Age-related changes in cognitive ERPs of attenuation.

This investigation explored developmental changes in passive and effortful components of ERPs associated with a visual attention task in children, adolescents, and adults. The task was a 'go-go' version of a continuous performance task, coupled with a passive attending phase in which the subjects merely watched the stimuli of the task. The three age groups featured a constellation of ERP components that shared the same general morphological appearance and distribution, but differences were seen with respect to latencies and amplitudes. Consistent with other studies, there was an inverse relationship with respect to age and peak latencies of the major passive and effortful components. With respect to peak amplitudes, however, the most impressive changes with age were observed in the passive processing components. For example, the P150 and P250 components presented greater amplitudes in children, whereas the N200 component presented its greatest amplitude in adults. While passive in the sense that their appearances were independent of the 'decision-making' process, these components were found to be upwardly adjustable by effort. The late positive component was found to be a combination of a passive P350 and an effortful P450. The P350 component was judged to be largely passive in character as it was well developed in subjects of all age groups when passively attending to the visual stimuli. There was no marked amplitude difference between the child and adult P450 components, but the components peaked in amplitude later in the children. Finally, the children's ERPs featured a distinct frontal negativity (FN) that was present in the Passive phase, but greatly enhanced during the Effortful phase. This study, as have many others, showed that there are reliable developmental changes in the components of visual ERPs. Therefore, the characteristics of the various components of cognitive ERPs may be effective markers of neurodevelopmental status, especially of those neuronal systems vital to attentional processing and effort regulation.

Enhancement of attention processing by Kantroll in healthy humans: a pilot study.

This is the first report in humans of the effects of daily ingestion of a specific amino acid mixture, Kantroll, on cognitive event-related potentials (ERPs) associated with performance. Cognitive ERPs were generated by two computerized visual attention tasks, the Spatial Orientation Task (SOT) and Contingent Continuous Performance Task (CCPT), in normal young adult volunteers, where each subject acted as his own control for testing before and after 28-30 days of amino acid ingestion. A statistically significant amplitude enhancement of the P300 component of the ERPs was seen after Kantroll for both tasks, as well as improvement with respect to cognitive processing speeds. The enhancement of neurophysiologic function observed in this study on normal controls is consistent with the facilitation of recovery of individuals with RDS (i.e., substance use disorder, ADHD, carbohydrate bingeing) following the ingestion of the amino acid supplement, Kantroll, and warrants additional placebo-controlled, double-blind, studies to confirm and extend these results.

Topographical analyses of attention disorders of childhood.

Cognitive ERPs and EEG spectral differences were compared in three groups of children: nonreferred controls, those with a dominant hyperactivity/impulsivity factor (ADHD-Im), and those with a dominant inattentive factor (ADHD-Ia). The results from the ERP analyses indicated that the P250, P350, and P500 components differed between the groups. The most marked differences were seen with respect to the amplitude of the P500 components. In addition, the topographic foci of the P500 components for the CON and ADHD-Im groups were symmetrical, but the ADHD-Ia group featured P250 and P350 components that were biased away from the right hemisphere. Nevertheless, the P500 was found to be an effective discriminator between the groups. The combined spectral and ERP results suggest that the attention disordered children have difficulty adjusting their level of physiological arousal, and are defective with respect to controlled (or effortful) processing.

Topographical analysis of adolescent affective disorders.

