The mismatch negativity (MMN) in basic research of central auditory processing: A review

In the present article, the basic research using the mismatch negativity (MMN) and analogous results obtained by using the magnetoencephalography (MEG) and other brain-imaging technologies is reviewed. This response is elicited by any discriminable change in auditory stimulation but recent studies extended the notion of the MMN even to higher-order cognitive processes such as those involving grammar and semantic meaning. Moreover, MMN data also show the presence of automatic intelligent processes such as stimulus anticipation at the level of auditory cortex. In addition, the MMN enables one to establish the brain processes underlying the initiation of attention switch to, conscious perception of, sound change in an unattended stimulus stream.     

Temporal processing ability is related to ear-asymmetry for detecting time cues in sound: a mismatch negativity (MMN) study

Temporal and spectral sound information is processed asymmetrically in the brain with the left-hemisphere showing an advantage for processing the former and the right-hemisphere for the latter. Using monaural sound presentation we demonstrate a context and ability dependent ear-asymmetry in brain measures of temporal change detection. Our measure of temporal processing ability was a gap-detection task quantifying the smallest silent gap in a sound that participants could reliably detect. Our brain measure was the size of the mismatch-negativity (MMN) auditory event-related potential elicited to infrequently presented gap sounds. The MMN indexes discrimination ability and is automatically generated when the brain detects a change in a repeating pattern of sound. MMN was elicited in unattended sequences of infrequent gap-sounds presented among regular no-gap sounds. In Study 1, participants with low gap-detection thresholds (good ability) produced a significantly larger MMN to gap sounds when sequences were presented monaurally to the right-ear than to the left-ear. In Study 2, we not only replicated a right-ear-advantage for MMN in silence in good temporal processors, but also showed that this is reversed to a significant left-ear-advantage for MMN when the same sounds are presented against a background of constant low-level noise. In both studies, poor discriminators showed no ear-advantage, and in Study 2, exhibited no differential sensitivity of the ears to noise. We conclude that these data reveal a context and ability-dependent asymmetry in processing temporal information in non-speech sounds.     

Negative bias in expression-related mismatch negativity(MMN) in remitted late-life depression: An event-related potential study

Negative bias in cognition is closely associated with susceptibility to recurrent episodes of depression. Given the high recurrence rate of depression, previous studies have focused on the attentive level in late-life depression (LLD), but depression relapse is difficult to detect as a lower chief complaint in elderly people. Facial expression mismatch negativity (EMMN) is a tool that can measure cognitive bias in pre-attentive processing. In this study, we sought to explore the cognitive bias in pre-attentive emotional information processing in LLD. Thirty patients with remitted LLD and 30 non-depressed, age- and gender-matched normal controls (NC) were enrolled in this study. Automatic emotional processing was elicited by using an expression-related oddball paradigm in all participants. There were no significant differences in N170 amplitude and latency between remitted LLD and NC. Compared with NC subjects, patients with remitted LLD demonstrated an attenuated mean amplitude of positive and negative EMMN, whereas the mean amplitude of negative EMMN in remitted LLD was much larger than that of positive EMMN. Our findings suggest that although basic processing of facial expressions is intact in remitted LLD, automatic processing of facial expressions in remitted LLD is impaired with a negative bias in cognition. Further investigation of the contributions of negative bias in EMMN to susceptibility to recurrence of LLD is warranted.     

Development of a minimally-invasive protocol for recording mismatch negativity (MMN) in the dog (Canis familiaris) using electroencephalography (EEG)

Mismatch negativity (MMN), observed in event-related potentials (ERPs), constitutes a measurable change in electrophysiological brain activity occurring after exposure to a novel stimulus. In humans, MMN is considered to be related to stimulus discrimination at the cortical level. ERP recording in dogs may present an opportunity to increase understanding of cognitive processes without reliance on observable behaviour, which may be confounded by motivation or training. Preliminary data are presented suggesting the existence of MMN, recorded using a minimally-invasive procedure equivalent to that used in humans, in unrestrained, unanaesthetised dogs. This is the first example of this ERP component in dogs and the method has substantial utility for future research exploring auditory, olfactory, and visual discrimination tasks, development, and breed differences.     

