Changes in event-related potentials in a three-stimulus auditory oddball task after mild head injury.

Previous research has demonstrated changes in event-related potentials in a variety of cognitive tasks after severe closed head injury. We sought to establish if similar changes were present in patients who had sustained only apparently mild head injury (MHI) by recording event-related potentials in a group of 24 mild head injured and 24 control participants during a three-stimulus auditory target detection task. For this "oddball" task participants were required to press a button every time they heard a rare target tone and to ignore rare novel sounds and frequent non-target tones. Neuropsychological test results indicated that the mild head injured group had mild memory and attention impairments. Analysis of behavioural performance on the three-stimulus "oddball" task showed no difference in reaction times or error rates between the two groups. Target condition N2 deflections appeared to be larger in the mild head injured but peak amplitude measures revealed that this effect was not significant. There were no significant differences in the amplitude or latency of the P3b evoked by target stimuli or the P3a evoked by novel stimuli. However, a putative "O-wave" or "reorienting negativity" following the P3a was more negative in the mild head injured group suggesting increased activation of components of the attention network. These findings lend support to the hypothesis that MHI can cause subtle cognitive impairments that are associated with abnormal allocation of attention resources in the context of normal behavioural performance.

Scopolamine impairs memory performance and reduces frontal but not parietal visual P3 amplitude.

It has been suggested that the P3 event-related potential (ERP) may mark the operation of certain working or long-term memory processes. It has also been reported that cholinergic blockade by scopolamine induces significant memory impairment and is associated with an increased latency, as well as amplitude reduction or abolition of the auditory P3, thus supporting hypothesised links between P3 and long-term memory function. An intriguing anomaly is that, while visual P3 latency is also increased by scopolamine, amplitude is not changed. The aim of this study was to make a more detailed assessment of the effects of scopolamine on the visual P3 at a drug dose known to induce memory impairment. After drug administration, memory performance was significantly impaired and visual P3 latency was significantly increased. There was little evidence of parietal P3 amplitude reduction, but frontal P3 amplitude was significantly reduced in both target and non-target conditions. These findings, when considered in the light of a more recent study of the effects of scopolamine on auditory P3, suggest that cholinergic blockade produces a common effect in both visual and auditory modalities of significant frontal P3 amplitude reduction, but no significant parietal P3 amplitude reduction. These results are consistent with the view that there are modality-independent generators of the parietal and frontal P3. The finding of drug-induced memory impairment and modulations of frontal ERP deflections is also consistent with recent evidence of a significant role for regions of the frontal lobe in encoding and retrieval of long-term memories.

Evidence that macrophages in atherosclerotic lesions contain angiotensin II.

BACKGROUND: We have reported that human mononuclear leukocytes contain large amounts of angiotensin II (Ang II). The goal of the present study was to test the hypothesis that Ang II is present in monocyte/macrophages in atherosclerotic lesions. METHODS AND RESULTS: Segments of thoracic aorta and left circumflex coronary artery were obtained from 3 groups of cynomolgus monkeys: normal, atherosclerotic, and regression. Samples of human coronary arterial atherosclerotic lesions were obtained from directional atherectomy. Sections were stained for Ang II with 3 different polyclonal rabbit anti-human Ang II antisera. In aorta and coronary arteries from normal monkeys, there was no or minimal anti-Ang II staining in endothelial cells. All sections from atherosclerotic monkeys displayed discrete, localized regions of staining for Ang II in intima-media. Macrophages were present throughout the atherosclerotic intima-media, and anti-Ang II staining appeared to colocalize with macrophages. All human coronary atherectomy samples stained positive for Ang II and macrophages. Staining for both Ang II and macrophages was observed in vascular lesions from all 5 monkeys after regression of atherosclerosis, but staining was less extensive than in atherosclerotic blood vessels from monkeys. CONCLUSIONS: These findings suggest that Ang II is present in atherosclerotic lesions in monkeys and humans, colocalizes with macrophages in intima-media of atherosclerotic vessels from monkeys, and decreases in lesions in monkeys with regression of atherosclerosis.

Cognitive brain potentials in a three-stimulus auditory "oddball" task after closed head injury.

