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Volitional control is at the core of brain-machine interfaces (BMI) adaptation and neuroprosthetic-driven learning to restore motor function for disabled patients, but neuroplasticity changes and neuromodulation underlying volitional control of neuroprosthetic learning are largely unexplored. To better study volitional control at annotated neural population, we have developed an operant neuroprosthetic task with closed-loop feedback system by volitional conditioning of population calcium signal in the M1 cortex using fiber photometry recording. Importantly, volitional conditioning of the population calcium signal in M1 neurons did not improve within-session adaptation, but specifically enhanced across-session neuroprosthetic skill learning with reduced time-to-target and the time to complete 50 successful trials. With brain-behavior causality of the neuroprosthetic paradigm, we revealed that proficiency of neuroprosthetic learning by volitional conditioning of calcium signal was associated with the stable representational (plasticity) mapping in M1 neurons with the reduced calcium peak. Furthermore, pharmacological blockade of adenosine A 2A receptors facilitated volitional conditioning of neuroprosthetic learning and converted an ineffective volitional conditioning protocol to be the effective for neuroprosthetic learning. These findings may help to harness neuroplasticity for better volitional control of neuroprosthetic training and suggest a novel pharmacological strategy to improve neuroprosthetic learning in BMI adaptation by targeting striatal A 2A receptors., (Copyright © 2020. Published by Elsevier Ltd.)

The impact of testosterone (T) on the exogenous (Experiment 1) and endogenous (Experiment 2) orienting of visual attention in males was examined. Sixteen male participants completed both an exogenous and an endogenous cuing task on two separate days. About 2-3h prior to testing, either a placebo or a dose of T was administered. The inhibition of return (IOR) phenomenon was observed during the exogenous cuing task, but IOR was not influenced by T. During the endogenous task, participants demonstrated the expected cuing effects on both days. However, longer reaction time to invalid target locations was observed following T-administration. The manipulation of T-levels in males provides converging evidence of dissociation between reflexive and volitional orienting of attention., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Physical exercise can improve cognition but whether this is related to motivation levels is unknown. Voluntary wheel running is a rewarding activity proposed as a model of motivation to exercise. To question the potential effects of exercise motivation on subsequent behaviour, we used a pharmacological approach targeting some reward mechanisms. The stress hormone corticosterone has rewarding effects mediated by activation of low affinity glucocorticoid receptors (GR). To investigate whether corticosterone synthesis motivates exercise via activation of GRs and subsequently, impacts on behaviour, we treated C57BL/6J mice acutely with the inhibitor of corticosterone synthesis metyrapone (35mg/kg) or repeatedly with the GR antagonist mifepristone (30mg/kg) prior to 1-h running wheel sessions. To investigate whether reducing motivation to exercise impacts on behaviour, we antagonised running-induced dopamine D2/D3 receptors activation with sulpiride (25 or 50mg/kg) and assessed locomotor, anxiety-related and memory performance after 20 running sessions over 4 weeks. We found that corticosterone synthesis contributes to running levels, but the maintenance of running behaviour was not mediated by activation of GRs. Intermittent exercise was not associated with changes in behavioural or cognitive performance. The persistent reduction in exercise levels triggered by sulpiride also had limited impact on behavioural performance, although the level of performance for some behaviours was related to the level of exercise. Altogether, these findings indicate that corticosterone and dopamine D2/D3 receptor activation contribute to the motivation for wheel running, but suggest that motivation for exercise is not a sufficient factor to alter behaviour in healthy mice., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Moral decisions and social relationships are often characterized by strong feelings of ambivalence which can be a catalyst for emotional distress and several health-related problems. The anterior cingulate cortex (ACC) has been identified as a key brain region in monitoring conflicting information, but the neurobiological substrates of ambivalence processing are still widely unknown. We have conducted two randomized, double-blind, placebo-controlled, functional magnetic resonance imaging experiments involving 70 healthy male volunteers to investigate the effects of the neuropeptide oxytocin (OXT) on neural and behavioral correlates of ambivalence. We chose moral decision-making and the imagery of partner infidelity as examples to probe volitional and emotional ambivalence. In both experiments, intranasal OXT diminished neural responses in the ACC to ambivalence. Under OXT, moral dilemma vignettes also elicited a reduced activation in the orbitofrontal cortex, and the imagery of partner infidelity was rated as less arousing. Interestingly, the OXT-induced differential activation in the ACC predicted the magnitude of arousal reduction. Taken together, our findings reveal an unprecedented role of OXT in causing a domain-general decrease of neural responses to ambivalence. By alleviating emotional distress, OXT may qualify as a treatment option for psychiatric disorders with heightened ambivalence sensitivity such as schizophrenia or obsessive-compulsive disorder., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

