Connie C. Duncan

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.

A Nosology of Disorders of Attention

Abstract: The trailblazing research on sleep mechanisms and petit mal epilepsy, conducted during the period from 1940 through 1970, illuminated the brain substrate for normal consciousness and attention, as well as their disorders. This research helped inform and structure our neuropsychologically based model of the “elements” of attention. The model has been used to assess attention in the research laboratory and clinic, and has led to a “nosology of disorders of attention,” which is presented here in preliminary form. The nosology reviews the possible causes of the symptom(s) of impaired attention, as well as suggesting a blueprint for future research in this area.

A model of attention and its relation to ADHD

We present a neuropsychological model of attention in normal and disordered states, including attention deficit hyperactivity disorder (ADHD). The model is based on a factor analysis of data derived from more than 600 children and adults. The robustness of the model is supported by its replication in a number of studies and its application in numerous investigations. It divides attention into a number of elements or factors including the capacities of encoding, focusing, and executing responses, sustaining attention, shifting attention, as well as a measure of response stability. The factors are assessed by measures derived from neuropsychological tests; we have posited a system of brain structures that maintains the elements of attention, each of which may be supported by a distinct cerebral region. We illustrate the use of the model in an investigation in progress of children referred to an inner-city family clinic for evaluation of ADHD. The ADHD study indicates that a number of aspects of attention are impaired in children diagnosed with ADHD, and that the deficient attention is probably not attributable to learning disorders. We also speculate on the possible role of immaturity of brain development in ADHD. MRDD Research Reviews 1999;5:169–176. Published 1999 Wiley-Liss, Inc.

Evaluation of traumatic brain injury: Brain potentials in diagnosis, function, and prognosis

The focus of this review is an analysis of the use of event-related brain potential (ERP) abnormalities as indices of functional pathophysiology in survivors of traumatic brain injury (TBI). TBI may be the most prevalent but least understood neurological disorder in both civilian and military populations. In the military, thousands of new brain injuries occur yearly; this lends considerable urgency to the use of highly sensitive ERP tools to illuminate brain changes and to address remediation issues. We review the processes thought to be indexed by the cognitive components of the ERP and outline the rationale for applying ERPs to evaluate deficits after TBI. Studies in which ERPs were used to clarify the nature of cognitive complaints of TBI survivors are reviewed, emphasizing impairment in attention, information processing, and cognitive control. Also highlighted is research on the application of ERPs to predict emergence from coma and eventual outcome. We describe primary blast injury, the leading cause of TBI for active duty military personnel in present day warfare. The review concludes with a description of an ongoing investigation of mild TBI, aimed at using indices of brain structure and function to predict the course of posttraumatic stress disorder. An additional goal of this ongoing investigation is to characterize the structural and functional sequelae of blast injury.

Event-related potential assessment of information processing after closed head injury.

We evaluated alterations in information processing after closed head injury as a function of task demands and stimulus modality. Visual and auditory discrimination tasks were administered to 11 survivors of a head injury and 16 matched healthy controls. In auditory tasks, compared with controls, the survivors had smaller N100s, smaller and later N200s, a more posterior scalp distribution of N200, and longer P300 and response latencies. Auditory N200 and P300 correlated highly with duration of unconsciousness. In contrast, in visual tasks, only a reduced N200 in the survivors differentiated the groups. Our results indicate that processing of auditory stimuli, including the perception and discrimination of stimulus features and the evaluation and categorization of stimuli, may be impaired after head trauma. Visual sensory processing may be spared, but higher-order visual processing involved in stimulus classification may be compromised.

Season, gender, and P300

Light therapy in patients with seasonal affective disorder has been reported to enhance visual P300 amplitude. This findings raises the possibility that variations in P300 occur naturally in nonpatients as a function of seasonal variation in sunlight. In the present investigation, P300 was studied in a sample of psychiatrically screened normal subjects who were tested at different times of the year. P300 was larger in women than men and varied in relation to season. This pattern is relevant to studies in which subjects are tested under varying sunlight conditions, such as different seasons. In addition, variations in P300 in normal subjects may be relevant to an understanding of the effectiveness of light therapy for patients with seasonal affective disorder.