The use of conditional inference to reduce prediction error—A mismatch negativity (MMN) study

The brain uses regularities in the sound environment to build inference models predicting the most likely attributes of subsequent sounds. When the inference model fails, a prediction-error signal (the mismatch negativity or MMN) is generated. This study is designed to explore the capacity to use information about when a deviant sound will occur to switch between inference models in memory. We measured MMN generated to rare frequency, duration, intensity and spatial deviant sounds randomly occurring in a stream of identical repeating “standard” sounds. We then measured MMN to the same deviants in a linked sequence where deviants were paired—duration deviants followed an intensity change and spatial deviants followed a frequency change. To minimise prediction error, the brain should use the occurrence of the intensity and frequency deviant to prompt a change in the dominant inference (“expect-the-standard”) to anticipate the characteristics of the linked deviant. Anticipation was quantified as the proportion decline in duration and spatial MMN in the linked versus random sequence. We report three main outcomes on a sample of 23 healthy adults: (1) a significant reduction in duration MMN amplitude in linked versus random sequence; (2) a subgroup of participants exhibited significant reduction in spatial MMN amplitude in linked versus random sequence; and (3) the capacity to anticipate a linked deviant (reduce MMN) was a related to performance on the Continuous Performance Task-Identical Pairs. The results are discussed with respect to a possible co-reliance of CPT-IP and inference models on the inferior frontal gyrus.     

The mismatch negativity (MMN) potential as a tool for the functional mapping of temporal lobe epilepsies

Temporal lobe epilepsies are associated with cognitive dysfunctions in memory which are important clues currently used clinically for the lateralization of the epileptic focus in evaluations for epilepsy surgery. Because these lobes also contain the primary auditory cortex, the study of auditory evoked potentials (AEPs) is a candidate, not yet established, complementary method to characterize epilepsy-induced dysfunction. We aimed to establish the clinical usefulness of auditory evoked potentials for the study of pediatric symptomatic temporal lobe epilepsies. A group of 17 patients (ages 4–16) with symptomatic epilepsies undergoing evaluation for epilepsy surgery epilepsy was submitted to auditory evoked potentials using 35-channel scalp EEG recordings. A control group of 10 healthy volunteers was studied with the same protocol. The P100 and mismatch negativity (MMN) potential latencies and normalized amplitudes were studied. We also performed a voxel-based lesion-symptom mapping (VLSM) to determine the anatomical areas associated with changes in the AEPs. Eleven patients had temporal lobe epilepsy, three had frontal lobe epilepsy, and three had occipital lobe epilepsy. Latencies for the P100 were normal in 15/17 and in 11/17 for the MMN, with no consistent correlation with the epilepsy type. The MMN amplitude was abnormal in 7/17 patients, all with temporal lobe epilepsies (sensitivity of 64%). Of these patients, four had a decreased MMN associated with a Heschl's gyrus lesion in the VLSM, and three had an increased MMN associated with hippocampal lesion. No extratemporal epilepsy showed MMN amplitude abnormalities (specificity of 100%). The P100 amplitude was abnormal in 3/17, two with temporal and one with frontal lobe epilepsies. The auditory MMN has a high specificity but a low sensitivity for temporal lobe epilepsy in symptomatic pediatric epilepsies. Amplitude decreases of the MMN are associated with homolateral Heschl's gyrus lesions, and MMN increases with hippocampal lesions.     

Functional connectivity of the frontotemporal network in preattentive detection of abstract changes: Perturbs and observes with transcranial magnetic stimulation and event‐related optical signal

Current theories of automatic or preattentive change detection suggest a regularity or prediction violation mechanism involving functional connectivity between the inferior frontal cortex (IFC) and the superior temporal cortex (STC). By disrupting the IFC function with transcranial magnetic stimulation (TMS) and recording the later STC mismatch response with event‐related optical signal (EROS), previous study demonstrated a causal IFC‐to‐STC functional connection in detecting a pitch or physical change. However, physical change detection can be achieved by memory comparison of the physical features and may not necessarily involve regularity/rule extraction and prediction. The current study investigated the IFC–STC functional connectivity in detecting rule violation (i.e., an abstract change). Frequent standard tone pairs with a constant relative pitch difference, but varying pitches, were presented to establish a pitch interval rule. This abstract rule was violated by deviants with reduced relative pitch intervals. The EROS STC mismatch response to the deviants was abolished by the TMS applied at the IFC 80 ms after deviance onset, but preserved in the spatial (TMS on vertex), auditory (TMS sound), and temporal (200 ms after deviance onset) control conditions. These results demonstrate the IFC–STC connection in preattentive abstract change detection and support the regularity or prediction violation account.     

