Alpha2-noradrenergic effects on ERP and behavioral indices of auditory information processing

Norepinephrine is believed to modulate CNS processing of environmental signals. However, its specific role in stimulus evaluation processes has not been delineated. We examined the effects of the alpha2 noradrenergic agents, clonidine and yohimbine, on ERP and performance measures of auditory information processing. Ten healthy participants performed a three-tone target detection experiment, receiving either placebo, 0.2 mg clonidine, or 30 mg yohimbine, in a double-blind randomized design. The principal locus of action of the noradrenergic agents occurred between 100 and 200 ms poststimulus. P200 latency was sped by yohimbine and slowed by clonidine, and the frontal P3a was shifted in tandem. Components related to target detection (N250 and P3b) were unaffected. The results suggest that norepinephrine modulates CNS mechanisms of selective attention to infrequent stimuli. This may be relevant for patients with schizophrenia, a subset of whom exhibit selective abnormalities of these same ERP components. Our results offer a possible link between these two sets of findings, suggesting that some patients with schizophrenia may have dysfunctional noradrenergic systems.     

Neurochemical modulation of the P13 midlatency auditory evoked potential in the rat.

Previous studies have shown that the vertex-recorded P13 auditory evoked potential in the rat appears to be the rodent equivalent of the human P1 (or P50) potential. This sleep state-dependent potential appears to be generated, at least in part, by cholinergic pedunculopontine nucleus projections. The present studies used localized microinjections of neuroactive compounds into the region of the pedunculopontine nucleus in order to modulate the vertex-recorded P13 potential. Both the GABAergic agonist, muscimol, and the noradrenergic alpha2 receptor agonist, clonidine, were found to reduce the amplitude of the P13 potential in a dose-dependent manner. The suppressive effect of clonidine on P13 potential amplitude was blocked by pretreatment with the noradrenergic alpha2 receptor antagonist, yohimbine. In addition, habituation of the P13 potential, measured using a paired stimulus paradigm, was increased by micro-injection of a dose of muscimol or clonidine which did not change the amplitude of the P13 potential induced by the first stimulus of a pair. In contrast, microinjection of yohimbine decreased habituation of the P13 potential. These results show that the vertex-recorded P13 potential and its habituation can be modulated by activation of known inhibitory synapses, both GABAergic and noradrenergic, at the level of the pedunculopontine nucleus. This provides further evidence that the P13 potential is generated, at least in part, by pedunculopontine nucleus outputs.     

The relationship between reaction time and response variability and somatosensory No-go potentials

We investigated the relationship between reaction time (RT) and response variability and somatosensory Go/No-go potentials. Event-related potentials following electrical stimulation of the second (Go stimulus) or fifth (No-go stimulus) digit of the left hand were recorded from 16 subjects, and Go and No-go stimuli were presented at an even probability. The subjects were instructed to respond to the Go stimuli by pushing a button with their right thumb. We analyzed the correlation between RT and the N140 and P300 components, and between the standard deviation (SD) of RT and the N140 and P300. Neither the amplitude nor latency of the No-go-N140 (N140 evoked by No-go stimuli) or the Go-N140 (N140 evoked by Go stimuli) related significantly with RT and the SD of RT. There was a significant negative correlation between RT and the amplitude of the No-go-P300 (P300 evoked by No-go stimuli) at Fz and C3, indicating that subjects with a shorter RT had a No-go-P300 of larger amplitude. The latency of the Go-P300 (P300 evoked by Go stimuli) at Pz and C3 showed a significant correlation with RT. The SD of RT was significantly correlated with the amplitudes of the No-go-P300 at C3 and Go-P300 at Pz and C4, and the latency of the No-go-P300 at Cz and Go-P300 at Fz, Cz, Pz, C3, and C4. Our results suggest that response speed and variability for the Go stimulus in Go/No-go paradigms affect No-go-related neural activity for the No-go stimulus.     

The effect of response execution on P3 latency, reaction time, and movement time.