Event-related potentials (ERPs) were recorded in a three stimulus oddball task from 16 patients who had sustained a severe closed head injury at least 6 months before testing, and from 16 control subjects. The stimuli comprised a random sequence of frequent non-target tones (P = 0.70), rare target tones (P = 0.15), and rare novel sounds (P = 0.15). The task requirement was to respond promptly to each target tone. From a latency of 200 msec onwards, the ERPs evoked by frequent non-targets were substantially more negative-going in the head-injured than in the control group. When this difference in the ERPs to the frequent tones was taken into account, there was no evidence to suggest that either the latency or the amplitude of the target-evoked N2 and P3b components differed between the groups. The novel stimuli evoked a prominent P3a component. The amplitude and scalp distribution of this component differed little between the groups, but its peak latency was reliably longer in the head-injured subjects. The findings in respect of the N2 and P3b components suggest that impairments in early processing of task-relevant stimuli are not an invariant feature of closed head injury. The findings regarding P3a suggest that, in the majority of patients, head injury has only a limited effect on the neural systems underlying involuntary shifts of attention.

Event related potentials, reaction time, and cognitive performance in idiopathic Parkinson's disease.

Sixteen non-demented patients with idiopathic Parkinson's disease (PD) with varying degrees of cognitive impairment and sixteen age-, sex- and education-matched normal controls were examined with (1) an auditory oddball paradigm requiring counting or a motor response in separate determinations, (2) a reaction time task with movement time component and (3) a detailed clinical and neuropsychological test battery. Patients were impaired on a number of neuropsychological tests. They also showed an increased P2 and N2 latency, but no significant increase in P3 latency. Their response initiation times and reaction times during the oddball experiment were not different from controls, whereas movement time was significantly increased. Increased peak latencies, particularly for N2, were moderately associated with Parkinsonian motor impairment in patients and with the Benton Multiple Choice Visual Retention Test in patients and controls. Movement time was associated with P3 latency only in controls and in both groups with the Benton Multiple Choice Visual Retention Test. The observed pattern of results suggests that in non-demented PD patients ERP peak latencies, visuo-spatial task performance and Parkinsonian motor impairment share a significant degree of variance. While impairments in neuropsychological tests and delay in the earlier peaks P2 and N2 do not appear to be sensitive to medication with L-DOPA, normal P3 latencies might indicate good pharmacological symptom control in the absence of dementia.

The effect of different high-pass filter settings on peak latencies in the event-related potentials of schizophrenics, patients with Parkinson's disease and controls.

Eighteen schizophrenic patients, 16 patients with idiopathic Parkinson's disease, and the same numbers of age, sex and education matched controls were examined with oddball experiments for the generation of P3. Individual averages were high-pass filtered at different cut-off frequencies with single-pole digital filters with equivalent analogue Butterworth filter profiles. The purpose of this procedure was to simulate analogue high-pass filters used in clinical studies from different centres and to examine their potential effect on group differences. Increasing high-pass filters resulted in a phase lead for all peaks examined (N1, P2, N2, P3). The only group differences were found for P3, which showed a greater phase lead in controls than in the patient groups, usually resulting in a more pronounced group difference. Similar wave forms and filter properties could be modelled by synthetic wave forms consisting of sine waves of different frequencies.

The effects of scopolamine on event-related potentials in a continuous recognition memory task.

Event-related potentials (ERPs) were recorded during a task requiring continuous recognition memory for visually-presented words. Twelve subjects each performed the task twice, once following the administration of scopolamine, and once after receiving a saline placebo. In the placebo condition, correctly detected "old" words (i.e., words that had been presented once before during the task) evoked more positive-going ERPs than did "new" words. Scopolamine caused a substantial impairment in task performance, but did not reduce the size of these old-word/new-word ERP differences. It is concluded that old/new ERP effects are unlikely to reflect cholinergically-mediated neural activity underlying normal recognition memory.

Event-related potentials related to recognition memory. Effects of unilateral temporal lobectomy and temporal lobe epilepsy.

