The effect of Parkinson's disease on interference control during action selection.

Basal ganglia structures comprise a portion of the neural circuitry that is hypothesized to coordinate the selection and suppression of competing responses. Parkinson's disease (PD) may produce a dysfunction in these structures that alters this capacity, making it difficult for patients with PD to suppress interference arising from the automatic activation of salient or overlearned responses. Empirical observations thus far have confirmed this assumption in some studies, but not in others, due presumably to considerable inter-individual variability among PD patients. In an attempt to help resolve this controversy, we measured the performance of 50 PD patients and 25 healthy controls on an arrow version of the Eriksen flanker task in which participants were required to select a response based on the direction of a target arrow that was flanked by arrows pointing in the same (congruent) or opposite (incongruent) direction. Consistent with previous findings, reaction time (RT) increased with incongruent flankers compared to congruent or neutral flankers, and this cost of incongruence was greater among PD patients. Two novel findings are reported. First, distributional analyses, guided by dual-process models of conflict effects and the activation-suppression hypothesis, revealed that PD patients are less efficient at suppressing the activation of conflicting responses, even when matched to healthy controls on RT in a neutral condition. Second, this reduced efficiency was apparent in half of the PD patients, whereas the remaining patients were as efficient as healthy controls. These findings suggest that although poor suppression of conflicting responses is an important feature of PD, it is not evident in all medicated patients.

Critical issues in assessing the behavioral effects of amphetamine.

Amphetamine induces a behavioral syndrome in mammals that includes a variety of repetitive behaviors. An integral component of this syndrome in humans is the presence of a thought disturbance not unlike that manifest in idiopathic paranoid schizophrenia. The consistent pattern of behavioral changes produced by amphetamine across species, when considered in light of the psychosis it elicits in humans, has suggested to many that these drug-induced changes in animals may provide a model of the endogenous psychosis in humans. Amphetamine-induced changes in open-field behavior in the rat have been the most widely studied in attempts to formulate a model for investigating the neurobiological mechanisms underlying amphetamine psychosis and paranoid schizophrenia in humans and for testing the therapeutic efficacy of new antipsychotic drugs. The procedures used to assess the behavioral response to amphetamine, however, typically include rating scales or automated recordings that by their very nature ignore those components of the behavioral response that may be most critical for developing a viable animal model of the naturally occurring psychosis. Further, open-field behavior is often recorded during arbitrarily selected intervals without consideration for the multiphasic nature of the entire amphetamine response. We discuss how incomplete descriptive analyses of the amphetamine behavioral response in rats has led to confusion in the literature and describe behavioral research that is paradigmatic of the work we believe is most likely to eventuate in significant progress in the field.

Is handwriting posture associated with differences in motor control? An analysis of asymmetries in the readiness potential.

Levy and Reid's [1] hypothesis that persons who write using the inverted posture have ipsilateral control of distal limb movements, particularly those involved in handwriting, was tested in three experiments in which asymmetries in the readiness potential (RP) were measured. In the first experiment, each subject executed a self-paced repetitive squeeze. Contralaterally larger RPs were recorded from all subjects, irrespective to handwriting posture. In two other experiments, subjects performed the self-paced squeeze in one condition and wrote a single word repetitively in an analogous condition. Larger RPs were recorded over the contralateral cerebral hemisphere in most inverted-writing subjects in both conditions. Ipsilaterally larger RPs were recorded, however, from some left-handers while writing. These findings suggest that, although control of certain movements may originate from the ipsilateral motor cortex in a small proportion of left-handers, handwriting posture does not index this difference.

Exercise reduces age-dependent decrease in platelet protein kinase C activity and translocation.

BACKGROUND: This study examined the effect of age and aerobic exercise performed on a regular basis on human platelet protein kinase C (PKC) activity and translocation. METHODS: Blood platelets were obtained from young (20-36 years) and older (61-78 years) healthy male human subjects. Platelets were incubated with PMA, 5-HT, or thrombin; PKC activities were measured in partially purified extracts of cytosolic and membranous fractions. RESULTS: Platelet PKC activities associated with both the membranes and the cytosol cellular fractions were significantly reduced in older nonexercisers. Redistribution of platelet PKC activity elicited by stimulating the cell surface receptors for 5-HT or thrombin or by direct PKC stimulation (PMA) was found to be reduced in the elderly subjects. Maintenance of aerobic fitness in the older group of exercisers partially prevented the age-associated decline in platelet PKC activity and in stimuli-induced enzyme redistribution. CONCLUSIONS: These results indicate that platelet PKC activity and its translocation may be biological markers of aging and that aerobic exercise may serve to slow the rate at which enzyme activation declines during senescence.