This study examined the effect of response selection and execution on P3 latency during the performance of simple reaction time (RT) and stimulus-response compatibility tasks. Response time on these tasks was defined in terms of RT and movement time (MT). Event-related brain potentials were recorded from 67 female participants concurrently with the performance measures. On the simple RT task, the distance of the response button from the home button was varied (7, 15, and 23 cm). When stimulus evaluation demands were minimal, response execution affected P3 latency, with increased response button distance resulting in increased P3 latency. However, these movement effects were modest, and in most protocols, would not be a confounding factor. The stimulus-response compatibility task examined the interaction of stimulus evaluation demands and response requirements. RT, MT, and P3 latency were affected by stimulus congruency, whereas RT and P3 amplitude were affected by response compatibility.     

Taking into account latency, amplitude, and morphology: improved estimation of single-trial ERPs by wavelet filtering and multiple linear regression

Across-trial averaging is a widely used approach to enhance the signal-to-noise ratio (SNR) of event-related potentials (ERPs). However, across-trial variability of ERP latency and amplitude may contain physiologically relevant information that is lost by across-trial averaging. Hence, we aimed to develop a novel method that uses 1) wavelet filtering (WF) to enhance the SNR of ERPs and 2) a multiple linear regression with a dispersion term (MLR(d)) that takes into account shape distortions to estimate the single-trial latency and amplitude of ERP peaks. Using simulated ERP data sets containing different levels of noise, we provide evidence that, compared with other approaches, the proposed WF+MLR(d) method yields the most accurate estimate of single-trial ERP features. When applied to a real laser-evoked potential data set, the WF+MLR(d) approach provides reliable estimation of single-trial latency, amplitude, and morphology of ERPs and thereby allows performing meaningful correlations at single-trial level. We obtained three main findings. First, WF significantly enhances the SNR of single-trial ERPs. Second, MLR(d) effectively captures and measures the variability in the morphology of single-trial ERPs, thus providing an accurate and unbiased estimate of their peak latency and amplitude. Third, intensity of pain perception significantly correlates with the single-trial estimates of N2 and P2 amplitude. These results indicate that WF+MLR(d) can be used to explore the dynamics between different ERP features, behavioral variables, and other neuroimaging measures of brain activity, thus providing new insights into the functional significance of the different brain processes underlying the brain responses to sensory stimuli.     

Changes in the somatosensory N250 and P300 by the variation of reaction time

We investigated the relationship between somatosensory event-related potentials (ERP) and the variation of reaction time (RT). For this purpose, we recorded the ERPs (N250 and P300) in fast- and slow-reaction trials during a somatosensory discrimination task. Strong, standard, and weak target electrical stimuli were randomly delivered to the left median nerve at the wrist with a random interstimulus interval (900–1,100 ms). All the subjects were instructed to respond by pressing a button with their right thumb as fast as possible whenever a target stimulus was presented. We divided all the trials into fast- and slow-RT trials and averaged the data. N250 latency tended to be delayed when the RT was slow, but not significantly. P300 latency was delayed significantly when the RT was slow, but to a much lesser extent than the RT delay, so we concluded that the change of RT was not fully determined by the processes reflected by the somatosensory N250 or P300. Furthermore, the larger and earlier P300 in the fast-RT trials implied that when larger amounts of attentional resources were allocated to a given task, the speed of stimulus evaluation somewhat increased and RT was shortened to a great extent. N250 amplitude did not significantly vary in the two RT clusters. In conclusion, the somatosensory N250 reflects active target detection, which is relatively independent of the modulation of the response speed, whereas the somatosensory P300 could change without manipulation of either the stimulus or the response processing demand. Electronic Publication     

Does Methylphenidate Affect Information Processing? Findings From Two Studies on Performance and P3b Latency