The role of inferior frontal cortex in belief-bias reasoning: An rTMS study

The belief-bias effect in syllogistic reasoning refers to the tendency for subjects to be erroneously biased when logical conclusions are incongruent with belief about the world. This study examined the role of inferior frontal cortex (IFC) in belief-bias reasoning using repetitive transcranial magnetic stimulation (rTMS). We used an off-line rTMS method to disrupt IFC activity transiently. Right IFC stimulation significantly impaired incongruent reasoning performance, enhancing the belief-bias effect. Subjects whose right IFC was impaired by rTMS may not be able to inhibit irrelevant semantic processing in incongruent trials. Although left IFC stimulation impaired congruent reasoning, it paradoxically facilitated incongruent reasoning performance, eliminating the belief-bias effect. Subjects whose left IFC was impaired by rTMS may not suffer from interference by irrelevant semantic processing. This study demonstrates for the first time the roles of left and right IFC in belief-bias reasoning using an rTMS approach.     

Failure of de-activation in the medial frontal cortex in mania: evidence for default mode network dysfunction in the disorder

Abstract

Objectives. Manic patients have been found to show reduced activation in the prefrontal cortex and other regions during performance of cognitive tasks. However, little is known about de-activations associated with the disorder. This study aimed to examine, at the whole-brain level, abnormal patterns of task-related activation and de-activation during performance of a working memory task. Methods. Twenty-nine DSM-IV bipolar patients and 46 healthy controls underwent fMRI during performance of the n-back task. The patients were scanned while they were in a manic episode. Linear models were used to obtain maps of within-group activations and areas of differential activation between the groups. Results. The manic patients showed reduced activation compared to the controls in the bilateral dorsolateral prefrontal cortex and the right parietal cortex. They also showed failure of de-activation in the medial frontal cortex, extending to the temporal poles and parts of the limbic system bilaterally. The failure of activation in the dorsolateral prefrontal cortex disappeared when differences in task performance were controlled for in the analysis. However, the medial frontal failure of de-activation survived controlling for this. Conclusions. This study suggests that, in addition to reduced prefrontal activation, failure of de-activation is an important functional imaging abnormality in mania. This, together with its location in the medial prefrontal cortex, implies default mode network dysfunction in the disorder.     

The role of the rostral frontal cortex (area 10) in prospective memory: a lateral versus medial dissociation

Using the H(2)(15)O PET method, we investigated whether previous findings of regional cerebral blood flow (rCBF) changes in the polar and superior rostral aspects of the frontal lobes (principally Brodmann's area (BA) 10) during prospective memory (PM) paradigms (i.e. those involving carrying out an intended action after a delay) can be attributed merely to the greater difficulty of such tasks over the baseline conditions typically employed. Three different tasks were administered under four conditions: baseline simple RT; attention-demanding ongoing task only; ongoing task plus a delayed intention (unpracticed); ongoing task plus delayed intention (practiced). Under prospective memory conditions, we found significant rCBF decreases in the superior medial aspects of the rostral prefrontal cortex (BA 10) relative to the baseline or ongoing task only conditions. However more lateral aspects of area 10 (plus the medio-dorsal thalamus) showed the opposite pattern, with rCBF increases in the prospective memory conditions relative to the other conditions. These patterns were broadly replicated over all three tasks. Since both the medial and lateral rostral regions showed: (a) instances where rCBF was lower during a more effortful condition (as estimated by increased RTs and error rates) than in a less effortful one; and (b) there was no correlation between rCBF and RT durations or number of errors in these regions, a simple task difficulty explanation of the rCBF changes in the rostral aspects of the frontal lobes during prospective memory tasks is rejected. Instead, the favoured explanation concentrates upon the particular processing demands made by these situations irrespective of the precise stimuli used or the exact nature of the intention. Moreover, the results suggest different roles for medial and lateral rostral prefrontal cortex, with the former involved in suppressing internally-generated thought, and the latter in maintaining it.     

Automatic detection of violations of statistical regularities in the periphery is affected by the focus of spatial attention: A visual mismatch negativity study

We investigated the effect of spatial attention on an event‐related potential signature of automatic detection of violations of statistical regularities, namely, the visual mismatch negativity (vMMN). To vary the task‐field and the location of vMMN‐related stimulation, in the attentional field the stimuli of a tracking task with a steady and a moving (target) bar were presented. The target stimuli of the task appeared either relatively close or far from a passive (task‐irrelevant) oddball or equiprobable sequence at the lower part of the screen. Stimuli of the oddball sequence were shapes tilted either 45° (standard, p = 0.8) or 135° (deviant, p = 0.2), while the equiprobable sequence consisted of additional three shapes with identical number of lines to the oddball stimuli. Deviant stimuli in close proximity to a continuously attended field elicited larger vMMN than similar stimuli farther away from the stimulus field. In the condition with a smaller distance between the field of the tracking task and the vMMN‐related field, the deviant stimuli and the vMMN was followed by a posterior positivity. According to these results, spatial attention modulates vMMN and is capable of initiating further processing of the deviant stimuli.     

