John F. Connolly

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.

Event-related potential components reflect phonological and semantic processing of the terminal word of spoken sentences

An event-related brain potential (ERP) reflecting the acoustic-phonetic process in the phonological stage of word processing was recorded to the terminal words of spoken sentences. The peak latency of this negative-going response occurred between 270 and 300 msec after the onset of the terminal word. The independence of this response (the phonological mismatch negativity, PMN) from the ERP component known to be sensitive to semantic violations (N400) was demonstrated by manipulating sentence endings so that phonemic and semantic violations occurred together or separately. Four conditions used sentences that ended with (1) the highest Cloze probability word (e.g., The piano was out of tune.), (2) a word having the same initial phoneme of the highest Cloze probability word but that was, in fact, semantically anomalous (e.g., The gambler had a streak of bad luggage.), (3) a word having an initial phoneme different from that of the highest Cloze probability word but that was, in fact, semantically appropriate (e.g., Don caught the ball with his glove.), or (4) a word that was semantically anomalous and, therefore, had an initial phoneme that was totally unexpected given the sentences context (e.g., The dog chased our cat up the queen). Neither the PMN nor the N400 was found in the first condition. Only an N400 was observed in the second condition while only a PMN was seen in the third. Both responses were elicited in the last condition. Finally, a delayed N400 occurred to semantic violations in the second condition where the initial phoneme was identical to that of the highest Cloze probability ending. Results are discussed with regard to the Cohort model of word recognition.

Event-related potential sensitivity to acoustic and semantic properties of terminal words in sentences

This experiment was concerned with the effects of phonologically correct masking on the electrophysiological responses to terminal words of spoken sentences differing in contextual constraint. Two event-related potential (ERP) components, the N400 and N200, were recorded to the terminal words of high and low constraint sentences in four conditions. In the Control condition, subjects (Ss) simply attended to the sentences with no explicit task instructions. In the Semantic condition, Ss were required to listen to the stimuli in order to make semantic judgements about the terminal word of each sentence. The Control+Masking condition was identical to the Control condition except for the simultaneous presentation of a masking stimulus. The Semantic+Masking condition had Ss listening to sentences in the presence of masking with the task of making semantic judgements about the terminal word of each sentence. ERPs were recorded from Fz, Cz, Pz, T3, and T4 in 10 subjects. Amplitudes of both the N200 and the N400 were sensitive to contextual constraint with larger responses elicited by the terminal words of low constraint sentences. In addition to demonstrating the co-occurrence of the N200 and N400, this experiment highlighted a functional separation between the two components. Masking had no statistically significant effect on N200 latency but N400 latency was delayed in the masked conditions relative to those in the unmasked conditions. It is proposed that the N200 and N400 are manifestations of two different processes; the N200 reflects the acoustic/phonological processing of the terminal word while the N400 reflects the cognitive/linguistic processing. The relationship between the N200 recorded in this experiment and the discrimination N200 is discussed.

Hemispheric lateralization in preattentive processing of speech sounds.

Event-related magnetoencephalographic (MEG) responses to infrequently presented spoken deviant syllables [di] and [ba] among repetitive standard [da)]syllables were recorded in subjects who either attended to these stimuli in order to discriminate the [ba] syllables or ignored them while attending a silent movie. In both conditions, the deviant syllables elicited a mismatch response (MMNm, the magnetic counterpart of mismatch negativity), which was stronger in the left than in the right auditory cortex, indicating left-hemispheric dominance in speech processing already at a preattentive processing level.

Semantic Cortical Activation in Dyslexic Readers

The combined temporal and spatial resolution of MEG (magnetoencephalography) was used to study whether the same brain areas are similarly engaged in reading comprehension in normal and developmentally dyslexic adults. To extract a semantically sensitive stage of brain activation we manipulated the appropriateness of sentence-ending words to the preceding sentence context. Sentences, presented visually one word at a time, either ended with a word that was (1) expected, (2) semantically appropriate but unexpected, (3) semantically anomalous but sharing the initial letters with the expected word, or (4) both semantically and orthographically inappropriate to the sentence context. In both subject groups all but the highly expected sentence endings evoked strong cortical responses, localized most consistently in the left superior temporal cortex, although additional sources were occasionally found in more posterior parietal and temporal areas and in the right hemisphere. Thus, no significant differences were found in the spatial distribution of brain areas involved in semantic processing between fluent and dyslexic readers. However, both timing and strength of activation clearly differed between the two groups. First, activation sensitivity to word meaning within a sentence context began about 100 msec later in dyslexic than in control subjects. This is likely to result from affected presemantic processing stages in dyslexic readers. Second, the neural responses were significantly weaker in dyslexic than in control subjects, indicating involvement of a smaller or less-synchronous neural population in reading comprehension. Third, in contrast to control subjects, the dyslexic readers showed significantly weaker activation to semantically inappropriate words that began with the same letters as the most expected word than to both orthographically and semantically inappropriate sentence-ending words. Thus, word recognition by the dyslexic group seemed to be qualitatively different: Whereas control subjects perceived words as wholes, dyslexic subjects may have relied on sublexical word recognition and occasionally mistook a correctly beginning word for the one they had expected.

