Patricia T. Michie

Event-related potentials in clinical research: Guidelines for eliciting, recording, and quantifying mismatch negativity, P300, and N400

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.

Decrement of the N1 auditory event-related potential with stimulus repetition: Habituation vs. refractoriness

We examined whether the amplitude decrement traditionally found for the N1 peak of the event-related potential (ERP) with repetition of auditory stimuli results from the process of habituation or from the refractory period of the neural elements underlying the N1 response. These competing accounts of the process underlying the N1 decrement with repetition differ in terms of the predicted effects of variations in stimulus repetition and interstimulus interval (ISI). These predictions were examined using a short-term habituation design with a factorial combination of stimulus repetition and ISI. Forty-five subjects received 21 stimulus trains, each consisting of seven innocuous tones, all at 1 kHz except the sixth, which was a 1.5-kHz tone. Each subject was assigned to one of three ISI conditions (either 1, 3 or 10 s). The results provide little support for the view that N1 response decrement with stimulus repetition reflects a process of habituation. The present results provide greater support for the view that this decrement is based on the separate refractory periods or recovery cycle processes of at least two neural generators contributing to activity in the N1 peak latency range.

Differential impairments of selective attention due to frequency and duration of cannabis use

The evidence for long-term cognitive impairments associated with chronic use of cannabis has been inconclusive. We report the results of a brain event-related potential (ERP) study of selective attention in long-term cannabis users in the unintoxicated state. Two ERP measures known to reflect distinct components of attention were found to be affected differentially by duration and frequency of cannabis use. The ability to focus attention and filter out irrelevant information, measured by frontal processing negativity to irrelevant stimuli, was impaired progressively with the number of years of use but was unrelated to frequency of use. The speed of information processing, measured by the latency of parietal P300, was delayed significantly with increasing frequency of use but was unaffected by duration of use. The results suggest that a chronic buildup of cannabinoids produces both short- and long-term cognitive impairments.

What has MMN revealed about the auditory system in schizophrenia

Evidence that deficits in early auditory processing occur in schizophrenia was first provided by an ERP study demonstrating that mismatch negativity (MMN) to duration increments is reduced in medicated patients. Our subsequent research, which is reviewed in this paper, demonstrates that duration MMN reduction cannot be attributed to neuroleptic medication, and is specific to schizophrenia. It is not dependent upon the nature of the task used to distract attention away from the auditory modality. Most importantly, a reduced duration MMN in schizophrenia is a replicable result, having been observed in multiple independently-selected groups of patients from two separate laboratories. It also occurs in unaffected first-degree relatives of patients, suggesting that it may be a vulnerability marker of the disorder. The most intriguing questions however, relate to what underpins the reduced MMN to duration increments in schizophrenia and therefore, what it reveals about the nature of the auditory system deficit in this disorder. Three hypotheses are considered here: a pervasive problem in auditory sensory memory; a specific impairment in duration processing; or an abnormality within the window of temporal integration, coincident with the early phase of auditory sensory memory. Our data so far offer preliminary support for the third hypothesis only, although the possibility of a more broadly defined deficit in temporal processing restricted to brief or rapidly-presented auditory stimuli is canvassed.

Electrophysiological correlates of anticipatory and poststimulus components of task switching

Task-switching paradigms can shed light on cognitive and neural processes underlying attentional control mechanisms. An alternating runs task-switching paradigm (R. D. Rogers & S. Monsell, 1995) is used to identify ERP components associated with anticipatory and poststimulus components of task-switching processes. Subjects alternated between two tasks in a predictable series (AABB). Reaction time (RT) switch cost reduced with increasing response-stimulus (R-S) interval and a residual switch cost remained at the longest R-S interval. A switch-related positivity (D-Pos) developed in the R-S interval. D-Pos was time-locked to response onset, peaked around 400 ms post-response onset, and was unaffected by task-set interference. A switch-related negativity (D-Neg) emerged after stimulus onset. D-Neg peaked earlier with increasing R-S interval and its amplitude and latency were affected by task-set interference. D-Pos and D-Neg were interpreted within current models of task-switching.

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.

Genetic Evidence for a Distinct Subtype of Schizophrenia Characterized by Pervasive Cognitive Deficit

A novel phenotyping strategy in schizophrenia, targeting different neurocognitive domains, neurobehavioral features, and selected personality traits, has allowed us to identify a homogeneous familial subtype of the disease, characterized by pervasive neurocognitive deficit. Our genome scan data indicate that this subtype, which accounts for up to 50% of our sample, has a distinct genetic basis and explains linkage to chromosome 6p24 reported previously. If representative of other populations, the ratio of schizophrenia subtypes observed in our families could have a profound impact on sample heterogeneity and on the power of genetic studies to detect linkage and association. Our proposed abbreviated battery of tests should facilitate phenotype characterization for future genetic analyses and allow a focus on a crisply defined schizophrenia subtype, thus promoting a more informed search for susceptibility genes.

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.

Auditory hallucinations in schizophrenia: Intrusive thoughts and forgotten memories

Introduction. This paper presents a new cognitive model of auditory hallucinations in schizophrenia. We suggest that auditory hallucinations are auditory representations derived from the unintentional activation of memories and other irrelevant current mental associations. Our model proposes that a combination of deficits in intentional inhibition and contextual memory is critical to the experience of auditory hallucinations. The failure in intentional inhibition produces unwanted and uncontrollable mental events which are not recognised because they have lost the contextual cues that would normally facilitate recognition. Methods. This article amalgamates recently published data and presents a reanalysis of the findings on 43 patients with a diagnosis of schizophrenia (Badcock, Waters, Maybery, & Michie, 2005; Waters, Badcock, Maybery, & Michie, 2003a; Waters, Maybery, Badcock, & Michie, 2004a). Relative risk was also estimated to determine whether the combination of deficits increases the risk of having auditory hallucinations. Results. Almost 90% of patients currently experiencing auditory hallucinations showed the predicted combination of deficits on both inhibition and context memory, compared to only a third of patients without hallucinations. In addition, the results showed that those patients with the specified cognitive deficits were at an especially increased risk of having auditory hallucinations relative to patients without the deficits. Conclusions. The results of our investigations strongly support the role of intentional inhibition and context memory in auditory hallucinations. Critical consideration of the findings also suggests that additional cognitive processes might be important for the expression of this symptom.

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.