Two studies were conducted to assess the impact of methylphenidate on normal young adults in a fixed version of Steinberg's memory scanning task. Both studies yielded characteristic monotonic increases in reaction time (RT) and P3b latency as a function of memory load. Also, in both studies, methylphenidate speeded up RT as and decreased error rates and intra subject RT variability. However, the slope of RT as a function of memory load, i.e. the rate of memory search, was not altered by the stimulant. In Study 1, P3b latency also was not affected by methylphenidate, a result suggesting that the stimulant brought about the decrease in RT by acting after the completion of evaluation, presumably by accelerating response processes. However, in Study 2, the drug significantly shortened P3b latency and the interval between RT and P3b latency. Thus, a speeding of both evaluation as well as motor processes was achieved. A review of procedural differences between the two studies suggests some possible explanations. In combination, the two studies indicate that methylphenidate consistently shortened the timing of motor processes and, under some circumstances, the duration of evaluation processes as well.     

Sequence effects in the Go/NoGo task: Inhibition and facilitation

Facilitation and inhibition are asymmetric aspects of attention that differentially affect response times (RTs), accuracy and neuroelectric activity in many experimental tasks. Both vary as a function of stimulus context, with stimulus repetitions, for example, often resulting in facilitation in terms of speed, accuracy or reduced neural activity. Although inhibition has been extensively studied in the Go/NoGo task, facilitation has been overlooked. Twenty healthy adults performed an adapted Go/NoGo task which manipulated levels of facilitation and inhibition. Event-related potential (ERP) and behavioural measures were averaged according to preceding stimulus sequences. Established Go/NoGo effects for N2 and P3 components were replicated. Behavioural and ERP measures, however, showed strong sequence effects. Correlates of facilitation included reduced P1 and N1 latencies, and topographic effects in P1, to Go stimulus repetitions. Manipulations of inhibitory load through increasing Go before NoGo stimuli resulted in incremental increases in N1, P2 and N2 latencies. Several additional ERP and RT measures showed quadratic effects, with indications of facilitation or inhibition which reversed towards the end of longer stimulus trains. The results suggest that both facilitatory and inhibitory processes underlie performance in the Go/NoGo task. As Go stimuli are typically more frequently repeated than NoGo stimuli, the two processes may be confounded when sequence effects are not considered. Additionally, analysing stimuli by context indicates that the timing of the Go-P3 latency is closely related to responses, and the prolongation of N1, P2 and N2 with increasing difficulty of inhibition supports a possible relation of these components to inhibition.     

Instability in the latency of P3a/P3b brain potentials and cognitive function in aging

Instability in performance is a prominent feature of aging. In this study, 133 participants evenly distributed across the adult lifespan underwent a three-stimulus event-related potentials (ERPs) paradigm, and instability in P3a/P3b latency and reaction time (RT) were measured. P3a is related to alertness or reorientation of attention and it was elicited by distractor stimuli. P3b is related to controlled attentional processes and it was triggered by target stimuli. Maximum-likelihood estimation (MLE) was used to quantify the level of variability in latency across the single sweep ERPs. The results revealed increased variability in RT but not in P3a/P3b latency with age. Variability in P3a/P3b latency was related to executive functions, and variability in RT to speed. Generally, the relationships tended to increase with age. It can be concluded that increased variability in RT with age is caused by instability in processes related to response execution and possibly response selection, but not stimulus classification. Further, the results indicate that intraindividual variability is not a uniform concept, but has unique explanatory value at the neurophysiological and behavioral level.     

Single-trial latency variability of auditory evoked potentials may indicate immediate memory in the albino rat.