Criteria for early detection of conduction block in multifocal motor neuropathy (MMN): a study based on control populations and follow-up of MMN patients

Motor conduction block (MCB) has been used as the main diagnostic criterion in multifocal motor neuropathy (MMN). Nonetheless, no agreed definition of block currently exists; the proposed required percent decrement of proximal compound muscle action potential (CMAP) amplitude varies from > 20% to > 50%. The aim of this work was to evaluate, through a follow-up study of patients with MMN, the behaviour of MCB over time. The percent decrement and temporal dispersion of proximal CMAP have also been calculated in normal controls and in patients affected by amyotrophic lateral sclerosis (ALS). The results show that MCB in patients with MMN is a dynamic entity which greatly varies over time and that a > 50% CMAP amplitued reduction may well be preceded by a smaller decrement that is nonetheless indicative of focal myelin damage in the appropriate clinical context. This datum and the results obtained in the control group and in patients with ALS suggest that a reappraisal of the diagnostic criteria for MCB, in cases with clinical and electrophysiological data strongly indicative of MMN, should be considered. Since MMN is a treatable disorder, the use of the proposed less restrictive criteria for the identification of MCB could allow for a promp and more effective treatment. Received: 31 December 1996 Received in revised form: 1 August 1997 Accepted: 13 August 1997     

The brain's code and its canonical computational motifs. From sensory cortex to the default mode network: A multi-scale model of brain function in health and disease

A variety of anatomical and physiological evidence suggests that the brain performs computations using motifs that are repeated across species, brain areas, and modalities. The computational architecture of cortex, for example, is very similar from one area to another and the types, arrangements, and connections of cortical neurons are highly stereotyped. This supports the idea that each cortical area conducts calculations using similarly structured neuronal modules: what we term canonical computational motifs. In addition, the remarkable self-similarity of the brain observables at the micro-, meso- and macro-scale further suggests that these motifs are repeated at increasing spatial and temporal scales supporting brain activity from primary motor and sensory processing to higher-level behaviour and cognition.Here, we briefly review the biological bases of canonical brain circuits and the role of inhibitory interneurons in these computational elements. We then elucidate how canonical computational motifs can be repeated across spatial and temporal scales to build a multiplexing information system able to encode and transmit information of increasing complexity. We point to the similarities between the patterns of activation observed in primary sensory cortices by use of electrophysiology and those observed in large scale networks measured with fMRI.We then employ the canonical model of brain function to unify seemingly disparate evidence on the pathophysiology of schizophrenia in a single explanatory framework. We hypothesise that such a framework may also be extended to cover multiple brain disorders which are grounded in dysfunction of GABA interneurons and/or these computational motifs.     

Domain-related differentiation of working memory in the Japanese macaque (Macaca fuscata) frontal cortex: a positron emission tomography study

The lateral prefrontal cortex (LPFC) is important for working memory (WM) task performance. Neuropsychological and neurophysiological studies in monkeys suggest that the lateral prefrontal cortex is functionally segregated based on the working memory domain (spatial vs. non-spatial). However, this is not supported by most human neuroimaging studies, and the discrepancy might be due to differences in methods and/or species (monkey neuropsychology/physiology vs. human neuroimaging). We used positron emission topography to examine the functional segregation of the lateral prefrontal cortex of Japanese macaques (Macaca fuscata) that showed near 100% accuracy on spatial and non-spatial working memory tasks. Compared with activity during the non-working memory control tasks, the dorsolateral prefrontal cortex (DLPFC) was more active during the non-spatial, but not during the spatial, working memory task, although a muscimol microinjection into the dorsolateral prefrontal cortex significantly impaired the performance of both working memory tasks. A direct comparison of the brain activity between the two working memory tasks revealed no differences within the lateral prefrontal cortex, whereas the premotor area was more active during the spatial working memory task. Comparing the delay-specific activity, which did not include task-associated stimulus/response-related activity, revealed more spatial working memory-related activity in the posterior parietal and premotor areas, and more non-spatial working memory-related activity in the dorsolateral prefrontal cortex and hippocampus. These results suggest that working memory in the monkey brain is segregated based on domain, not within the lateral prefrontal cortex but rather between the posterior parietal-premotor areas and the dorsolateral prefrontal-hippocampus areas.     