This Viewpoint emphasizes interoceptive discriminative stimulus modulation of voluntary operant behavior (a la B. F. Skinner), rather than elicitation of Pavlovian conditioned reflexes. In doing so, I will restate how the operant drug discrimination paradigm may not only elucidate smoking and other addictive behaviors but also anxiety (Troisi, J. R., II. (2003) Spontaneous recovery during, but not following, extinction of the discriminative stimulus effects of nicotine in rats: Reinstatement of stimulus control. Psychol. Rec. 53, 579-592).

Blood gases levels imbalances belong to important factors triggering central nervous system (CNS) functional disturbances. Hypoxia can be illness-related, like in many COPD patients, or it may be caused by broad range of external or iatrogenic factors - including influence of drugs depressing respiration, failure to keep the patient's prosthesis-supported airways patent, or a mistake in the operation of medical equipment supporting patient's respiration. Hypoxia, especially when it is not accompanied by rapid carbon dioxide retention, can go unnoticed for prolonged times, deepening existing CNS disorders, sometimes rapidly triggering their manifestation, or evoking quite new conditions and symptoms - like anxiety, agitation, aggressive behavior, euphoria, or hallucinations. Those, in turn, often result in situations raising interest in law enforcement institutions which need forensic medicine specialist's assistance and opinion. The possibility of illness or drug-related hypoxia, especially in terminal patients, is used to raise questions about the patients' ability to properly express their will in the way demanded by law - it also must be considered as a factor limiting the patients' responsibility in case they commit crimes. The possibility of hallucinations in hypoxia patients limits their credibility as witnesses or even their ability to report crime or sexual abuse they have been subjected to.

In order to analyze functional connectivity in untreated and treated patients with schizophrenia, resting-state fMRI data were obtained for whole-brain functional connectivity analysis from 22 first-episode neuroleptic-naïve schizophrenia (NNS), 61 first-episode neuroleptic-treated schizophrenia (NTS) patients, and 60 healthy controls (HC). Reductions were found in untreated and treated patients in the functional connectivity between the posterior cingulate gyrus and precuneus, and this was correlated with the reduction in volition from the Positive and Negative Symptoms Scale (PANSS), that is in the willful initiation, sustenance, and control of thoughts, behavior, movements, and speech, and with the general and negative symptoms. In addition in both patient groups interhemispheric functional connectivity was weaker between the orbitofrontal cortex, amygdala and temporal pole. These functional connectivity changes and the related symptoms were not treated by the neuroleptics. Differences between the patient groups were that there were more strong functional connectivity links in the NNS patients (including in hippocampal, frontal, and striatal circuits) than in the NTS patients. These findings with a whole brain analysis in untreated and treated patients with schizophrenia provide evidence on some of the brain regions implicated in the volitional, other general, and negative symptoms, of schizophrenia that are not treated by neuroleptics so have implications for the development of other treatments; and provide evidence on some brain systems in which neuroleptics do alter the functional connectivity.

Past research found that the ingestion of glucose can enhance self-control. It has been widely assumed that basic physiological processes underlie this effect. We hypothesized that the effect of glucose also depends on people's theories about willpower. Three experiments, both measuring (experiment 1) and manipulating (experiments 2 and 3) theories about willpower, showed that, following a demanding task, only people who view willpower as limited and easily depleted (a limited resource theory) exhibited improved self-control after sugar consumption. In contrast, people who view willpower as plentiful (a nonlimited resource theory) showed no benefits from glucose--they exhibited high levels of self-control performance with or without sugar boosts. Additionally, creating beliefs about glucose ingestion (experiment 3) did not have the same effect as ingesting glucose for those with a limited resource theory. We suggest that the belief that willpower is limited sensitizes people to cues about their available resources including physiological cues, making them dependent on glucose boosts for high self-control performance.

