Background Reduction in a pre-attentive measure of auditory change detection, mismatch negativity (MMN), is one of the most consistent findings in schizophrenia. Recently, our group showed a ...reduction in MMN to changes in the duration and intensity of background sounds in those within 5 years of illness onset, whereas reduced MMNs to changes in sound frequency were only seen in patients with longer illness duration. In this report, we examine whether reduced MMN, as well as P3a, another index of auditory deviance detection, to duration changes is evident even earlier in the illness, that is, in individuals in the first episode of a psychosis (FEP) and individuals identified as being at ultra-high risk of developing schizophrenia (UHR). Methods Mismatch negativity and P3a were measured in 30 UHR individuals, 10 FEP individuals, and 20 healthy control subjects to both long (100 msec) and short (50 msec) duration deviant sounds. Results Mismatch negativity was reduced to both duration deviants not only in the FEP group but also in the UHR group. P3a amplitude was also reduced in the UHR group but at trend level only in FEP. However, MMN and P3a reductions were unrelated in both UHR and FEP groups, suggesting that they reflect distinct deficits. Conclusions These results suggest that MMN, as well as P3a, to duration deviants are reduced in very early stages of a psychotic illness including those in an at-risk mental state. Both should be considered as potential markers of the prodrome.
•Mismatch negativity (MMN) in humans is a very specific phenomenon with several important attributes.•One of the most important attributes of MMN in humans is deviance detection.•Several studies in ...rats have now demonstrated that the rat brain is capable of generating an MMN-like deviance detection response.
The mismatch negativity (MMN) component of the auditory event-related potential, elicited in response to unexpected stimuli in the auditory environment, has great value for cognitive neuroscience research. It is changed in several neuropsychiatric disorders such as schizophrenia. The ability to measure and manipulate MMN-like responses in animal models, particularly rodents, would provide an enormous opportunity to learn more about the neurobiology underlying MMN. However, the MMN in humans is a very specific phenomenon: how do we decide which features we should focus on emulating in an animal model to achieve the highest level of translational validity? Here we discuss some of the key features of MMN in humans and summarise the success with which they have been translated into rodent models. Many studies from several different labs have successfully shown that the rat brain is capable of generating deviance detection responses that satisfy of the criteria for the human MMN.
Abstract This paper describes recommended methods for the use of event-related brain potentials (ERPs) in clinical research and reviews applications to a variety of psychiatric and neurological ...disorders. Techniques are presented for eliciting, recording, and quantifying three major cognitive components with confirmed clinical utility: mismatch negativity (MMN), P300, and N400. Also highlighted are applications of each of the components as methods of investigating central nervous system pathology. The guidelines are intended to assist investigators who use ERPs in clinical research, in an effort to provide clear and concise recommendations and thereby to standardize methodology and facilitate comparability of data across laboratories.
The onset of schizophrenia is typically preceded by a prodromal period lasting several years during which sub-threshold symptoms may be identified retrospectively. Clinical interviews are currently ...used to identify individuals who have an ultra-high risk (UHR) of developing a psychotic illness with a view to provision of interventions that prevent, delay or reduce severity of future mental health issues. The utility of bio-markers as an adjunct in the identification of UHR individuals is not yet established. Several event-related potential measures, especially mismatch-negativity (MMN), have been identified as potential biomarkers for schizophrenia. In this 12-month longitudinal study, demographic, clinical and neuropsychological data were acquired from 102 anti-psychotic naive UHR and 61 healthy controls, of whom 80 UHR and 58 controls provided valid EEG data during a passive auditory task at baseline. Despite widespread differences between UHR and controls on demographic, clinical and neuropsychological measures, MMN and P3a did not differ between these groups. Of 67 UHR at the 12-month follow-up, 7 (10%) had transitioned to a psychotic illness. The statistical power to detect differences between those who did or did not transition was limited by the lower than expected transition rate. ERPs did not predict transition, with trends in the opposite direction to that predicted. In exploratory analysis, the strongest predictors of transition were measures of verbal memory and subjective emotional disturbance.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Mismatch negativity (MMN) is a change-detection response.•MMN generation requires intact sensory memory processes and synaptic plasticity.•MMN responses are reduced by antagonists of the NMDA ...receptor.•Recent studies have also shown that other neurotransmitters may play a role in MMN.
