Juanita Todd

Duration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders

BACKGROUND One of the most consistent findings in schizophrenia research over the past decade is a reduction in the amplitude of an auditory event-related brain potential known as mismatch negativity (MMN), which is generated whenever a deviant sound occurs in a background of repetitive auditory stimulation. The reduced amplitude of MMN in schizophrenia was first observed for deviant sounds that differ in duration relative to background standard sounds, and similar findings have been observed for sounds that are deviant in frequency. The aim of this study was to determine whether first-degree relatives of schizophrenia patients show a similar reduction in MMN amplitude to duration deviants. METHODS We measured MMN to duration increments (deviants 100 msec vs. standards 50 msec) in 22 medicated patients with a diagnosis in the schizophrenia spectrum, 17 individuals who were first-degree unaffected relatives of patients, and 21 healthy control subjects. RESULTS Mismatch negativity amplitude was reduced in patients and relatives compared with control subjects. There were no significant differences between patients and relatives. In contrast, the subsequent positive component, P3a, was larger in relatives compared with patients. CONCLUSIONS These findings suggest that a reduced MMN amplitude may be an endophenotype marker of the predisposition to schizophrenia.

Deviant Matters: Duration, Frequency, and Intensity Deviants Reveal Different Patterns of Mismatch Negativity Reduction in Early and Late Schizophrenia

BACKGROUND A reduction in the size of the auditory event-related potential component known as mismatch negativity (MMN) is a consistent finding in schizophrenia. This study was designed to test the hypothesis that sound intensity and duration might be more sensitive to MMN reduction early in the development of schizophrenia because of the computational complexity in extracting these two sound dimensions. METHODS The MMN elicited to sounds deviating in duration, frequency, or intensity was measured in participants with a short (n = 14, mean 2.6 years) and longer length of illness (n = 29, mean 18.9 years) relative to healthy age-matched control subjects. RESULTS For participants early in the illness, a clear reduction was evident in MMN to duration and intensity but not frequency deviants. A different pattern was observed in patients with a longer length of illness--that is, a reduction in frequency and in duration to a lesser degree but not intensity MMN. CONCLUSIONS The results indicate a pronounced age-related decline in duration and intensity MMN in control subjects that might reduce the sensitivity of these indices in schizophrenia when measured later in the course of the illness. The MMN elicited to changes in different sound properties provides potentially complementary information on the onset and progression of neuropathological changes that underlie the reduction in MMN in schizophrenia.

Duration and frequency mismatch negativity in schizophrenia

OBJECTIVES The aim of the present study was to elucidate the reasons for apparent inconsistencies in the schizophrenia literature with respect to the mismatch negativity (MMN) waveform of the event-related potential (ERP). While most previous research has shown that MMN is reduced in schizophrenia, there are a small number of studies reporting that frequency MMN is not reduced. METHODS We recorded ERPs to auditory stimuli with different frequencies and durations from patients with schizophrenia (N = 14) and control subjects (N = 17) of similar age and sex. MMNs to small but discriminable frequency deviants were contrasted with large frequency deviants and duration deviants. RESULTS Only the MMN to duration deviants was significantly reduced in patients, although there was evidence of a similar trend for large frequency deviants. CONCLUSIONS The results together with a review of the frequency MMN literature suggest that there are 3 variables which are important in determining whether patients exhibit a reduced MMN to frequency deviants: deviant probability, degree of deviance and interstimulus interval. The results also indicated that patients with schizophrenia may have particular deficits in processing the temporal properties of auditory stimuli. This finding has implications for the pathophysiology of the disorder as time-dependent processing is reliant on the integrity of an extensive network of brain areas consisting of auditory cortex, areas of pre-frontal cortex, the basal ganglia and cerebellum.

Preliminary investigation of gene expression profiles in peripheral blood lymphocytes in schizophrenia.

Schizophrenia is a heterogenous disorder that is phenomenologically characterised by a combination of negative, positive, and cognitive symptoms with variable expression in the course of illness. Here, we investigated differential gene expression in relation to age to address the heterogeneity of this disorder We used 6000 gene cDNA microarrays to generate gene expression profiles from peripheral blood lymphocytes from 14 individuals with schizophrenia and 14 non-psychiatric controls. Genes showing altered expression were identified and 18 genes with brain-related functions were altered, 4 of which, endothelial differentiation gene 2 (Edg-2), ezrin-radixin-moesin phosphoprotein 50 (EBP50), Myc-associated zinc finger protein (MAZ) and Tumor Necrosis Factor Receptor 2 (TNFR2), were confirmed by relative real-time PCR. Dendrograms were constructed using genes that showed significantly different expression (p<0.05) between groups based on median split of age dividing the matched pairs into distinct subclasses. Our findings suggest that distinct gene expression profiles in peripheral blood lymphocytes associated with schizophrenia phenotypes may provide a first step towards the biological classification of schizophrenia subtypes. The validity of this approach may lead to better methods of defining this enigmatic disease.

Impairment in activation of a frontal attention-switch mechanism in schizophrenic patients.