Chronic administration of ethanol induces persistent accumulation of ΔFosB, an important transcription factor, in the midbrain dopamine system. This process underlies the progression to addiction. Previously, we have shown that cytisine, a neuronal nicotinic acetylcholine receptor (nAChR) partial agonist, reduces various ethanol-drinking behaviors and ethanol-induced striatal dopamine function. However, the effects of cytisine on chronic ethanol drinking and ethanol-induced up-regulation of striatal ΔFosB are not known. Therefore, we examined the effects of cytisine on chronic voluntary ethanol consumption and associated striatal ΔFosB up-regulation in C57BL/6J mice using behavioral and biochemical methods. Following the chronic voluntary consumption of 15% (v/v) ethanol under a 24-h two-bottle choice intermittent access (IA; 3 sessions/week) or continuous access (CA; 24 h/d and 7 d/week) paradigm, mice received repeated intraperitoneal injections of saline or cytisine (0.5 or 3.0 mg/kg). Ethanol and water intake were monitored for 24 h post-treatment. Pretreatment with cytisine (0.5 or 1.5 mg/kg) significantly reduced ethanol consumption and preference in both paradigms at 2 h and 24 h post-treatment. The ΔFosB levels in the ventral and dorsal striatum were determined by Western blotting 18-24 h after the last point of ethanol access. In addition, cytisine (0.5 mg/kg) significantly attenuated up-regulation of ΔFosB in the ventral and dorsal striatum following chronic ethanol consumption in IA and CA paradigms. The results indicate that cytisine modulates chronic voluntary ethanol consumption and reduces ethanol-induced up-regulation of striatal ΔFosB. Further, the data suggest a critical role of nAChRs in chronic ethanol-induced neurochemical adaptations associated with ethanol addiction., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Incomplete spinal cord injury (SCI) can result in profound impairments in volitional strength and reflex excitability, which contribute to loss of function. Human and animal models suggest that disruption of endogenous monoaminergic input, particularly serotonin (5-HT), from supraspinal centers contributes to this impaired motor function following SCI. In the present study, we investigated the effects of 5-HT medications on motor function in individuals with chronic (>1 year) SCI. Clinical measures of strength, spasticity/spasms, and walking ability were assessed in 12 individuals with chronic incomplete SCI following acute administration of either 8 mg cyproheptadine, a 5-HT antagonist, or 10 mg escitalopram, a selective 5-HT reuptake inhibitor (SSRI), in a double-blinded, randomized, crossover fashion. Results indicated that 5-HT medications modulated both volitional and reflexive behaviors with little change in walking performance; 5-HT antagonist medications depressed clinical measures of strength and spasticity/spasms, whereas SSRIs augmented both strength and spasticity/spasms. These changes are consistent with the dysregulation of 5-HT sensitive spinal neurons following SCI. This understanding may augment clinicians' awareness of the motor consequences of 5-HT medications.

Aims: The aim of the present study was to investigate the predictive value of qualitative psychomotor performance levels and subaspects of the negative syndrome for quantitative motor activity levels in patients with schizophrenia., Methods: Twenty-seven stabilized patients with schizophrenia and 22 age- and sex-matched healthy controls were included in the study. An extensive battery of psychomotor performance tests (Finger Tapping Test, Purdue Pegboard Test, Line Copying Test, Neurological Evaluation Scale, Salpêtrière Retardation Rating Scale), clinical rating scales (Positive and Negative Syndrome Scale) and 24-hour actigraphy were administered to all participants., Results: Correlational analyses showed that motor activity levels were associated with avolition as well as clinically assessed psychomotor slowing. However, in a regression model, only avolition was found to be a significant predictor for motor activity levels in patients with schizophrenia; none of the psychomotor performance tests nor the severity of emotional expressivity deficits contributed to the model., Conclusion: Qualitative and quantitative psychomotor deficits seem to be independent phenomena in stabilized patients with schizophrenia. The diminishing in motor activity in patients with schizophrenia is related to a loss of drive and not to problems in the quality of movement execution., (© 2013 S. Karger AG, Basel.)

Respiratory depression limits provision of safe opioid analgesia and is the main cause of death in drug addicts. Although opioids are known to inhibit brainstem respiratory activity, their effects on cortical areas that mediate respiration are less well understood. Here, functional magnetic resonance imaging was used to examine how brainstem and cortical activity related to a short breath hold is modulated by the opioid remifentanil. We hypothesized that remifentanil would differentially depress brain areas that mediate sensory-affective components of respiration over those that mediate volitional motor control. Quantitative measures of cerebral blood flow were used to control for hypercapnia-induced changes in blood oxygen level-dependent (BOLD) signal. Awareness of respiration, reflected by an urge-to-breathe score, was profoundly reduced with remifentanil. Urge to breathe was associated with activity in the bilateral insula, frontal operculum, and secondary somatosensory cortex. Localized remifentanil-induced decreases in breath hold-related activity were observed in the left anterior insula and operculum. We also observed remifentanil-induced decreases in the BOLD response to breath holding in the left dorsolateral prefrontal cortex, anterior cingulate, the cerebellum, and periaqueductal gray, brain areas that mediate task performance. Activity in areas mediating motor control (putamen, motor cortex) and sensory-motor integration (supramarginal gyrus) were unaffected by remifentanil. Breath hold-related activity was observed in the medulla. These findings highlight the importance of higher cortical centers in providing contextual awareness of respiration that leads to appropriate modulation of respiratory control. Opioids have profound effects on the cortical centers that control breathing, which potentiates their actions in the brainstem.