Event-related potentials (ERPs) were recorded during a continuous recognition memory task for visually presented words, with a 6 item lag between the first and second presentation of each word. The subjects consisted of: (i) a control group of patients with primary generalized epilepsy; (ii) patients who had undergone either a left or a right anterior temporal lobectomy; (iii) unoperated patients with either left or right unilateral temporal lobe epilepsy. In the controls, ERPs to detected 'old' words were reliably more positive-going in the interval 300 to 600 ms post-stimulus than were ERPs to 'new' items. In both left and right lobectomy patients, 'old/new' ERP differences in the same latency range were significantly smaller than in the controls, and did not differ significantly from zero. At midline electrodes, old/new effects in the temporal lobe epilepsy patients were of similar magnitude to those of the controls. In contrast to the control data, the old/new effects in the temporal lobe epilepsy patients were asymmetric, in that they were smaller over the hemisphere ipsilateral to the seizure focus than over the contralateral hemisphere. No relationship was found across subjects between the magnitude of old/new ERP effects and verbal memory performance. In a second task, occasional non-words had to be discriminated against a background of sequentially presented words, some of which were repetitions of the immediately preceding item. ERPs evoked by repeated words were more positive-going than were those to first presentations; this effect was reliable, and of equivalent size, in all patient groups. It is concluded that in the recognition task, old/new ERP effects are dependent on temporal lobe functioning, but that the anterior temporal lobe is not the principal locus of the generators of these effects. The cognitive processes reflected by these effects do not appear to be strongly lateralized to one hemisphere, and neither do they seem to be necessary for normal verbal memory.

Normal P300 following extensive damage to the left medial temporal lobe.

Event-related potentials (ERPs) were recorded during auditory and visual "oddball" tasks from a patient with a severe verbal memory deficit due to a low grade infiltrating glioma which involved the full extent of the left medial temporal lobe. In both sensory modalities, the patient's oddball-evoked P300s were symmetrical and of normal amplitude. These findings are difficult to reconcile with the hypothesis that the hippocampus, or any other medial temporal structure, makes a substantial contribution to the scalp P300.

P300 and smooth eye pursuit: concordance of abnormalities and relation to clinical features in DSM-III schizophrenia.

Twenty-five DSM-III-diagnosed schizophrenics and 37 normal and age-matched controls were examined using an oddball paradigm for the generation of P300 and smooth eye-pursuit tasks. Results were compared between groups and related to clinical characteristics, including a family history of psychiatric illness. Group differences were found for P300 amplitudes, latencies and eye-tracking. A family history of psychiatric illness was associated with normal eye-tracking in patients. Small P300 amplitudes alone and in combination with long P300 latencies were associated with a family history in controls.

Endogenous event-related potentials from sphenoidal electrodes.

Event-related potentials (ERPs) were recorded from left and right sphenoidal electrodes during 2 cognitive tasks (visual oddball and a word repetition procedure) known to evoke endogenous ERP activity in the medial temporal lobe. Both tasks gave rise to large, reliable modulations of scalp-recorded ERPs. In the oddball task, no consistent task-related ERP activity could be recorded from the sphenoidal electrodes concurrently with the scalp-recorded P3 component, although in the latency region following the peak of P3 these electrodes exhibited an enhanced late negative wave to target stimuli. In the word repetition task, no consistent repetition-related ERP effects of any kind were observed from the sphenoidal electrodes. Sphenoidal electrodes do not appear to detect the endogenous ERP components that are generated in the medial temporal lobe concurrently with scalp-recorded components.

Co-culture of dissociated hippocampal and sympathetic cells from the neonatal rat.

When sympathetic neurones, obtained from superior cervical ganglia of postnatal rats, were grown in microcultures with cells of the postnatal hippocampal formation for 6-44 days, about 70% of the sympathetic neurones formed functional synapses on themselves or a neighbouring sympathetic neurone. In all forty-four cases in which hexamethonium (0.5-1 mM) was applied it strongly or completely blocked the synaptic interaction. This indicates that the synaptic interaction was cholinergic and raises the possibility that the denervated cells of the hippocampal formation induced the cholinergic function in the co-cultured sympathetic neurones.

Seizure-like activity and cellular damage in rat hippocampal neurons in cell culture.