Fast habituation (FH) is defined as a decrease in auditory evoked potential (AEP) amplitude in response to the second of a pair of temporally juxtaposed (e.g. 1-s) tones. The degree of FH may depend, in part, on the subject's ability to anticipate the stimulus sequence. This paradigm has been used in our laboratory to study cognitive functioning in human subjects. We have also developed an animal model to investigate, more comprehensively, the anatomical and physiological basis of this phenomenon seen in human subjects. In the present investigation, we wished to determine the relationship between single-trial latency variability and AEP amplitude for two conditions: one for which FH is known to occur and one for which it is not present, due to the length of the interstimulus interval (ISI). Here AEPs were obtained to 40 pairs of 100-ms pure tone stimuli (70-dB SPL, 1- and 5-s ISI, 10-s interpair interval) from 19 chronically implanted, unanesthetized, restrained male Sprague-Dawley rats. The AEP latencies, amplitudes, and the single-trial latency variabilities were obtained for each component (P1, N1, P2 and N2). Findings indicated that FH was present for the 1-s ISI condition but not for the 5-s ISI condition. In addition, single-trial latency variability was negatively correlated with both Tones 1 and 2 AEP amplitudes in the 5-s ISI condition but only with Tone 1 amplitude in the 1-s ISI condition. Thus, single-trial latency variability predicted AEP amplitude only when FH did not occur. These results support earlier findings reported from our laboratory suggesting that the decrease in amplitude during FH is not related to increased variability in the time domain but rather to decreased neuronal output.     

ERP differences in visual attention processing between attention-deficit hyperactivity disorder and control boys in the absence of performance differences

Event-related potentials (ERPs) were recorded during a visual two-choice reaction time (RT) task in attention-deficit hyperactivity disorder (ADHD) and control boys selected using strict inclusion and exclusion criteria. No group differences were found in mean RT and correct responses. Although early occipital ERPs were not affected in the ADHD group, the peak latency of early anterior ERPs (N1, P1, N2) was significantly delayed. ADHD showed a larger effect of stimulus type on the frontal negativity (N530) and the posterior late negativity (nSW) and a smaller effect of stimulus type on anterior N2 and posterior P3b amplitude. The development of N530 and P450 amplitude across blocks of five trials was analyzed using orthogonal polynomial trend analysis of variance software. In the control group, P450 amplitude to "frequent" stimuli reduced across blocks. In the ADHD group, N530 amplitude increased for "rare" stimuli across blocks. It is suggested that the ADHD group showed a lack of automatization of the categorization process with increasing time on task for which they compensated by controlled attentional processes.     

Effects of Methylphenidate on Stimulus Evaluation and Response Processes: Evidence from Performance and Event-Related Potentials

This study investigated the effects of methylphenidate in a memory scanning task with two levels of high cognitive load (memory set sizes 2 and 4 presented in displays of size 4) and two response requirements (simple mapping or rotation). Twenty young adults were tested under placebo and methylphenidate (0.3 mg/Kg) in a double-blind protocol. As expected, memory load increased misses, false alarms, confusions, and failures to respond by the deadline. In turn, the rotation requirement increased confusions and nonresponses. Reaction time (RT) was slowed by both factors. P3b latency also was increased by memory load and, to some extent, by the rotation requirement. These results are consistent with the proposition that P3b latency reflects largely evaluation, rather than response processes. Misses and reaction time were decreased in response to targets presented in the center vs. the periphery of the display. Confusions, however, showed the opposite trend. The display position did not affect P3b latency. These results can be explained by assuming that the subject was focusing on the center of the display and that accuracy diminished when stimuli were presented toward the periphery of the display. The stimulant challenge speeded up reaction times overall and specifically reduced the slowing effect of rotation. However, P3b latency was not affected by methylphenidate, so that the speeding of reaction time by the stimulant can be attributed to post-evaluation processes.     

Ontogeny of noradrenergic effects on ultrasonic vocalizations in rat pups

The ontogeny of noradrenergic effects and the interaction of opioid and noradrenergic systems on vocalizations in rat pups from Day 10 to Day 18 were evaluated. Day 10 pups given clonidine (0.05 or 0.5 mg/kg) ip showed a sustained high level of calling throughout a 25-min isolation period that was reversed with yohimbine (0.1 mg/kg). Day 15 pups showed identical profiles with a lower baseline rate. Day 17 pups' calls were differentially affected according to dose; Day 18 pups reduced vocalizing with clonidine. In addition, it was found that at all ages when clonidine increased calling during isolation, the pups vocalized in the nest as well. Naltrexone, an opioid antagonist, lost its effectiveness to increase vocalizations after Day 15 unless it was given subsequent to clonidine. These results suggest that pups' vocalizations are differentially affected by noradrenergic and opioid stimulation or inhibition with developmental changes.     