Repeated exposure to nicotine induces adaptive changes in the central nervous system including the mesolimbic dopamine (DA) projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). These modifications can modulate nicotine reward and reinforcement, but also anxiety and depression-related behaviors. The development of addiction-related phenotypes is known to be modulated by regulation of glutamate receptors, as well as activation of transcription factors including cAMP response element-binding protein (CREB), in the NAc. We investigated the effects of nicotine pre-exposure on nicotine preference and levels of GluR1/2 and CREB in the mesolimbic system in male mice C57BL/6J and BALB/c inbred mice. We also evaluated locomotor activity, anxiety-like and depression-like behaviors known to be affected by nicotine. There were few behavioral changes in mice subjected to chronic nicotine exposure, but there was a marked regulation of GluR2 in the mesolimbic system. Both treated and non-treated animals showed a significant preference for nicotine when facing a choice with a control solution. These results suggest that voluntary nicotine drinking induces nicotine preference in mice, but does not alter a number of affective behaviors. In addition, alterations in CREB and GluR1 levels are not sufficient to explain preference for nicotine in a 2-bottle choice paradigm.

Conditional execution and suppression of gaze shift are important in everyday life. To examine the possible involvement of the lateral prefrontal cortex (LPFC) in this process, we induced a local and reversible inactivation by injecting muscimol into 66 sites within the LPFC of monkeys and examined muscimol's effect on their performance in an oculomotor Go/No-Go task. This task required a subject to execute (Go) or suppress (No-Go) its gaze toward a target location in response to an instructional visual cue. Local injection of muscimol into 22 regions of the LPFC resulted in significant increases in the number of error saccades toward a few specific target locations during No-Go trials, whereas there were no error saccades in the Go trials. The onset latency of error saccades in No-Go trials was significantly longer than that of correct saccades in Go trials, but their velocity and amplitude were similar to those of correct saccades in Go trials. Go correct saccades appeared intact after the injections. These findings provide evidence that different regions of the LPFC are involved in the conditional suppression of gaze shift toward a few specific target locations, which may occur through a top-down suppressive mechanism.

Preclinical and observational studies in ovariectomized (OVX) animals and pre- and postmenopausal women, respectively, have suggested the cardioprotective effects of estrogen replacement therapy. However, randomized clinical trials have not confirmed estrogen-mediated cardioprotection. Although uncertainties about the duration and optimal type of estrogen replacement regimen might explain the disparity, other factors that may mask the protective effects of 17beta-estradiol (E2) on cardiovascular outcome need scrutiny. Increased ethanol consumption may be one such factor. We examined the effect of E2 supplementation on ethanol consumption in OVX mice and the effect of ethanol consumption on E2-mediated vascular repair, in vivo. OVX mice implanted with E2 pellets consumed significantly more ethanol, compared with those receiving placebo pellets. E2-induced increase in ethanol consumption was not affected by the absence of either estrogen receptor-alpha or -beta. Reendothelialization after carotid artery denudation was repressed, and neovascularization in ischemic hind limbs was blunted in mice consuming ethanol, despite E2 supplementation. In vitro, ethanol dose-dependently attenuated E2-induced endothelial cell (EC) proliferation and tube formation activity and enhanced EC apoptosis, suggesting that ethanol blocks E2-induced EC survival and function. Taken together our data suggest that increased ethanol consumption after E2 supplementation blunts the beneficial effects of E2 on EC function and that novel approaches to estrogen replacement for cardioprotection may benefit from the control of alcohol consumption.

