison of the 'alt-mnt' difference waveforms recorded with single and paired stimuli supported the refractoriness hypothesis. A mismatch negativity-like wave, however, was also observed, questioning the constraint of 'at least two consecutive standards before deviant' presumed in most mismatch negativity studies. This paradigm made it possible to delineate the ERP components related to refractoriness and mismatch detection processes.     

Cholinergic gating of response to auditory stimuli in rat hippocampus.

Rapid decrement of response to repeated stimuli is a characteristic of hippocampal neurons. To assess the possible role in this process of cholinergic afferents from the medial septal nucleus, a series of cholinergic antagonists were administered intraventricularly to chloral hydrate-anesthetized rats. Auditory stimuli were delivered in pairs to the rats, and the evoked response was recorded from an electrode in the CA3 layer of the hippocampus. The most prominent component of the auditory evoked potential recorded in this region (N40) showed over 60% decrement in the amplitude of the response to the second stimulus when the two stimuli were delivered 0.5 s apart. Only neuromuscular-type nicotinic antagonists, alpha-bungarotoxin and (+)-tubocurarine, disrupted this decrement of response to repeated auditory stimuli. The muscarinic antagonist, scopolamine, and the ganglionic-type nicotinic antagonists, kappa-bungarotoxin and mecamylamine, were without effect. The results suggest that a subset of nicotinic receptors mediate the gating of response to auditory stimuli in the hippocampus.     

Activation in the anterior left auditory cortex associated with phonological analysis of speech input: localization of the phonological mismatch negativity response with MEG

The spatio-temporal dynamics of cortical activation underlying auditory word recognition, particularly its phonological stage, was studied with whole-head magnetoencephalography (MEG). Subjects performed a visuo-auditory priming task known to evoke the phonological mismatch negativity (PMN) response that is elicited by violations of phonological expectancies. Words and non-words were presented in separate conditions. In each of the 318 trials, the subjects first saw a word/non-word (e.g., 'cat') that was soon followed by a prime letter (e.g., 'h'). Their task was to replace mentally the sound of the first letter of the word/non-word with the prime letter, thus resulting in a new word/non-word (e.g., 'hat'). Finally, an auditory word/non-word either matching or mismatching with the anticipated item was presented. In most subjects, a PMNm followed by a later, N400m-like negativity was obtained in the left hemisphere to the mismatching auditory stimuli. A similar response pattern was obtained in the right hemisphere only in a few subjects. Source localization of the N1m, an index of acoustic analysis, and the PMNm and N400m-like responses was performed using L1 minimum-norm estimation. In the left hemisphere, the PMNm source for the words was significantly more anterior than the source of the N400m-like response; for the non-words, the PMNm source was significantly more anterior than the sources of the N1m and the N400m-like response. These results suggest that the left-hemisphere neuronal networks involved in sub-lexical phonological analysis are at least partly different from those responsible for the earlier (acoustic) and later (whole item) processing of speech input.     

Computed EEG topography of response to visual and auditory stimuli

EEG activity was monitored in 15 normal subjects at rest and while they were given 10 sec continuous light or tone stimuli of different intensities. Topographical cortical changes were assessed using 16-channel EEG power estimate maps of the left hemisphere. Statistical analyses were performed using analyses of variance and t test, and the reactivity of the EEG, i.e., the percent change from the baseline state, in response to stimulation, was topographically mapped. Significant EEG reactivity was recorded in alpha, theta and delta bands without modification in the beta band. Stimulation-induced effects were maximum in the posterior part of the brain for both tone and light. The light effect was stronger than tone in the alpha band, but no differences in modality effect were recorded in the delta or theta band. Analysis of frequency bands within the alpha and theta band revealed a different pattern of reactivity with different regional involvements for tone and light. EEG reactivity occurred mainly in 7-10 Hz frequency bands with no significant change in 5, 6, 11, 12 and 13 Hz. Reactivity was maximal in the temporal area during tone for 7-9 Hz and in the occipital region during light for 8-10 Hz. The 8 and 9 Hz frequency bands showed increased blocking with an increase in stimulus intensity. Taken together, the results indicate that visual and auditory stimuli both produce an EEG amplitude decrease which is greatest over their respective primary sensory cortex.     

Modulation of the auditory cortex during speech: an MEG study

Several behavioral and brain imaging studies have demonstrated a significant interaction between speech perception and speech production. In this study, auditory cortical responses to speech were examined during self-production and feedback alteration. Magnetic field recordings were obtained from both hemispheres in subjects who spoke while hearing controlled acoustic versions of their speech feedback via earphones. These responses were compared to recordings made while subjects listened to a tape playback of their production. The amplitude of tape playback was adjusted to match the amplitude of self-produced speech. Recordings of evoked responses to both self-produced and tape-recorded speech were obtained free of movement-related artifacts. Responses to self-produced speech were weaker than were responses to tape-recorded speech. Responses to tones were also weaker during speech production, when compared with responses to tones recorded in the presence of speech from tape playback. However, responses evoked by gated noise stimuli did not differ for recordings made during self-produced speech versus recordings made during tape-recorded speech playback. These data suggest that during speech production, the auditory cortex (1) attenuates its sensitivity and (2) modulates its activity as a function of the expected acoustic feedback.