Lactation-induced reduction in rats' acoustic startle is associated with changes in noradrenergic neurotransmission.

The acoustic startle response (ASR) with or without fear conditioning was compared between cycling (CYC) and lactating (LACT) female rats. ASR sensitivity to changes in endogenous noradrenergic (NA) release was examined using the alpha-2 NA receptor drugs yohimbine and clonidine. Groups of CYC and LACT females were also tested in the open field. ASR was reduced in all LACT, compared with that in CYC females. Both groups exhibited a robust response to fear conditioning and unpotentiated ASR subsequent to conditioning was increased in LACT females. The lowest dose of yohimbine significantly increased ASR in LACT females, but not in CYC females. Clonidine reduced ASR in both groups of females, with a greater potency in CYC females. In the open field, LACT females displayed a shorter latency to emerge, less freezing behavior, and more entries into the field than did CYC females. The authors concluded that (a) LACT females are less anxious in a novel environment and that decreased anxiety can be efficiently counteracted by fear conditioning, and (b) changes in NA neurotransmission contribute to lactation-induced modifications in ASR.     

Target-to-target interval, intensity, and P300 from an auditory single-stimulus task

Target-to-target interval (TTI) is a primary determinant of P300 amplitude, such that longer TTIs yield larger components than shorter intervals. Systematic manipulations of TTI affect component amplitude, latency, and associated response time in a fashion that suggests that the template update hypothesis can account for these outcomes. The present study examines whether manipulations of TTI (from 1 to 16 s) and stimulus intensity (soft and loud tones) produce outcomes consistent with this hypothesis. A single-stimulus task was employed in which only target stimuli were presented. P300 amplitude increased, peak latency decreased, and response time increased as TTI became longer, with less effect for soft compared to loud stimulus conditions on P300 amplitude at Pz. TTI increases also augmented N100 amplitude, with consistently smaller amplitudes obtained for soft relative to loud stimuli. Overall, P300 measures are sensitive to both temporal and physical stimulus factors. Theoretical implications are discussed.     

Electrocortical correlates of intra-subject variability in reaction times: average and single-trial analyses

Intra-subject variability of reaction times (ISV), generally considered secondary to measures of central tendency, has become increasingly important for cognitive neuroscience. Event-related potential (ERP) research suggests an inverse relationship between ISV and P3b amplitude; however ERP methods’ reliance on averaged waveforms may be unsuitable for studying ISV due to potentially distorting effects of latency jitter. The present study investigates the neural bases of ISV through single-trial analysis of P3bs in groups with low and high ISV, using Infomax-rotated principal components analysis of ERP data. Results indicate that while latency jitter contributes to the reduced P3b amplitude seen in average ERPs of high ISV participants, group differences in amplitude survive the use of single-trial methods that are robust to such distortions. A decoupling of P3b and RT was also seen in the high ISV group. The results are discussed in the context of the P3b's dimensionality, and its possible catecholaminergic underpinnings.     

Localization of temporal preparation effects via trisected reaction time

Previous research using nonchronometric measures in humans and animals has shown that warning signals can influence stages of processing throughout the reaction time (RT) interval. However, latency measures indicate that warning effects on RT are not due to the speeding of motor processes, at least not late ones. To better isolate the chronometric effects of temporal preparation, we used lateralized event-related potentials to divide mean RT into three time segments. Foreperiod duration had only a small, nonsignificant influence on the first and last segments (early visual and late motor processes, respectively). The chronometric effect was mainly restricted to the middle interval, which extended from onset of the N2pc component to onset of the lateralized readiness potential. The results imply that temporal preparation primarily speeds late perception, response selection or early motor processes.     