Mismatch negativity (MMN) is an electrophysiological signature that occurs in response to unexpected stimuli. It is often referred to as a measure of memory-based change detection, because the elicitation of a prediction error response relies on the formation of a prediction, which in turn, is dependent upon intact memory of previous auditory stimulation. As such, the MMN is altered in conditions in which memory is affected, such as Alzheimer’s disease, schizophrenia and healthy aging. The most prominent pharmacological finding for MMN strengthens the link between MMN and synaptic plasticity, as glutamate N-methyl-d-aspartate receptor (NMDA-R) antagonists reduce the MMN response. However, recent data has begun to demonstrate that the link between NMDA-R function and MMN is not as clear as once thought, with low dose and low affinity NMDA-R antagonists observed to facilitate MMN.
Access to cannabis and cannabinoid products is increasing worldwide for recreational and medicinal use. Two primary compounds within cannabis plant matter, Δ
9
-tetrahydrocannabinol (THC) and ...cannabidiol (CBD), are both psychoactive, but only THC is considered intoxicating. There is significant interest in potential therapeutic properties of these cannabinoids and of CBD in particular. Some research has suggested that CBD may ameliorate adverse effects of THC, but this may be dose dependent as other evidence suggests possible potentiating effects of THC by low doses of CBD. We conducted a randomised placebo controlled trial to examine the acute effects of these compounds alone and in combination when administered by vaporisation to frequent and infrequent cannabis users. Participants (
n
= 36; 31 male) completed 5 drug conditions spaced one week apart, with the following planned contrasts: placebo vs CBD alone (400 mg); THC alone (8 mg) vs THC combined with low (4 mg) or high (400 mg) doses of CBD. Objective (blind observer ratings) and subjective (self-rated) measures of intoxication were the primary outcomes, with additional indices of intoxication examined. CBD showed some intoxicating properties relative to placebo. Low doses of CBD when combined with THC enhanced, while high doses of CBD reduced the intoxicating effects of THC. The enhancement of intoxication by low-dose CBD was particularly prominent in infrequent cannabis users and was consistent across objective and subjective measures. Most effects were significant at
p
< .0001. These findings are important to consider in terms of recommended proportions of THC and CBD in cannabis plant matter whether used medicinally or recreationally and have implications for novice or less experienced cannabis users.
Trial registration: ISRCTN Registry Identifier: ISRCTN24109245.
Mismatch negativity (MMN) is a component of the event-related potential elicited by deviant auditory stimuli. It is presumed to index pre-attentive monitoring of changes in the auditory environment. ...MMN amplitude is smaller in groups of individuals with schizophrenia compared to healthy controls. We compared duration-deviant MMN in 16 recent-onset and 19 chronic schizophrenia patients versus age- and sex-matched controls. Reduced frontal MMN was found in both patient groups, involved reduced hemispheric asymmetry, and was correlated with Global Assessment of Functioning (GAF) and negative symptom ratings. A cortically-constrained LORETA analysis, incorporating anatomical data from each individual's MRI, was performed to generate a current source density model of the MMN response over time. This model suggested MMN generation within a temporal, parietal and frontal network, which was right hemisphere dominant only in controls. An exploratory analysis revealed reduced CSD in patients in superior and middle temporal cortex, inferior and superior parietal cortex, precuneus, anterior cingulate, and superior and middle frontal cortex. A region of interest (ROI) analysis was performed. For the early phase of the MMN, patients had reduced bilateral temporal and parietal response and no lateralisation in frontal ROIs. For late MMN, patients had reduced bilateral parietal response and no lateralisation in temporal ROIs. In patients, correlations revealed a link between GAF and the MMN response in parietal cortex. In controls, the frontal response onset was 17 ms later than the temporal and parietal response. In patients, onset latency of the MMN response was delayed in secondary, but not primary, auditory cortex. However amplitude reductions were observed in both primary and secondary auditory cortex. These latency delays may indicate relatively intact information processing upstream of the primary auditory cortex, but impaired primary auditory cortex or cortico-cortical or thalamo-cortical communication with higher auditory cortices as a core deficit in schizophrenia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mismatch negativity (MMN) is a scalp-recorded electrical potential that occurs in humans in response to an auditory stimulus that defies previously established patterns of regularity. MMN amplitude ...is reduced in people with schizophrenia. In this study, we aimed to develop a robust and replicable rat model of MMN, as a platform for a more thorough understanding of the neurobiology underlying MMN. One of the major concerns for animal models of MMN is whether the rodent brain is capable of producing a human-like MMN, which is not a consequence of neural adaptation to repetitive stimuli. We therefore tested several