Age-related decreases in lymphocyte protein kinase C activity and translocation are reduced by aerobic fitness.

This study investigated the effects of advancing age and long-term aerobic fitness on lymphocyte protein kinase C (PKC) activity and translocation. Lymphocytes were obtained from young (20-36 years old) and older (61-78 years old) healthy men who were either aerobically conditioned or deconditioned. Both baseline PKC activity and the response of this enzyme to the direct PKC stimulating agent, phorbol 12-myristate, 13-acetate (PMA) or to the mitogen, phytohaemagglutinin (PHA), were measured in partially purified extracts of cytosolic and membranous fractions of lymphocytes. Basal PKC activity, PMA-induced redistribution of PKC, and PHA-induced enhancement of PKC activity were reduced among older subjects in both lymphocyte cytosolic and membranous fractions. However, the magnitudes of these reductions were smaller among the older subjects who were aerobically fit. Lymphocyte PKC activity and translocation may be biological markers of aging, and the maintenance of aerobic fitness into later life may serve to slow the rate at which activation of this enzyme declines during senescence.

Left visual field superiority in a letter-naming task for both left- and right-handers.

Subjects identified on the basis of sex, handedness, and handwriting posture performed a letter-naming task. Single letters were shown briefly in the left or right visual field and the subject was required to name the letter as quickly as possible. Both left- and right-handers had shorter response latencies when the stimulus was presented in the left visual field. Response latency decreased across trials, however, the decrement was largest to right visual field stimuli. In addition, males produced significantly faster reaction than did females.

A psychophysiological investigation of the continuous flow model of human information processing.

Twelve subjects responded to target letters "H" or "S" by squeezing dynamometers with the left or right hand. Targets could be surrounded by compatible (e.g., HHHHH) or incompatible noise (SSHSS) letters. Measures of the P300 component of the event-related brain potential and of correct and incorrect electromyographic and squeeze activity were used to study stimulus evaluation and response-related processes. When incorrect squeeze activity was present, execution of the correct response was prolonged, indicating a process of response competition. This process occurred more often under incompatible noise conditions, which were also associated with a delayed P300. Thus, the noise/compatibility manipulation influenced both stimulus evaluation and response competition processes. In contrast, a warning tone that preceded array presentation on half the trials, increased response speed without influencing evaluation time. The data suggest that the latency and accuracy of overt behavioral responses are a function of (a) a response activation process controlled by an evaluation process that accumulates evidence gradually, (b) a response priming process that is independent of stimulus evaluation, and (c) a response competition process.

On the transmission of partial information: inferences from movement-related brain potentials.

Results are reported from a new paradigm that uses movement-related brain potentials to detect response preparation based on partial information. The paradigm uses a hybrid choice-reaction go/nogo procedure in which decisions about response hand and whether to respond are based on separate stimulus attributes. A lateral asymmetry in the movement-related brain potential was found on nogo trials without overt movement. The direction of this asymmetry depended primarily on the signaled response hand rather than on properties of the stimulus. When the asymmetry first appeared was influenced by the time required to select the signaled hand, and when it began to differ on go and nogo trials was influenced by the time to decide whether to respond. These findings indicate that both stimulus attributes were processed in parallel and that the asymmetry reflected preparation of the response hand that began before the go/nogo decision was completed.

Mental slowing in elderly persons: a cognitive psychophysiological analysis.

In recent attempts to formulate an integrative model of mental slowing in elderly persons, regression analyses have been done in which reaction-time data from a large number of studies spanning a broad range of speeded decision-making tasks were combined. The results of these meta-analyses were then used to support the conclusion that there is a generalized, proportional decline in mental processing speed among elderly adults that affects all elements of mentation equally. We present a series of similar regression analyses in which both reaction time and the latency of the P300 component of the event-related brain potential are included. The results of these analyses indicate that there are elements of mental processing that may be slowed additively, not proportionately, in older persons. Furthermore, the results raise some questions about the logic underlying the interpretation of the meta-regression analysis.

Discovery of the P300: a tribute.

The significant and enduring contributions made to cognitive psychophysiology by Samuel Sutton and his colleagues in the first two papers on the P300 component of the event-related brain potential are discussed. The remarkable quality of these contributions is revealed in the fact that the issues that motivated the series of experiments reported by these investigators continue to be of core importance to the field.

Is the age-complexity effect mediated by reductions in a general processing resource?