The effects of phonological and semantic features of sentence-ending words on visual event-related brain potentials

Event-related brain potentials (ERPs) were recorded to terminal words of visually presented sentences that were identical to those used in an auditory modality study examining the effects of phonological and semantic characteristics of words on ERPs (Connolly and Phillips, 1994). Phonological and/or semantic characteristics of terminal words were manipulated in 4 conditions in which: (1) the terminal word was the highest cloze probability ending for the sentence and was thus phonologically and semantically appropriate to the sentence context (e.g., Ray fell down and skinned his knee(s).; (2) the terminal word had the initial phonemic sound of the highest cloze probability sentence-ending word but was semantically anomalous to the context of the sentence (e.g., They sat together without saying a single worm. [word]); (3) the initial phoneme of the terminal word was phonologically unexpected but the word was semantically correct (e.g., The dough was put in the hot pan. [oven]); or (4) the initial phoneme of the terminal word was phonologically unexpected and the word was semantically inappropriate to the sentence context (e.g., Bill jumped into the lake and made a big farm. [splash]). A left fronto-temporally distributed negative peak was observed in the 250-300 msec range to varying degrees in all conditions but was largest in the condition in which terminal words were both phonologically unexpected and semantically inappropriate. A second, parietally distributed, symmetrical negativity (the N400) was found which peaked around 365 msec and was largest in the two conditions involving semantically anomalous terminal words. Results are discussed in terms of modality factors in ERP manifestations of receptive language functions and the implications of ERP modality differences for theories of word recognition.

Assessment of working memory abilities using an event-related brain potential (ERP)-compatible digit span backward task ☆

OBJECTIVE This study investigated the effectiveness of an ERP-compatible Digit Span Backward (ERP-DB) task to determine working memory abilities in healthy participants. METHODS Participants were administered both the standard digit span backward and ERP-DB tasks. The ERP-DB task was divided into two sections, consisting of 2, 4, 6 and 8 (Group 1) and 3, 5, and 7 (Group 2) set sizes. A set of digits was aurally presented, followed by a second set that either corresponded to the reverse order of the first set (correct condition) or had one digit in the sequence replaced by an incorrect digit (incorrect condition). RESULTS Two posterior positive components were found to distinguish the two conditions; an earlier positive component (P200/P300) was elicited in the correct condition, whereas a comparatively robust and prolonged positive slow wave (PSW) was elicited in the incorrect condition. Furthermore, the PSW and the difference in PSW amplitude between incorrect and correct conditions (dPSW) dissipated as working memory load increased and were related to working memory capacity. CONCLUSIONS The PSW, dPSW and P200/P300 components were found to be associated with working memory abilities and may have the potential to act as neurophysiological markers for the assessment of working memory capacity. SIGNIFICANCE This research lends support for the utility of the ERP-DB task as a means of assessing working memory abilities, which may have implications for testing patients with expressive communication impairments.

Separating Phonological and semantic processing in auditory sentence processing: A high-resolution event-related brain potential study

Phonological and semantic processing was studied using high‐resolution event‐related brain potentials (ERPs) during a sentence‐matching task to investigate the spatial distribution of the phonological mismatch negativity (PMN) and the N400 response. It was hypothesized that the two components were spatially separable and that the activity matched prior localization knowledge. Participants examined visual–auditory sentence pairs that related within a semantic hierarchy (e.g., visual: “The man is teaching in the classroom”; Auditory: “The man is in the…school/barn”). Semantic congruency was varied for the final words of the spoken sentences. Incongruent words mismatched expectation in terms of both the initial phonological features (unexpected sound) and semantic features (unexpected meaning). In addition, the category–exemplar probability of the final words was either high or low, with low probability words being more difficult to anticipate. Low probability words were predicted to selectively affect PMN activity. We found that incongruent words elicited a PMN (287 msec) and a N400 (424 msec), for both the high and low probability words. As expected, low probability congruent words elicited a small PMN but no N400. In contrast, high probability congruent words elicited neither a detectible PMN nor a N400. The primary PMN sources were in left inferior frontal and inferior parietal lobes. The primary N400 source activation occurred along the left perisylvian cortex, consistent with prior N400 source localization work. From these results, it was concluded that the PMN and N400 were localized to separate cortical language (and memory) regions and had different source activation patterns. Hum. Brain Mapping 22:42–53, 2004.

Innovations in neuropsychological assessment using event-related brain potentials

Historically, clinicians have utilized evoked potentials for evaluating sensory functions and neuropsychological tests for evaluating cognitive functions. However, the clinical implementation of event-related brain potentials (ERPs), an on-line index of cognitive processing, remains to be developed fully. We describe a new method for assessing language functions using neuropsychological tests that are formatted for computer presentation with simultaneous ERP recordings. From its inception, there have been two major objectives of this ERP language assessment research. Practically, we have sought to develop assessment techniques that would enable clinicians to evaluate the language functions of individuals with limited behavioral and communicative abilities. Conceptually, we have endeavored to increase the precision of neuropsychological testing through the development of measures that are sensitive to readily identifiable and objective neural responses. This article summarizes the issues central to the development of ERP assessment techniques, reviews recent normative studies with healthy individuals, and suggests some future avenues of research in this area.

Effect of propranolol and phenothiazines on electrodermal orienting and habituation in schizophrenia.

Bilateral electrodermal orienting responses were measured to repeated auditory stimuli in schizophrenic patients and controls. In 3 studies phasic activity to moderate intensity sounds of patients on no drugs or phenothiazines was predominantly hyper- or hypo-responsive. Controls showed moderate or slow habituation. Propranolol was found to facilitate habituation in slow habituators and to reinstate responses in half of non-responders, especially when given as the sole drug. The effects seldom had a counterpart in changes in non-specific responses or levels of skin conductance. Modulatory influences on stimulus and response processing and on lateral asymmetries in responses may underlie propranolols efficacy in treating schizophrenia.