Neurons dissociated from the hippocampal formations of neonatal rats were grown in medium containing kynurenic acid (a glutamate receptor antagonist) and elevated Mg2+. Such chronically blocked neurons, when first exposed to medium without blockers (after 0.5-5.0 months), generated intense seizure-like activity. This consisted of bursts of synchronous electrical responses that resembled paroxysmal depolarization shifts and sustained depolarizations that, in some neurons, nearly abolished the resting potential. Sustained depolarizations were usually reversed by timely application of kynurenate or 2-amino-5-phosphonovalerate, indicating that continuous activation of glutamate receptors was required for their maintenance. Prolonged periods of intense seizure-like activity usually killed most neurons in the culture. This system allows seizure-related cellular mechanisms to be studied in long-term cell culture.

Specialized face processing and hemispheric asymmetry in man and monkey: evidence from single unit and reaction time studies.

Experimental and clinical studies have generally shown that the neural mechanisms for face processing in man are (1) designed to deal with the configuration of upright faces and (2) located predominantly in the right cerebral hemisphere. Monkeys would seem to process faces in a different manner to humans since they appear to show no hemispheric asymmetry and to treat upright and inverted faces equivalently. We re-examine these claims. Our reaction time studies reveal that monkeys do behave like human subjects since they process facial configuration faster when stimuli are presented upright as compared with horizontal or inverted. Single unit studies in the monkey reveal patches of neurones responsive to faces in the upper bank and fundus of the left superior temporal sulcus (STS). Recording from the right hemisphere also reveals cells responsive to faces but in this hemisphere such cells appear less numerous. These cells process upright faces faster than inverted faces. Face processing in monkeys and man appears to utilize qualitatively similar mechanisms, but the extent and/or direction of cerebral asymmetry in these mechanisms may not be similar.

Synaptic functions in rat sympathetic neurons in microcultures. IV. Nonadrenergic excitation of cardiac myocytes and the variety of multiple-transmitter states.

In the first 3 papers of this series (Furshpan et al., 1986a, b; Potter et al., 1986), a sensitive microculture procedure was used to show that sympathetic principal neurons, dissociated from newborn or adult superior cervical ganglia and grown singly on cardiac myocytes, display adrenergic, cholinergic, and purinergic functions, sometimes in isolation but more often in combination. In this paper we describe additional effects on cardiac myocytes evoked by these neurons; the effects were excitatory and insensitive to adrenergic blocking agents (and to agents that block the inhibitory effects of acetylcholine and purines). In some of these microcultures, evidence consistent with secretion of serotonin was obtained; the nonadrenergic excitatory effect was diminished or abolished by serotonin blockers or reserpine. Further evidence for serotonergic transmission is presented in the accompanying paper by Sah and Matsumoto (1987). In other cases, an as-yet-unidentified agent "X" also produced a nonadrenergic excitation. The X effect characteristically required a prolonged train of neuronal impulses, had a time course of 50-200 sec, and was insensitive to agents that affected the other transmitters, including serotonin. In addition, we discuss 2 remarkable features of the transmitter repertoire of the microcultured sympathetic neurons: expression of the several transmitters in a variety of combinations, including at-least-quadruple function, and expression of the transmitters within a particular combination in varying relative strengths. The result is a diversity of transmitter release greater than that previously reported for vertebrate or invertebrate neurons.

Synaptic functions in rat sympathetic neurons in microcultures. II. Adrenergic/cholinergic dual status and plasticity.

This is the second in a series of papers that describes the use of a sensitive microculture procedure to investigate the transmitter status of sympathetic neurons. Cultured immature principal neurons, dissociated from the superior cervical ganglia of newborn rats, are known to be plastic with respect to transmitter status; under certain culture conditions, populations of neurons that display (at least) adrenergic properties at the outset can be induced to display a variety of cholinergic properties, including the formation of functional neuron-neuron cholinergic synapses, as adrenergic properties decline. With the microculture procedure described in the preceding paper (Furshpan et al., 1986a), we have examined the transmitter status of individual neonate-derived neurons during this transition. Many such neurons secreted both norepinephrine and ACh (adrenergic/cholinergic dual function); examination of such neurons with the EM revealed a mixed population of synaptic vesicles. Direct evidence for a transition via this dual status was obtained by serial physiological assays of 14 neurons. The neonate-derived neurons were markedly heterogeneous in the rate of change of transmitter status. Principal neurons derived from adult superior cervical ganglia also displayed dual status, but the incidence was lower than in neonate-derived neurons cultured for similar periods. In preliminary serial assays of adult-derived neurons, many of the neurons did not acquire detectable cholinergic function, but in two cases evidence consistent with plasticity was obtained. While it is known that several types of neurons will form functional junctions in the presence of agents that block electrical activity, sympathetic principal neurons have apparently not been tested. In microculture, neuron-neuron synapses and junctions with cardiac myocytes were formed by sympathetic neurons grown chronically in the presence of blocking concentrations of TTX and hexamethonium.