This study evaluated the EEG spectral content and the components of the cognitive ERPs evoked by a visual sustained-selective attention task from adolescents diagnosed as having an affective disorder and those who did not (nonreferred controls, CON) to determine if there were different electrophysiological profiles associated with major subtypes of affective disorders; i.e., Dysthymic Disorder (DysD) and Cyclothymic Disorder (CycD). Distinctive ERP and EEG profiles were found to be associated with the DysD and CycD groups. While both groups of depressives presented diminished P3b amplitudes, the DysD group showed a relatively greater suppression over the right temporal regions, whereas the CycD group exhibited relatively greater suppression over the left temporal region. In addition, there were differences with respect to the earlier components associated with information processing. For instance, the P1 was found deficient in the DysD group as compared to the other groups, whereas the N2 component was deficient in the CycD groups as compared to CON and DysD groups. In contrast to these amplitude differences, no significant latency differences were seen with respect to any component elicited by this paradigm. With respect to the EEG spectra, the CON group showed greater relative power in the Beta range than either the CycD or the DysD group, with the depressives featuring more midline frontal Theta activity. Characteristically, both depressant groups showed a greater anterior distribution of Alpha activity. In addition, the foci of the various spectral bands for the DysD subjects were shifted away from the right hemisphere as was the case for the P3b. Overall, the profiles suggested that those who fit the diagnostic classification of DysD have deficit function in right post-Rolandic zones, along with anomalous frontal function. It was also suggested that there may be a core disturbance of physiological arousal in unipolar depression. The CycD subjects, on the other hand, featured no hemispheric bias with respect to the P3b components or spectral foci, but did not show similar features of being cortically "hypoaroused" so that actively depressed adolescent CycD subjects did share certain physiological features with unipolar subjects.

Evidence of temporal lobe activation by discriminative spatial orientation.

The results from this spatial orientation, or cue priming, investigation found that targets presented to the contralateral visual fields differentially activated the temporal zones. For instance, stimulation within the right visual field lead to activation of the left temporal zones, as indexed by the relative prominence of the association negativity, N2. The converse was true for left visual field stimulation. For both visual field stimulation, the N2 component also showed an occipital and parietal distribution. The P300 component, which is presumed to be modulated by medial temporal lobe structures, showed the classic centroparietal distribution. Somewhat surprisingly, differences between the primed (e.g., 'facilitated') and 'normal' conditions for the N2 component appeared restricted to the occipital zones. Here, the significant variable was the N2 peak latency. Hence, the priming cue appears to quicken the maximal development of the N2 processing component, preferentially over the occipital cortex, and this may partially explain the faster reaction times in the 'facilitated' conditions for both visual fields.

Energy metabolism in rat hippocampus during and following seizure activity.

The hippocampus exhibits a post-ictal phenomenon in which it is unresponsive to further stimulation. It has been suggested that this loss of excitability is the basis of post-seizure amnesia. The biochemical events associated with this phenomenon are unclear. In the present study, energy metabolites were measured in the stratum oriens, stratum pyramidale and stratum radiatum in rat hippocampus, and correlated with field potential recordings. Wistar rats were anesthetized and the calvarium removed. Following removal of the cortex by aspiration, the hippocampus was covered with oil, and stimulating and recording electrodes were placed. Stimulation consisted of a train of stimuli at 100 Hz (10-20 m Amps). This stimulation was found to be effective in evoking self-sustaining after-discharges and post-ictal depression. Tissues for metabolite analysis were taken from a series of controls, from animals during active self-sustaining seizures, and from animals which were totally unresponsive to further electrical stimulation. Hippocampal tissue for metabolite analysis was obtained by pouring liquid N2 on the exposed tissue, then removing the frozen tissue. Glucose, ATP, and phosphocreatine were measured in hippocampal layers of CA1 using fluorescence techniques and enzymatic cycling. Results showed that during seizure activity, glucose, ATP, and phosphocreatine were all decreased from 40-80% in the three layers of the hippocampus, whereas from 60 seconds after the onset of hippocampal shutdown, energy metabolites had returned toward normal. Thus, at a time when the hippocampus was unresponsive, energy metabolites were at control levels. These data suggest that the shutdown phenomenon occurs in the presence of adequate energy stores.

Status epilepticus-induced changes in primate cortical energy metabolism.

The objective of this study was to evaluate changes in cortical energy metabolism in experimentally induced seizures in the primate. Cynamologus fascicularis monkeys were anesthetized, and a craniotomy was performed. Small samples from the motor cortex were removed for measurement of energy metabolites just prior to intravenous bicuculline infusion (0.6 mg/kg), 20 min after the onset of seizures, and 2 h after the second sample. Samples were also taken for electron microscopy. Results showed decreased phosphocreatine values 20 min after the onset of seizures, whereas ATP levels were normal. Two hours after the onset of seizures, phosphocreatine had returned to normal, but ATP levels were below normal. Examination of tissue by electron microscopy showed evidence of cell damage 2 h, 20 min after the onset of seizures. These findings are consistent with the concept that sustained seizures may lead to irreversible cell damage and that alterations in energy metabolism may contribute to the cell death.

