Cognitive function predicts neural activity associated with pre-attentive temporal processing.

Temporal processing, or processing time-related information, appears to play a significant role in a variety of vital psychological functions. One of the main confounds to assessing the neural underpinnings and cognitive correlates of temporal processing is that behavioral measures of timing are generally confounded by other supporting cognitive processes, such as attention. Further, much theorizing in this field has relied on findings from clinical populations (e.g., individuals with schizophrenia) known to have temporal processing deficits. In this study, we attempted to avoid these difficulties by comparing temporal processing assessed by a pre-attentive event-related brain potential (ERP) waveform, the mismatch negativity (MMN) elicited by time-based stimulus features, to a number of cognitive functions within a non-clinical sample. We studied healthy older adults (without dementia), as this population inherently ensures more prominent variability in cognitive function than a younger adult sample, allowing for the detection of significant relationships between variables. Using hierarchical regression analyses, we found that verbal memory and executive functions (i.e., planning and conditional inhibition, but not set-shifting) uniquely predicted variance in temporal processing beyond that predicted by the demographic variables of age, gender, and hearing loss. These findings are consistent with a frontotemporal model of MMN waveform generation in response to changes in the temporal features of auditory stimuli.

Research review: Cholinergic mechanisms, early brain development, and risk for schizophrenia.

The onset of diagnostic symptomology for neuropsychiatric diseases is often the end result of a decades-long process of aberrant brain development. Identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal. However, there are few models for how this goal might be achieved. This review uses the development of a psychophysiological correlate of attentional deficits in schizophrenia to propose a developmental model with translational primary prevention implications. Review of genetic and neurobiological studies suggests that an early interaction between alpha7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Therapeutic implications, including perinatal dietary choline supplementation, are discussed.

P50 sensory gating is related to performance on select tasks of cognitive inhibition.

P50 suppression deficits have been documented in clinical and nonclinical populations, but the behavioral correlates of impaired auditory sensory gating remain poorly understood. In the present study, we examined the relationship between P50 gating and healthy adults' performance on cognitive inhibition tasks. On the basis of load theory (Lavie, Hirst, de Fockert, & Viding, 2004), we predicted that a high perceptual load, a possible consequence of poor auditory P50 sensory gating, would have differential (i.e., positive vs. negative) effects on performance of cognitive inhibition tasks. A dissociation was observed such that P50 gating was negatively related to interference resolution on a Stroop task and positively related to response inhibition on a go/no-go task. Our findings support the idea that a high perceptual load may be beneficial to Stroop performance because of the reduced processing of distractors but detrimental to performance on the go/no-go task because of interference with stimulus discrimination.

Nicotine enhances automatic temporal processing as measured by the mismatch negativity waveform.

INTRODUCTION: Cholinergic agonists and, more specifically, nicotine, have been found to enhance a number of cognitive processes. The effect of nicotine on temporal processing is not known. The use of behavioral measures of temporal processing to measure its effect could be confounded by the general effects of nicotine on attention. Mismatch negativity (MMN) has been used as a physiological measure of automatic temporal processing to avoid this potential confound. METHODS: A total of 20 subjects (11 nonsmokers and 9 smokers following 2 hr of abstinence) participated in a two-visit single-blind, placebo-controlled crossover study of the effect of nicotine on MMN indices in response to an interstimulus interval deviant. RESULTS: Nicotine-enhanced MMN amplitudes from baseline recording to postdrug recording greater than did the placebo condition. This enhancement was seen in both nonsmokers and smokers. Nicotine had no significant effect on MMN latency or N100 amplitude or latency. DISCUSSION: This is the first study to demonstrate a nicotine-related enhancement of MMN amplitude to an interstimulus interval duration deviant and confirms our hypothesis that nicotine enhances preattentive temporal processing. Nicotinic agonists may represent a potential therapeutic option for individuals with abnormalities in early sensory or temporal processing related to cholinergic system abnormalities. Methodologically, our paradigm of nicotine administration in abstinent smokers is important because it resulted in both minimal withdrawal symptoms and meaningful data that are not attributable solely to relief of withdrawal.

Perinatal choline deficiency produces abnormal sensory inhibition in Sprague-Dawley rats.