Synaptic functions in rat sympathetic neurons in microcultures. III. A Purinergic effect on cardiac myocytes.

In the first two of this series of papers, a sensitive microculture procedure was used to show that rat sympathetic neurons grown singly on small islands of heart cells release norepinephrine (NE) and/or acetylcholine (ACh). We report here the release of a third transmitter in response to stimulation of these neurons. This agent was recognized by its effect on the cocultured cardiac myocytes: an inhibition of beating or a hyperpolarization that, in contrast to cholinergic inhibition, was unaffected by atropine (up to 5 microM). Evidence described here indicates that this agent was primarily adenosine (or a closely related compound): the atropine-resistant myocyte inhibition was antagonized by adenosine-receptor blockers [8-phenyltheophylline, theophylline, 7-(2-chloroethyl) theophylline] and was attenuated by an enzyme (adenosine deaminase) that hydrolyzes adenosine to pharmacologically inactive inosine. Many of the neurons, whether initially dissociated from ganglia of newborn or adult rats, evoked this purinergic response, almost always in combination with adrenergic and cholinergic responses. In a few cases it was the only detectable response. The relative strength of the adrenergic, cholinergic, and purinergic responses varied widely from neuron to neuron, suggesting that the adrenergic and purinergic or the cholinergic and purinergic agents were not stored at constant stoichiometric ratios.

Synaptic functions in rat sympathetic neurons in microcultures. I. Secretion of norepinephrine and acetylcholine.

This is the first of a series of four papers that describes the use of a sensitive "microculture" procedure for examining the neurotransmitter profile of a neuron by assaying the transmitter(s) it releases. Sympathetic principal neurons isolated from the superior cervical ganglia of neonatal or adult rats were grown for 10 d to several months on small islands of cardiac myocytes (island diameter, ca. 0.5 mm). To assay transmitter status a neuron and a myocyte in the same microculture were impaled with microelectrodes, the neuron was stimulated and the pharmacology of the effect(s) on the group of electrically coupled myocytes, and on the neuron itself, was investigated. Because the growing axonal processes were confined to the island, the innervation of the myocytes became dense; transmission from neuron to myocytes occurred reliably and was often intense. Most experiments were done on islands containing only a single neuron so that the observed effect(s) on the myocytes could be confidently assigned to that neuron. After the physiological assay, the fine structure or cytochemistry of the neuron was often examined. With single-neuron microcultures the physiology and anatomy of the neuron, including the fine structure of its synaptic endings and varicosities, could be correlated unambiguously. During the course of this work, we have observed five pharmacologically distinct effects exerted on the myocytes by either neonate- or adult-derived neurons. Three of these effects, one exerted at least in large part by adenosine and the others by agents still under study (one appears to be 5-HT), are described by Furshpan et al. (1986), Matsumoto et al. (in press), and D. Sah and S. G. Matsumoto (unpublished observations). This paper is concerned with evidence for secretion by these neurons of norepinephrine (NE) and acetylcholine (ACh). The physiological effects of the secretion of these two substances onto the myocytes (excitation and inhibition, respectively) were generally similar to those reported in vivo. The minimal latencies of the responses were short, probably due to the high density of innervation. ACh secreted by a neuron onto itself, at autapses, evoked fast nicotinic EPSPs. We have not detected autaptic effects attributable to the secretion of NE. A minority of the neurons were detectably only adrenergic or only cholinergic. The incidence of these transmitter states was strongly dependent on culture age and culture conditions; in a heterogeneous group of about 300 reasonably well-characterized neurons about 17% (12% of neonate-derived) were apparently purely adrenergic and about 10% (13% of neonate-derived) were apparently purely cholinergic.(ABSTRACT TRUNCATED AT 400 WORDS)