Characterization of fimbria input to nucleus accumbens.

The hippocampal input to the nucleus accumbens was studied by correlative electrophysiological and anatomical techniques in acutely prepared rabbits. Field and extracellular unitary potentials were recorded in the nucleus accumbens following ipsilateral fimbria stimulation. Analysis of the components of the field response was based on the relevant correlations with extracellular unitary activity. The cellular types that are the recipients of the hippocampal projection were determined by combined intracellular horseradish peroxidase (HRP) and Golgi analyses. The distribution of the hippocampal input was determined by combined field potential and current source density analyses. It was found that the ipsilateral fimbria projection was distributed to the dorsal two-thirds of the nucleus, with the projection being heaviest in the more caudal portions of the nucleus. The negative (N) component of the field response was studied by correlating its behavior with the appropriate extracellular unitary recordings. It was concluded that the N-component represented an envelope of monosynaptically activated action potentials. The positive (P) component of the field response throughout the nucleus accumbens was studied pharmacologically with the iontophoretic administration of bicuculline. The P-components, in both the dorsal and ventral regions of the nucleus, were diminished by bicuculline application, indicating that this potential results from the activation of gamma-aminobutyric acid (GABA) mechanisms. The cell populations that are the targets for the hippocampal projections were studied by the technique of intracellular staining with HRP. These results were correlated with the findings of a Golgi analysis. Two distinct cell types were found to respond in a monosynaptic manner to ipsilateral fimbria stimulation. The most common of the two were the small-to medium-sized spiny neurons, and they were distributed throughout the nucleus. These cells have a spherical dendritic arrangement. The second, and most distinctive, of the cell types were the large aspiny neurons. These cells were distributed medially and caudally in the nucleus. Two of the outstanding features of these cells were the expanse of their dendritic domains and the fact that axons originated from relatively remote portions of the dendrites.

Dopamine action in the nucleus accumbens.

The action of dopamine was studied in the nucleus accumbens of acutely prepared rabbits. Dopamine was applied iontophoretically to those cells and cell populations that responded in a monosynaptic excitatory manner to ipsilateral fimbrial stimulation. This strategy was adopted to isolate the effects of dopamine on postsynaptic receptors thus avoiding the bias resulting from activation of presynaptic dopamine receptors on dopaminergic afferents. Dopamine was found to have a suppressive effect on the excitatory (N) component of the field response and on driven extracellular unitary discharges. The specificity of dopamine's effect with receptors was indicated by the facts that fluphenazine effectively antagonized dopamine's effect, whereas bicuculline did not. The effect of dopamine was dependent on the rate of fimbrial stimulation. Dopamine has a marked suppressive effect on the fimbria-induced response at 0.5 Hz of stimulation but not at 6.0 Hz. This frequency specificity could not be linked directly to a cyclic adenosine 3',5'-cyclic monophosphate (cyclic AMP) mechanism because the iontophoresis cyclic AMP and dibutyryl cyclic AMP had suppressive effects at both 0.5 and 6.0 Hz rates of stimulation. It is suggested that dopamine acts in the nucleus accumbens to increase the "signal-to-noise" ratio. This might be a form of "contrast enhancement" of an incoming hippocampal message.

Cholinergic modulation of mediodorsal thalamic input into cingulate cortex.

Field potentials in cingulate cortex (area 24) produced by electrical stimulation of the mediodorsal thalamic nucleus were diminished by iontophoretic ejection of the cholinergic agonist, carbachol. The effect was frequency dependent: field potentials produced by 7.0 Hz stimulation were reduced by 34%. Potentials produced by 0.5 Hz stimulation were not significantly changed. This reduction was blocked by muscarinic but not nicotinic antagonists.