The rate of information processing, as revealed in measures of reaction time, slows with advancing age and this slowing is most evident as processing complexity increases. This phenomenon, known as the Age-Complexity effect, has been attributed to general changes in the speed of processing that affect all components of processing indiscriminantly, both within and across tasks in a particular processing domain. That the slowing is thought to be task- and process-independent has led to the additional inference that it reflects reductions in a general processing resource. On the basis of converging evidence identified in a review of both behavioral and chronopsychophysiological studies, we argue that the slowing induced by older age is not generalized, but rather is both task-dependent and process-specific and, as such, cannot be explained in terms of a diminished general processing resource. We close by speculating that elements of the age-induced slowing can be interpreted within the context of the cognitive-energetical model.

Alterations of spontaneous neuronal activity in the caudate-putamen, nucleus accumbens and amygdaloid complex of rats produced by D-amphetamine.

Changes in spontaneous neuronal activity in the caudate-putamen, accumbens nucleus and amygdaloid complex of immunobilized, locally anesthetized rats were recorded following intraperitoneal injection of 2.5 mg/kg d-amphetamine sulfate. In each site, d-amphetamine typically produced a prolonged depression of firing rate which, in most cases, occurred after an inital, brief potentiation of activity. However, the onset of the amphetamine-induced depression occurred signficantly later in the amygdala. Subsequent IP administration of either 5.0 mg/kg chlorpromazine or 2.0 mg/kg haloperidol reversed, to varying degrees, the amphetamine-induced depression of neuronal activity in each area. These results are discussed in terms of the known biochemical effects of amphetamine on catecholaminergic transmission and the alleged role of the nigro-neostriatal mesolimbic dopamine systems in the amphetamine behavioral response.

Differential actions of classical and atypical antipsychotic drugs on spontaneous neuronal activity in the amygdaloid complex.

Classical antipsychotic drugs such as haloperidol produce akinesia and catalepsy, whereas clozapine and related atypical antipsychotics fail to elicit these behaviors even at relatively high doses. Despite these behavioral differences, a cataleptic dose of haloperidol (2.0 mg/kg) produces changes in neuronal activity in the neostriatum and nucleus accumbens comparable to those produced by a non-cataleptic dose of clozapine (20.0 mg/kg). To further elucidate the brain mechanisms underlying the differential behavioral response to these drugs, an electrophysiological analysis was extended to neurons in the rat amygdaloid complex. Whereas an intraperitoneal injection of 2.0 mg/kg haloperidol generally failed to alter the firing rate of amygdaloid neurons, 20.0 mg/kg clozapine typically produced a prolonged increase in activity. Similarly, clozapine, but not haloperidol, reversed the depression of firing rate produced by 1.0 mg/kg d-amphetamine. The results suggest that neurons in the amygdaloid complex are more responsive to antipsychotic drugs devoid of extrapyramidal side effects than to antipsychotics which elicit parkinsonian-like motor dysfunctions.

Cataleptogenic potency of the antipsychotic drugs is inversely correlated with neuronal activity in the amygdaloid complex of the rat.

At doses known to elicit catalepsy in rats, haloperidol (1.0 and 2.0 mg/kg) and pimozide (4.0 mg/kg), injected intraperitoneally, failed to alter the spontaneous activity of neurons in the amygdaloid complex of locally anesthetized, immobilized rats. In contrast, clozapine and thioridazine, which are devoid of cataleptic effects even at high doses (10.0 and 20.0 mg/kg), caused a dramatic and prolonged increase in firing rate, whereas chlorpromazine, which produces relatively mild catalepsy at doses of 5.0 and 10.0 mg/kg, produced an intermediate response. These results, which were obtained throughout the amygdaloid complex, indicate that the cataleptogenic potency of the antipsychotic drugs is inversely correlated with their ability to accelerate neuronal activity. This finding is discussed in relation to the known mechanisms of action of these drugs on various neurotransmitter systems in the amygdaloid complex.

"Classical" and "atypical" antipsychotic drugs: differential antagonism of amphetamine- and apomorphine-induced alterations of spontaneous neuronal activity in the neostriatum and nucleus accumbens.

The ability of clozapine and haloperidol to antagonize the depression of firing rate produced by d-amphetamine and apomorphine in the neostriatum and nucleus accumbens was tested in immobilized, locally anesthetized rats. In the neostriatum, an intraperitoneal injection of 2.5 mg/kg d-amphetamine or 1.0 mg/kg apomorphine produced a prolonged inhibition of neuronal activity that was reversed by a subjsequent injection of either 20 mg/kg clozapine or 2.0 mg/kg haloperidol. An analysis of the onset and magnitude of the blockade revealed that clozapine was more effective than haloperidol in reversing the amphetamine response but that both antipsychotic drugs produced a comparable blockade of the apomorphine-induced depression. Similar results were obtained in the nucleus accumbens. The data indicate that although clozapine acts equieffectively in the neostriatum and nucleus accumbens, this atypical antipsychotic drug, aside from blocking postsynaptic dopamine receptors, may exert at least some of its effects by preventing dopamine release.