methods that have been used to control for adaptation and differential exogenous responses to stimuli within the oddball paradigm. Epidural electroencephalographic electrodes were surgically implanted over different cortical locations in adult rats. Encephalographic data were recorded using wireless telemetry while the freely-moving rats were presented with auditory oddball stimuli to assess mismatch responses. Three control sequences were utilized: the flip-flop control was used to control for differential responses to the physical characteristics of standards and deviants; the many standards control was used to control for differential adaptation, as was the cascade control. Both adaptation and adaptation-independent deviance detection were observed for high frequency (pitch), but not low frequency deviants. In addition, the many standards control method was found to be the optimal method for observing both adaptation effects and adaptation-independent mismatch responses in rats. Inconclusive results arose from the cascade control design as it is not yet clear whether rats can encode the complex pattern present in the control sequence. These data contribute to a growing body of evidence supporting the hypothesis that rat brain is indeed capable of exhibiting human-like MMN, and that the rat model is a viable platform for the further investigation of the MMN and its associated neurobiology.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•MMN reduction in schizophrenia most likely arises from reduced neural synchrony of brain activity.•Decreased expression of the obligatory NR1 subunit of NMDA receptors in schizophrenia could ...underpin reduced neural synchrony.•Early ERP components in the middle latency range (MLR) and MMN exhibit deviance detection in healthy individuals.•Whether deviance detection in MLRs is affected in schizophrenia has not been investigated.•An unresolved issue is whether reduced MMN in schizophrenia is due to deficits in adaptation or impaired deviance detection•Use of animal models and novel methodologies are needed to advance understanding of reduced MMN in schizophrenia.
Although the scientific community appears to know a lot about MMN, about its neural generators and the computational processes that underlie its generation, do we have sufficient knowledge to understand what causes the reduction of MMN amplitude in schizophrenia? Here we attempt to integrate the evidence presented in this series of papers for the special issue on MMN in schizophrenia together with evidence from other new relevant research and ask—what have we learnt? While MMN research was the purview for decades of psychophysiologists interested in event-related potentials derived from scalp recorded EEG, it is now part of mainstream neuroscience research attracting the interest of basic auditory neuroscientists, neurobiologists and computational modellers. The confluence of these developments together with increasing clinical research has certainly advanced our understanding of the causes of reduced MMN in schizophrenia as this integrative review attempts to demonstrate—but much remains to be learnt. Future advances will rely on the application of multiple methodologies and approaches in order to arrive at better understanding of the neurobiology of MMN and implications for schizophrenia.
Reduced mismatch negativity (MMN), a robust finding in schizophrenia, has prompted interest in MMN as a preclinical biomarker of schizophrenia. The rat brain can generate human‐like mismatch ...responses (MMRs) which therefore enables the exploration of the neurobiology of reduced MMRs. Given epidemiological evidence that two developmental factors, maternal infection and adolescent cannabis use, increase the risk of schizophrenia, we determined the effect of these two developmental risk factors on rat MMR amplitude in different auditory contexts. MMRs were assessed in awake adult male and female Wistar rats that were offspring of pregnant dams treated with either a viral infection mimetic (poly I:C) inducing maternal immune activation (MIA) or saline control. In adolescence, subgroups of the prenatal treatment groups were exposed to either a synthetic cannabinoid (adolescent cannabinoid exposure: ACE) or vehicle. The context under which MMRs were obtained was manipulated by employing two different oddball paradigms, one that manipulated the physical difference between rare and common auditory stimuli, and another that manipulated the probability of the rare stimulus. The design of the multiple stimulus sequences across the two paradigms also allowed an investigation of context on MMRs to two identical stimulus sequences. Male offspring exposed to each of the risk factors for schizophrenia (MIA, ACE or both) showed a reduction in MMR, which was evident only in the probability paradigm, with no effects seen in the physical difference. Our findings highlight the importance of contextual factors induced by paradigm manipulations and sex for modeling schizophrenia‐like MMN impairments in rats.
Our findings demonstrate a schizophrenia‐like reduction in the size of the mismatch responses in a developmental risk factor rat model, a novel finding as the previous research have shown similar effects in pharmacologically manipulated animal models only. The current results underscore the importance of paradigm in utilizing the mismatch negativity as a biomarker for schizophrenia in future studies.
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