Cingulate cortex response to electrical stimulation of the mediodorsal thalamic nucleus.

Electrical stimulation of the lateral, parvocellular part of the mediodorsal thalamic nucleus of the rabbit was found to evoke field potentials and drive single cells in the anterior cingulate cortex. Furthermore, the laminar distribution of the field responses and the population of effected cells were dependent on the frequency of the stimulation. Excitatory current sinks were produced in layers I and III (primary layers of mediodorsal input) only when the stimulus frequency was in the theta range (6 to 8 Hz); the majority of cells were reliably driven only by stimulation within this range. Lower-frequency stimulation, e.g., 0.5 Hz, produced a current sink in layer V. Cells that were driven at low frequencies might be antidromically activated. The study suggests that modulation of mediodorsal outflow in the theta range may be necessary for effective information transfer to the cortex.

Effects of CCK-8 in the nucleus accumbens.

The electrophysiological effects of CCK-8 were studied in the rabbit nucleus accumbens. CCK-8 was found to influence neurotransmitter (modulator) systems so as to enhance their action. For example, CCK-8 enhanced the effects of stimulation of the glutaminergic pathways, the fimbria. In addition, when CCK-8 was co-administered with dopamine and acetylcholine, their suppressive effect on the fimbria evoked response was enhanced. Therefore, CCK-8 appears to be capable of enhancing the influence of multiple neurotransmitter (modulator) systems.

Evidence for cholinergic muscarinic receptors on mediodorsal thalamic projections to the anterior cingulate cortex.

Cholinergic muscarinic receptor binding was analyzed in the rat brain anterior cingulate cortex following lesions of the mediodorsal or anterior thalamic nuclei, or the diagonal band of Broca. A significant change in receptor binding was noted only after lesions of the mediodorsal projection, suggesting that cholinergic muscarinic receptors are located on these terminals. These findings suggest that the projection from the diagonal band of Broca which is cholinergic may act as a modulator of the mediodorsal thalamic projection.

Origin of cingulate cortex cholinergic innervation in the rat.

The relative contribution of the n. diagonal band and thalamic nuclei to the cholinergic innervation of the cingulate cortex was examined. Lesions were placed in the n. diagonal band, anterior thalamus, and medial thalamus of rats, and changes in choline acetyltransferase in discrete regions of the cingulate cortex were determined. The n. diagonal band lesion produced a large decrease in choline acetyltransferase activity while the thalamic lesions produced no significant change in activity.

Evidence for a cyclic GMP mechanism in the mediation of hippocampal post-tetanic potentiation.

Correlative electrophysiological and biochemical techniques were used to study hippocampal post-tetanic potentiation in acutely prepared rabbits following stimulation of the medial septal region and contralateral hippocampal field CA3. The results indicate that calcium ions, guanosine-3':5'-monophosphate, and phosphodiesterase inhibitors selectively enhanced the duration of post-tetanic potentiation. Potassium ions selectively enhanced tetanic potentiation. Adenosine-3':5'-cyclic monophosphate suppressed both tetanic and post-tetanic potentiation. The electrophysiological findings were supported by biochemical observations that guanosine-3':5'-monophosphate levels show marked increases following tetanic stimulation of either the medial septal region or contralateral hippocampal field CA3 pathways. The data suggest that a calcium-dependent process in the presence of a guanosine-3':5'-monophosphate mechanism promotes periods of hippocampal pyramidal cell hyperexcitability. The mechanism by which the cyclic nucleotide alters potentiation does not appear to be coupled to a single receptor variety.

Regional distribution of catecholamines in nucleus accumbens of the rabbit.

The nucleus accumbens is an important telencephalic region, which is the target limbic and mesolimbic pathways. Because of an ongoing physiological study of the effects of dopamine, we wanted to determine regional differences of dopamine and norepinephrine concentrations in the nucleus. As determined by radioenzymatic assays, dopamine levels were not significantly different in the anterior-posterior dimension, averaging approximately 187 ng dopamine/mg protein. Substantial amounts of norepinephrine were found throughout the nucleus, but the levels were significantly higher in the caudal portions of the nucleus, being approximately 4.5 times higher than in the anterior portions.