Attentional influence on the P50 component of the auditory event-related brain potential.

To determine if attentional factors influence the suppression of the auditory P50 in a conditioning-testing paradigm, known as the 'sensory gating' effect, we tested 10 healthy young adults in four experimental conditions. The first condition was the traditional passive conditioning-testing paradigm in which a pair of identical auditory clicks is administered at an interstimulus interval fixed at 500 ms. The effect of interest is a reduction of P50 amplitude in response to the second stimulus. In the next condition, the second stimulus could be one of two possible frequencies and subjects were required to count one and to ignore the other. The third and fourth experimental conditions involved a motor response. In the third condition, subjects were required to make a unimanual button press to the occurrence of the second stimulus. In the fourth condition, subjects were required to discriminate among two possible second stimuli, and make a unimanual button press to the occurrence of the designated stimulus. Subjects also completed four matched blocks of single stimulus (i.e., unpaired) presentations to provide a baseline for assessing the effect of the warning stimulus on the evoked response. We found, in agreement with previous results, that passive exposure to the paired stimuli produced a suppression of P50 amplitude to the second stimulus. However, we also found that suppression of P50 amplitude was not evident when subjects selectively counted the designated stimuli, and was reduced in magnitude when a simple motor response was required and when a selective motor response was based on stimulus discrimination. In addition, we observed that the amplitude of the P50 was larger with unpaired single stimuli than it was either with the first or second stimulus of a pair, regardless of processing demands. Furthermore, variations in processing demands did not affect P50 amplitude when a single stimulus was presented. This pattern of results suggests that the 'sensory gating' effect is not a simple 'hard-wired' inhibitory phenomenon. Rather, it may be one manifestation of an attention regulation process that is activated by a warning stimulus and has either inhibitory or excitatory effects on neural transmission, determined by variations in processing demands. Presentation of a warning stimulus may have an additional, unselective suppressing effect, operating independently of this attention regulating process.

Some thoughts on neurocognitive slowing.

An historical review of the use of Brinley analyses in reaction time studies of age-related cognitive slowing is presented. The debate between critics and supporters of this procedure is discussed. It is concluded that the debate has served to sharpen our understanding of when and how this analytic procedure should be used. It is also argued that our insights into mental slowing may be deepened by studying this phenomenon using cognitive psychophysiological methods.

The temporal selectivity of additive factor effects on the reaction process revealed in ERP component latencies.

An experiment was conducted to relate individual components of the event-related brain potential to specific stages of information processing in a two-choice reaction time (RT) task in a group of undergraduate students. Specifically, the latency of the P300 component and the lateralized readiness potential (LRP) were studied as a function of variations in stimulus degradation and response complexity. It was hypothesized that degrading the stimulus would delay the P300 and LRP to the same extent as RT, and that increasing response complexity would affect RT but not P300 latency. The extant literature did not permit any hypothesis regarding the effect of response complexity on LRP latency. The two task variables were found to have additive effects on RT. As predicted, variations in stimulus degradation influenced the latencies of both components, whereas alterations in response complexity had no effect on P300 latency. A significant new finding was that the onset latency of the LRP remained unchanged across levels of response complexity. The overall pattern of results supports the notion of temporal selectivity of stage manipulations that is derived from discrete stage models of human information processing. Furthermore, these results refine the functional interpretation of the LRP by indicating that within the conceptual framework of a stage model the processes this component indexes succeed the start of response choice but preceded the start of motor programming.

Speed pressure in conflict situations impedes inhibitory action control in Parkinson's disease.

The current study investigated the effects of Parkinson's disease (PD) on the ability to resolve conflicts when performance emphasized speed vs. response accuracy. PD patients and healthy controls (HC) completed a Simon task, and a subset of participants provided movement-related potential (MRP) data to investigate motor cortex activation and inhibition associated with conflict resolution. Both groups adjusted performance strategically with speed or accuracy instructions. The groups experienced similar susceptibility to making fast errors in conflict trials, but PD patients were less proficient compared to HC at suppressing incorrect responses, especially under speed pressure. Analysis of MRPs showed attenuated inhibition of the motor cortex controlling the conflicting response in PD patients compared to HC. These results confirm the detrimental effects of PD on inhibitory control mechanisms with speed pressure and also suggest that a downstream effect of inhibitory dysfunction in PD might be due to diminished inhibition of the motor cortex.