The present study addresses the difference in activities of frontal and temporal mismatch negativity (MMN) generators between healthy controls and schizophrenic patients. Auditory MMNs were measured from 13 medicated schizophrenic patients in a post-acute phase and 12 healthy controls. The probabilities of the standard stimuli were, in different experimental blocks, 95, 90, 80 or 70%. The mean amplitude of the MMN recorded at Fz was significantly smaller in schizophrenic patients than healthy controls only in the conditions with high probability of standard stimuli, while that recorded at mastoid sites was not different in any condition. The present study suggested that schizophrenic patients might fail to cause involuntary attention switch to stimulus change reflected in the lowered MMN amplitude recorded at Fz; whereas the patients might index an adequate detection of the deviant event reflected by the similar amplitude of MMN recorded at mastoid sites.

Association between reduced duration mismatch negativity (MMN) and raised temporal discrimination thresholds in schizophrenia

OBJECTIVE The event-related potential known as mismatch negativity (MMN) is elicited whenever the auditory system detects a change against an invariant background of stimulation. A reduction in mismatch negativity is well established in schizophrenia. The present study explored the association between reduced duration mismatch negativity in schizophrenia and behavioural measures of temporal discrimination. METHOD Mismatch negativity amplitude to duration increments (125 vs. 50 ms) was compared between individuals with schizophrenia and healthy controls. Mismatch negativity amplitude was also related to two behavioural measures of temporal discrimination (silent and filled intervals) for detecting changes in stimuli of similar duration. RESULTS Patients produced higher discrimination threshold estimates and smaller amplitude mismatch negativity responses to temporally deviant stimuli. Temporal discrimination thresholds correlated with the amplitude of the phase reversal in mismatch negativity at the left mastoid such that patients who produced the highest thresholds produced the smallest mismatch response. CONCLUSIONS Imprecise representations of the temporal properties of auditory stimuli can account for some of the reduction in mismatch negativity amplitude in some patients but additional factors clearly contribute. The results suggest that patients who do and do not exhibit temporal processing deficits on behavioural tasks produce different patterns of reduction in duration mismatch negativity.

Mismatch Negativity: Translating the Potential

The mismatch negativity (MMN) component of the auditory event-related potential has become a valuable tool in cognitive neuroscience. Its reduced size in persons with schizophrenia is of unknown origin but theories proposed include links to problems in experience-dependent plasticity reliant on N-methyl-d-aspartate glutamate receptors. In this review we address the utility of this tool in revealing the nature and time course of problems in perceptual inference in this illness together with its potential for use in translational research testing animal models of schizophrenia-related phenotypes. Specifically, we review the reasons for interest in MMN in schizophrenia, issues pertaining to the measurement of MMN, its use as a vulnerability index for the development of schizophrenia, the pharmacological sensitivity of MMN and the progress in developing animal models of MMN. Within this process we highlight the challenges posed by knowledge gaps pertaining to the tool and the pharmacology of the underlying system.

Epidural Auditory Event-Related Potentials in the Rat to Frequency and duration Deviants: Evidence of Mismatch Negativity?

The capacity of the human brain to detect deviance in the acoustic environment pre-attentively is reflected in a brain event-related potential (ERP), mismatch negativity (MMN). MMN is observed in response to the presentation of rare oddball sounds that deviate from an otherwise regular pattern of frequent background standard sounds. While the primate and cat auditory cortex (AC) exhibit MMN-like activity, it is unclear whether the rodent AC produces a deviant response that reflects deviance detection in a background of regularities evident in recent auditory stimulus history or differential adaptation of neuronal responses due to rarity of the deviant sound. We examined whether MMN-like activity occurs in epidural AC potentials in awake and anesthetized rats to high and low frequency and long and short duration deviant sounds. ERPs to deviants were compared with ERPs to common standards and also with ERPs to deviants when interspersed with many different standards to control for background regularity effects. High frequency (HF) and long duration deviant ERPs in the awake rat showed evidence of deviance detection, consisting of negative displacements of the deviant ERP relative to ERPs to both common standards and deviants with many standards. The HF deviant MMN-like response was also sensitive to the extent of regularity in recent acoustic stimulation. Anesthesia in contrast resulted in positive displacements of deviant ERPs. Our results suggest that epidural MMN-like potentials to HF sounds in awake rats encode deviance in an analogous manner to the human MMN, laying the foundation for animal models of disorders characterized by disrupted MMN generation, such as schizophrenia.

Mismatch Negativity (MMN) in Freely-Moving Rats with Several Experimental Controls

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.

Sensory suppression effects to self-initiated sounds reflect the attenuation of the unspecific N1 component of the auditory ERP

The suppression of the auditory N1 event-related potential (ERP) to self-initiated sounds became a popular tool to tap into sensory-specific forward modeling. It is assumed that processing in the auditory cortex is attenuated due to a match between sensory stimulation and a specific sensory prediction afforded by a forward model of the motor command. The present study shows that N1 suppression was dramatically increased with long (≈ 3 s) stimulus onset asynchronies (SOA), whereas P2 suppression was equal in all SOA conditions (0.8, 1.6, 3.2 s). Thus, the P2 was found to be more sensitive to self-initiation effects than the N1 with short SOAs. Moreover, only the unspecific but not the sensory-specific N1 components were suppressed for self-initiated sounds suggesting that N1-suppression effects mainly reflect an attenuated orienting response. We argue that the N1-suppression effect is a rather indirect measure of sensory-specific forward models.