Adequate choline levels in rodents during gestation have been shown to be critical to several functions, including certain learning and memory functions, when tested at adulthood. Choline is a selective agonist for the alpha7 nicotinic receptor which appears in development before acetylcholine is present. Normal sensory inhibition is dependent, in part, upon sufficient numbers of this receptor in the hippocampus. The present study assessed sensory inhibition in Sprague-Dawley rats gestated on normal (1.1 g/kg), deficient (0 g/kg) or supplemented (5 g/kg) choline in the maternal diet during the critical period for cholinergic cell development (E12-18). Rats gestated on deficient choline showed abnormal sensory inhibition when tested at adulthood, while rats gestated on normal or supplemented choline showed normal sensory inhibition. Assessment of hippocampal alpha-bungarotoxin to visualize nicotinic alpha7 receptors revealed no difference between the gestational choline levels. These data suggest that attention to maternal choline levels for human pregnancy may be important to the normal functioning of the offspring.

Permanent improvement in deficient sensory inhibition in DBA/2 mice with increased perinatal choline.

RATIONALE: Schizophrenia patients and certain inbred mouse strains (i.e., DBA/2) show deficient sensory inhibition which has been linked to reduced numbers of hippocampal alpha7 nicotinic receptors and to underlying polymorphisms in the promoter region for the alpha7 gene. Increasing maternal dietary choline, a selective alpha7 agonist, during gestation has been shown to produce long-term changes in adult offspring behavior (i.e., improved learning and memory in rats). OBJECTIVES: The objective of this study is to improve sensory inhibition in DBA/2 mice through maternal choline supplementation. MATERIALS AND METHODS: DBA/2 dams were placed on normal (1.1 g/kg) or supplemented (5 g/kg) choline diet throughout gestation and lactation. Offspring were placed on normal diet at weaning and were assessed for sensory inhibition parameters at adulthood. Evoked EEG responses to identical paired auditory stimuli were compared. At the end of the study, the brains were collected for autoradiographic assessment of hippocampal levels of alpha-bungarotoxin binding to visualize alpha7 nicotinic receptors. RESULTS: Offspring mice which were choline supplemented during gestation showed significantly improved sensory inhibition compared to mice gestated on the normal choline diet. The improvement was produced by a significant reduction in the response to the second stimulus, demonstrating improved inhibition to that stimulus. There was a concurrent increase in alpha7 receptor numbers in both the CA1 and dentate gyrus regions of the hippocampus suggesting that this increase may be responsible for the improved inhibition. CONCLUSIONS: These data show that gestational choline supplementation produces permanent improvement in a deficit associated with schizophrenia and may have implications for human prenatal nutrition.

Gamma and beta neural activity evoked during a sensory gating paradigm: effects of auditory, somatosensory and cross-modal stimulation.

OBJECTIVE: Stimulus-driven salience is determined involuntarily, and by the physical properties of a stimulus. It has recently been theorized that neural coding of this variable involves oscillatory activity within cortical neuron populations at beta frequencies. This was tested here through experimental manipulation of inter-stimulus interval (ISI). METHODS: Non-invasive neurophysiological measures of event-related gamma (30-50 Hz) and beta (12-20 Hz) activity were estimated from scalp-recorded evoked potentials. Stimuli were presented in a standard "paired-stimulus" sensory gating paradigm, where the S1 (conditioning) stimulus was conceptualized as long-ISI, or "high salience", and the S2 (test) stimulus as short-ISI, or "low salience". Three separate studies were conducted: auditory stimuli only (N = 20 participants), somatosensory stimuli only (N = 20), and a cross-modal study for which auditory and somatosensory stimuli were mixed (N = 40). RESULTS: Early (20-150 ms) stimulus-evoked beta activity was more sensitive to ISI than temporally-overlapping gamma-band activity, and this effect was seen in both auditory and somatosensory studies. In the cross-modal study, beta activity was significantly modulated by the similarity (or dissimilarity) of stimuli separated by a short ISI (0.5 s); a significant cross-modal gating effect was nevertheless detected. CONCLUSIONS: With regard to the early sensory-evoked response recorded from the scalp, the interval between identical stimuli especially modulates beta oscillatory activity. SIGNIFICANCE: This is consistent with developing theories regarding the different roles of temporally-overlapping oscillatory activity within cortical neuron populations at gamma and beta frequencies, particularly the claim that the latter is related to stimulus-driven salience.

Age-related change in neural processing of time-dependent stimulus features.