Comparison of the effect of intrathecal administration of clonidine and yohimbine on the locomotion of intact and spinal cats

Several studies have shown that noradrenergic mechanisms are important for locomotion. For instance, L-dihydroxyphenylalanine (L-DOPA) can initiate "fictive" locomotion in immobilized acutely spinalized cats and alpha(2)-noradrenergic agonists, such as 2,6,-dichloro-N-2-imidazolidinylid-enebenzenamine (clonidine), can induce treadmill locomotion soon after spinalization. However, the activation of noradrenergic receptors may be not essential for the basic locomotor rhythmicity because chronic spinal cats can walk with the hindlimbs on a treadmill in the absence of noradrenergic stimulation because the descending pathways are completely severed. This suggests that locomotion, in intact and spinal conditions, is probably expressed and controlled through different neurotransmitter mechanisms. To test this hypothesis, we compared the effect of the alpha(2) agonist, clonidine, and the antagonist (16 alpha, 17 alpha)-17-hydroxy yohimbine-16-carboxylic acid methyl ester hydrochloride (yohimbine), injected intrathecally at L(3)--L(4) before and after spinalization in the same cats chronically implanted with electrodes to record electromyograms (EMGs). In intact cats, clonidine (50-150 microg/100 microl) modulated the locomotor pattern slightly causing a decrease in duration of the step cycle accompanied with some variation of EMG burst amplitude and duration. In the spinal state, clonidine could trigger robust and sustained hind limb locomotion in the first week after the spinalization at a time when the cats were paraplegic. Later, after the spontaneous recovery of a stable locomotor pattern, clonidine prolonged the cycle duration, increased the amplitude and duration of flexor and extensor bursts, and augmented the foot drag at the onset of swing. In intact cats, yohimbine at high doses (800--1600 microg/100 microl) caused major walking difficulties characterized by asymmetric stepping, stumbling with poor lateral stability, and, at smaller doses (400 microg/100 microl), only had slight effects such as abduction of one of the hindlimbs and the turning of the hindquarters to one side. After spinalization, yohimbine had no effect even at the largest doses. These results indicate that, in the intact state, noradrenergic mechanisms probably play an important role in the control of locomotion since blocking the receptors results in a marked disruption of walking. In the spinal state, although the receptors are still present and functional since they can be activated by clonidine, they are seemingly not critical for the spontaneous expression of spinal locomotion since their blockade by yohimbine does not impair spinal locomotion. It is postulated therefore that the expression of spinal locomotion must depend on the activation of other types of receptors, probably related to excitatory amino acids.     

Differential alpha-1 and alpha-2 adrenergic effects on hypothalamic corticotropin-releasing factor and plasma adrenocorticotropin

There is presently no consensus as to the nature of the catecholaminergic influence on the regulation of corticotropin-releasing factor. The potential role that the alpha-adrenergic system plays was investigated by measuring hypothalamic corticotropin-releasing factor-like immunoreactivity and plasma adrenocorticotropin, following manipulation of alpha-1 and alpha-2 adrenergic receptor activation. Administration of the alpha-1 agonist methoxamine did not significantly alter either plasma adrenocorticotropin or hypothalamic corticotropin-releasing factor. Administration of the alpha-2 agonist clonidine resulted in a 24-fold increase in plasma adrenocorticotropin and a significant decrease in median eminence corticotropin-releasing factor, consistent with its release. Corticotropin-releasing factor in the remainder of the hypothalamus was not altered. Concurrent administration of clonidine with the selective alpha-2 antagonist yohimbine prevented the clonidine-induced changes in plasma adrenocorticotropin and hypothalamic corticotropin-releasing factor, consistent with the clonidine effect being mediated through alpha-2 receptors. Concurrent administration of clonidine with methoxamine did not prevent these effects, suggesting that the effect of clonidine was not mediated through presynaptic inhibition of noradrenergic adrenergic neurotransmission. Inhibition of protein synthesis by anisomycin induced changes in corticotropin-releasing factor and adrenocorticotropin which were not altered by combined treatment with methoxamine or clonidine. These data suggest differential roles for alpha-1 and alpha-2 systems in the regulation of corticotropin-releasing factor. Results from alpha-2 adrenergic activation were consistent with stimulation of corticotropin-releasing factor release, an effect mediated by a postsynaptic alpha-2 mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)