When it's time for a change: Failures to track context in schizophrenia

INTRODUCTION Reduction of P300 event-related potential amplitude in schizophrenia is perhaps the most replicated biological reflection of the illness. P300 is typically elicited by infrequent deviant events that are imbedded in a series of identical frequent standard events. Deviants have features that explicitly distinguish them from standards, whereas standards can be distinguished from each other based on their local sequential probabilities within the stimulus series. The improbable occurrence of a standard should generate a P300, but only if the implicit local context generated by the recent stimulus history is processed. METHOD To assess the ability of schizophrenia patients to process this implicit contextual information, ERPs were elicited from 22 controls and 16 schizophrenia patients during an auditory oddball task containing infrequent target tones (15%) and novel distracter sounds (15%) imbedded pseudo-randomly in a series of standard tones (70%). Consecutively presented standards following deviant stimuli varied in sequential probability from p=1.0 for the 1st standard to p=0.16 for the 4th consecutive standard. RESULTS Patients compared to controls demonstrated smaller P300 (P3a) to the fourth consecutive standard. However, in controls but not patients a contingent negative variation (CNV) was observed prior to the fourth standard, and an N2b/mismatch negativity (MMN) was observed following it. CONCLUSIONS These outcomes suggest that patients are deficient in using the implicit context established by recent stimulus history to anticipate that an otherwise standard stimulus was unlikely and its occurrence unexpected.

Assessment of the attention impairment in absence epilepsy: comparison of visual and auditory P300.

We report an investigation of P300 measures of information processing in patients with generalized epilepsy of the absence type and those with complex partial epilepsy. Studies have demonstrated that absence patients perform more poorly than complex partial patients on behavioral tests of sustained attention (the Continuous Performance Test, or CPT). Duncan [Duncan, C.C., 1988. Application of event-related brain potentials to the analysis of interictal attention in absence epilepsy. In: Myslobodsky, M.S., Mirsky, A.F. (Eds.), Elements of Petit Mal Epilepsy. Peter Lang, New York, pp. 341-364] reported that P300 was significantly reduced in a group of absence patients as compared with healthy controls. The present investigation was undertaken to compare the attention deficit in absence patients to that in complex partial seizure patients. Thus, ERPs were recorded while participants with absence seizure disorder, complex partial seizure disorder, and healthy controls performed auditory and visual versions of the CPT. A significant reduction in the amplitude of P300 on the visual CPT was observed in both groups of seizure patients as compared to controls. In contrast, P300 on the auditory CPT was reduced only in the group with absence seizures. These ERP data support and amplify previous behavioral findings of the impaired capacity of absence patients to mobilize and sustain attentional resources. Auditory sustained attention seems to be more affected by the pathophysiology of absence epilepsy than visual attention. Two possible factors may be involved: (a) There are separate visual and auditory attention systems in the brain, and the latter is more vulnerable than the former [Duncan, C.C., Kosmidis, M.H., Mirsky, A.F., 2005. Closed head injury-related information processing deficits: An event-related potential analysis. Int. J. Psychophysiol. 58, 133-157]; and (b) Auditory processing depends on intact mechanisms in the brainstem, which are dysfunctional in patients with absence seizures.

Evidence for a new late positive ERP component in an attended novelty oddball task

In attended novelty oddball tasks, rare nontarget stimuli can elicit two late positive ERP components: P3a and P300. In passive oddball tasks, P300 is not elicited by these stimuli. In passive tasks, however, P3a is accompanied by another positive component, termed eP3a, which may have evaded detection in attended oddball tasks because of its spatiotemporal overlap with P300. To address this, temporal-spatial principal components analysis was used to quantify ERPs recorded in attended three-tone and novelty oddball tasks. As expected, novel stimuli elicited both P3a and P300. The analysis also identified a third component, evident in novelty ERPs as an inflection on the leading edge of P3a. This component has the same antecedent conditions as P3a, but is earlier and more centrally distributed. Its spatiotemporal characteristics suggest that it may be the eP3a component recently described in passive oddball tasks.

Brain potential indices of novelty processing are associated with preference for amphetamine.

A behavioral drug preference procedure was used to identify two groups of healthy individuals. One group preferred 10 mg of d-amphetamine over placebo (Choosers) and the other preferred placebo (Nonchoosers). In separate sessions, participants were administered placebo, 10, and 15 mg of d-amphetamine, and event-related brain potentials (ERPs) were recorded while participants performed two 3-stimulus oddball tasks. The effect of d-amphetamine on P3a, an ERP index of the orienting response, differed between groups: In Choosers, target stimuli elicited P3a after d-amphetamine but not after placebo; in Nonchoosers, the drug had no effect on P3a. Moreover, two group differences were evident after placebo and were unaffected by d-amphetamine. (1) N100 was larger in Nonchoosers than in Choosers, suggesting that Nonchoosers were more attentive than Choosers to the physical features of the stimuli. (2) The reorienting negativity (RON) elicited by targets in both tasks and by rare nontargets in a novelty oddball task (i.e., novel sounds) was larger in Nonchoosers than in Choosers. This suggests that Nonchoosers more effectively refocused attention on the task after distraction. It is hypothesized that these processing differences reflect a group difference in the balance between midbrain dopamine function and ascending cholinergic influences. The findings have implications for vulnerability to addiction and illustrate the promise of ERPs in parsing elemental phenotypes.