A critical role for D1 receptors in the 5-HT1A-mediated facilitation of in vivo acetylcholine release in rat frontal cortex

Subcutaneous administration of 8-OH-DPAT dose-dependently increased acetylcholine (ACh) output in frontal cortex of awake rats. The maximal effect of 8-OH-DPAT (0.5 mg/kg, s.c.) was prevented by the 5-HT_1A antagonist WAY 100635 (1 mg/kg, s.c.) and by the D₁ antagonists SCH 23390 or SCH 39166 (both 0.3 mg/kg, s.c.) but not seven days after chemical lesion of the raphe serotoninergic neurons. It is postulated that the 8-OH-DPAT activation of postsynaptic 5-HT_1A receptors enhances the release of dopamine which, by acting at D₁ receptors, stimulates the release of ACh in the frontal cortex.     

The intrastratial injection of an adenosine A(2) receptor antagonist prevents frontal cortex EEG abnormalities in a rat model of Huntington's disease.

The influence of 3,7-dimethyl-1-propargylxanthine (DMPX) an adenosine A(2) receptor antagonist, was studied in the quinolinic acid (QA) model of Huntington's disease. Male Wistar rats received bilateral intrastriatal injections of QA (300 nmol) alone or plus DMPX (0.02, 0.2 and 2 microg). At the dose of 0.2 microg, DMPX completely prevented QA-induced EEG abnormalities at the level of frontal cortex. The results support the hypothesis of a neuroprotective role of adenosine A(2) receptor antagonists.     

Metabolic changes after repetitive transcranial magnetic stimulation (rTMS) of the left prefrontal cortex: a sham-controlled proton magnetic resonance spectroscopy (1H MRS) study of healthy brain

Rapid transcranial magnetic stimulation is being increasingly used in the treatment of psychiatric disorders, especially major depression. However, its mechanisms of action are still unclear. The aim of this study was to assess metabolic changes by proton magnetic resonance spectroscopy following high-frequency rapid transcranial magnetic stimulation (20 Hz), both immediately after a single session and 24 h after a series of five consecutive sessions. Twelve healthy volunteers were enrolled in a prospective single-blind, randomized study [sham (n = 5) vs. real (n = 7)]. Three brain regions were investigated (right, left dorsolateral prefrontal cortex, left anterior cingulate cortex). A single as well as a series of consecutive rapid transcranial magnetic stimulations affected cortical glutamate/glutamine levels. These effects were present not only close to the stimulation site (left dorsolateral prefrontal cortex), but also in remote (right dorsolateral prefrontal cortex, left cingulate cortex) brain regions. Remarkably, the observed changes in glutamate/glutamine levels were dependent on the pre-transcranial magnetic stimulation glutamate/glutamine concentration, i.e. the lower the pre-stimulation glutamate/glutamine level, the higher the glutamate/glutamine increase observed after short- or long-term stimulation (5 days). In general, the treatment was well tolerated and no serious side-effects were reported. Neither transient mood changes nor significant differences in the outcome of a series of neuropsychological test batteries after real or sham transcranial magnetic stimulation occurred in our experiment. In summary, these data indicate that rapid transcranial magnetic stimulation may act via stimulation of glutamatergic prefrontal neurons.     

Structural evidence for the neurotoxicity of methylamphetamine in the frontal cortex of gerbils (Meriones unguiculatus): a light and electron microscopical study

Morphological alterations in the CNS were investigated in young gerbils treated with two injections of methylamphetamine (Meth) 8 h apart and killed 3, 5 and 7 days after treatment. In gerbils treated with 2 X 35 mg/kg or higher doses of Meth and prepared according to the terminal degeneration method of Gallyas et al. (Stain Technol., 55 (1980) 299-306), silver precipitates occurred in lamina II and III of the frontal cortex. Electron microscopical studies showed degenerated terminals and neurons. After 3 days of survival we found affected but not degenerating pyramidal cells in the same area. Light microscopical observations after 5 and 7 days of survival indicate a recovery of these cells. All described morphological alterations could be suppressed when Meth was administered in combination with haloperidol. These data and the comparison of aminergic projections to the cortex are discussed on the basis of evidence that Meth induces alteration of mesocortical dopamine nerve fibers and their postsynaptic structures in the frontal cortex (FC). Present results indicate that morphological alterations in young gerbils after Meth treatment are limited to the FC. This is in contrast to the literature, which describes neurotoxic effects of Meth in the neostriatum of various adult mammalian species.