Implications from studies of the nucleus accumbens: toward a multi-factor theory of schizophrenia.

A model is propose of dopamine and histamine modulation of afferent hippocampal activity in the nucleus accumbens. It is suggested that increased dopamine action leads to an increase in the signal/noise ratio or a form of contrast enhancement. To the contrary, the effect of an increased histamine action would be to inhibit the most salient incoming hippocampal message; i.e., a form of contrast reduction.

Histamine: correlative studies in nucleus accumbens.

The role of histamine as a neurotransmitter has been the subject of considerable controversy. Recent evidence suggests it to be involved in such complex activities as arousal and affect. The purpose of the present study is to examine the possible source, function, and pharmacology of histamine in the nucleus accumbens, an area of the brain also implicated in complex activities such as affect. The anatomical studies suggest that the most probable source of the histamine in nucleus accumbens is the complex region lateral to the mammillary nuclei. These areas are the intercalated nucleus and the tuberomammillary nucleus (nuclei gemini hypothalami). To a lesser degree, the supramammillary complex may also contribute histamine-containing axons to the accumbens area. Adenylate cyclase in the rabbit nucleus accumbens displayed activation in response to histamine agonists (histamine, 2-Me-histamine, and 4-Me-histamine). The action of the H1 antagonist promethazine was greater than the H2 antagonist metiamide in reducing enzyme activation by histamine and 2-Me-histamine. In contrast, metiamide was more potent than promethazine toward antagonism of the action of 4-Me-histamine. However, no additive effects were noted when agonists were added in combination. Based upon these data, it is suggested that activation of adenylate cyclase in the rabbit nucleus accumbens is mediated in part by mixed H1 and H2 receptors or cellular disruption reflects the loss of receptor specificity. Physiological studies demonstrated that the H2 agonist 4-Me-histamine had an inhibitory effect on the activity of neurons driven by stimulation of the fimbria. The magnitude of the effect was frequency dependent. The H1 agonist 2-Me-histamine had no significant effect. Iontophoretic application of 4-Me-histamine had minimal effect upon low frequency volleys (0.5 Hz) but had a pronounced effect upon higher frequency volleys (6.0 Hz). These effects were antagonized by metiamide. Iontophoretic application of metiamide alone produced an effect only upon the P component of the field response, which is also bicuculline sensitive. Bicuculline coadministration was also effective in antagonizing the 4-Me-histamine effect. The physiological data suggest that histamine works through H2 receptors in nucleus accumbens, perhaps by potentiating the effects of gamma-aminobutyric acid (GABA). Thus, histamine in nucleus accumbens appears to function as a modulatory substance whose effect is dependent upon the activity of other transmitter and afferent systems.

Ventromedial nucleus of the hypothalamus: convergent excitatory and inhibitory responses to fimbria and stria terminalis stimulation.

Field and extracellular unitary potentials were recorded in the ventromedial nucleus of the hypothalamus (VMH) of urethane-anesthetized rabbits after stimulation of the fimbria and stria terminalis. Stimulation of the lateral portion of the fimbria, which carries fibers from the ventral subiculum of the hippocampal formation, evoked a two-component response. An early excitatory response, with an average latency of 10 msec, predominated along the lateral margins of the VMH. A later inhibitory potential with an average latency of 15 msec was seen predominantly within the central portions of the VMH. Stimulation of the dorsal component of the stria terminalis produced two similar response patterns: an early excitatory response with an average latency of 16 msec, followed by an inhibitory potential with an average latency of 25 msec. The topographical distribution of these two components of the response was nearly identical to that produced by lateral fimbria stimulation. In contrast, stimulation of the ventral component of the stria terminalis evoked a simple excitatory response with an average latency of 10 msec which was maximal within the core of the VMH. Extracellular unitary recordings showed that the early negativity associated with stimulation of each of these three pathways reflects a monosynaptic excitation of VMH cells and that there was convergence of the three excitatory inputs at the single cell level.