Aging is associated with changes in automatic processing of task-irrelevant stimuli, and this may lead to functional disturbances including repeated orienting to nonnovel events and distraction from task. The effect of age on automatic processing of time-dependent stimulus features was investigated by measurement of the auditory mismatch negativity (MMN) in younger (18-23) and older (55-85) adults. Amplitude of MMN recorded during a paradigm involving low-probability deviation in interstimulus interval (from 500 ms to 250 ms) was found to be reduced in the older group at fronto-central sites. This effect was paralleled by, and correlated to, decreased sensory gating efficiency for component N1 recorded during a separate paradigm involving alternate presentation of auditory stimuli at long (9 s) and short (0.5 s) interstimulus intervals. Further, MMN amplitude was correlated to behavioral performance on a small subset of neuropsychological tests, including the Rey Auditory Verbal Learning Test, within a group of healthy older adults. The results support the hypothesis that aging is associated with declines in automatic processing of time-dependent stimulus features, and this is related to cognitive function. These conclusions are considered in the context of age-related declines in prefrontal cortex function and associated increases in susceptibility to task-irrelevant stimuli.

Behavioral and electrophysiological indices of temporal processing dysfunction in schizophrenia.

Timing deficits in schizophrenia have been noted in several behavioral studies. However, the involvement of mediating factors, such as inattention, has not been ruled out as contributing to these effects. Mismatch negativity (MMN), an electrophysiological measure, may provide a more direct index of stimulus processing ability in individuals with schizophrenia. The current study explored the relationship between behavioral time judgments and a time-based MMN paradigm. Participants were administered two MMN paradigms consisting of an "easy" or "difficult" deviant and an analogous behavioral measure of time processing. Matched against a healthy comparison group, patients exhibited decreased MMN amplitude on the "difficult" deviant interval only. However, on the behavioral paradigm, the patients made significantly more errors across all conditions. These results suggest that behavioral measures of time processing may reflect different processes than those captured by preattentive physiological measures in this population.

Comparison of sensory gating to mismatch negativity and self-reported perceptual phenomena in healthy adults.

To better understand the possible functional significance of electrophysiological sensory gating measures, response suppression of midlatency auditory event related potential (ERP) components was compared to the mismatch negativity (MMN) and to self-rated indices of stimulus filtering and passive attention-switching phenomena in an age-restricted sample of healthy adults. P1 sensory gating, measured during a paired-click paradigm, was correlated with MMN amplitude, measured during an acoustic oddball paradigm (intensity deviation). Also, individuals that exhibited less robust P1 suppression endorsed higher rates of "perceptual modulation" difficulties, whereas component N1 suppression was more closely related to "over-inclusion" of irrelevant sounds into the focus of attention. These findings suggest that the ERP components investigated are not redundant, but correspond to distinct-possibly related-pre-attentive processing systems.

Sensory gating impairment associated with schizophrenia persists into REM sleep.

Physiological measures of sensory gating are increasingly used to study biological factors associated with attentional dysfunction in psychiatric and neurologic patient populations. The present study was designed to assess sensory gating during rapid eye movement (REM) sleep in patients with schizophrenia, a population bearing a genetic load for gating impairment. Auditory event-related potentials (ERPs) were recorded in response to paired clicks during separate waking and overnight sleep recording sessions in controls and schizophrenia patients. Suppression of ERP component P50 was significantly impaired in the patient group during both waking and REM sleep, whereas the difference between groups for N100 gating was dependent on state. These results suggest that REM sleep is an appropriate state during which to assess P50 gating in order to disentangle the effects of state and trait on sensory gating impairment in other clinical populations.

Early postnatal development of sensory gating.

Sensory gating represents the nervous system's ability to inhibit responding to irrelevant environmental stimuli. In order to characterize the early development of acoustic sensory gating, suppression of auditory evoked potential component P1 (i.e. P50) in response to paired clicks was measured during REM sleep in healthy infants (1-4 months) that were without genetic risk for disrupted sensory gating function (i.e. having a relative with schizophrenia). As a group, the subjects exhibited significant response suppression. A correlation between increasing age and stronger response suppression was uncovered, even within this restricted age range. Parallel changes in sleep physiology could not be ruled out as the explanation for this change. Nevertheless, these results demonstrate that the neural circuits underlying sensory gating are functional very early in postnatal development.