The antisaccade task appears to be particularly suitable for analyzing processes involved in executive control of action. Schizophrenic patients show enhanced rates of erroneous reflexive saccades in this task. This is commonly interpreted as a failure of inhibitory mechanisms. The role of volitional saccade generation is largely neglected in these accounts. In this study, experimental variations of the antisaccade task were applied to manipulate the contribution of volitional processes on antisaccade performance. Fifteen patients with a diagnosis of schizophrenia and 15 healthy control participants performed antisaccade tasks requiring them to look to the mirror location of a peripheral visual stimulus at the onset of this stimulus (standard antisaccade task) or after a brief delay (delayed antisaccade task). As expected, schizophrenic patients showed more reflexive saccade errors than controls. In the delay conditions, reflexive errors decreased, and this effect was significantly stronger in schizophrenic patients. Latencies of correct antisaccades tended to be longer in patients than in control participants. The results suggest that the generation of voluntary saccades is at least in part responsible for the antisaccade deficit in schizophrenic patients. More comprehensive models to account for executive deficits in the antisaccade task must be considered.

Galanin is a 29/30 amino acid neuropeptide that has been shown to impair learning and memory task performance and also have roles in somatosensation, stress responses, sexual behavior, and feeding regulation. However, little is known about galanin involvement in higher cognitive processes, especially executive processes. Perseveration is a classic sign of frontal cortex damage and failure of executive control. Galanin has been shown to disrupt the performance of maze delayed alternation tasks and the operant, spatial delayed nonmatch-to-position (DNMTP) working memory task, tests especially sensitive to perseverative responding. To better understand this potential involvement of galanin in executive control, the present study tested the hypothesis that galanin induces perseveration. The first experiment examined the effects of galanin (10, 20 microg i.c.v.) on the performance of a simple operant response alternation task in which stimuli were assigned to one of two spatially distinct locations to produce extended sequences of presentations to one location, separated by a 10-s intertrial interval. The second experiment looked at the effects of galanin (5, 20 microg i.c.v.) on the performance of non-delayed match-to-position and nonmatch-to-position conditional discrimination operant tasks in which a minimal 1.0 s time interval separated responses. Finally, the effects of galanin (10, 20 microg i.c.v.) on delayed match-to-position (DMTP) performance were examined to determine whether response alternation (i.e., nonmatching) was critical to observing a galanin-induced impairment in this task. Galanin reduced the rate of trial completion in all the tasks, but did not alter simple or conditional discrimination accuracy. Galanin (10 microg) impaired DMTP performance in a delay-independent manner. Together, these data suggest that galanin does not produce perseveration, but are consistent with a galanin-induced decrease in reinforcer strength.

The ability of drugs that reduce NMDA receptor activity on the volitional consumption of ethanol in the genetic drinking rat, mHEP line, was investigated. After the consumption of ethanol solutions and water by each male or female mHEP rat had stabilized on its preferred concentration, different doses of LY 274614, a competitive NMDA antagonist, MK 801, a non-competitive NMDA antagonist, (+)-HA-966 or ACPC (1-aminocyclopropane-1-carboxylic acid), antagonists of the glycine site were administered daily for three days. The dose of 3.0 mg/kg i.p. LY 274614 reduced the consumption of ethanol by 64% compared to the pre-treatment baseline, while 0.3 mg/kg of MK 801 reduced consumption by 44%, 20 mg/kg (+)-HA-966 reduced consumption by 47% and 300 mg/kg of ACPC reduced consumption by 30%. These doses of LY 274614 and MK 801 reduced the ability of Sprague-Dawley rats to walk on a rotorod. Effects of these drugs on food intake were small except for the 20 mg/kg dose of (+)-HA-966. Therefore, the drugs did not have an anti-caloric effect and manipulations of the glutamatergic system through NMDA receptors may modify the consumption of ethanol. This interaction should be explored further for its therapeutic potential and to better understand the control by central neuronal systems of the consumption of ethanol.

Corticotropin releasing factor is a neuropeptide associated with the integration of physiological and behavioural responses to stress. More recently, corticotropin releasing factor has been implicated in the actions of abused drugs, including ethanol. Moreover, previous studies have demonstrated that the non-selective corticotropin releasing factor receptor antagonist, alpha-helical corticotropin releasing factor(9-41), can diminish some of the behavioural effects associated with ethanol withdrawal, whilst the selective corticotropin releasing factor(1) receptor antagonist CP-154,526 has been beneficial in decreasing stress-induced relapse into alcohol-seeking behaviour. However, as yet the ability of selective corticotropin releasing factor compounds to modulate volitional ethanol consumption has not been investigated. For these reasons the present study aims to examine the effects of antalarmin, a selective, centrally acting corticotropin releasing factor(1) receptor antagonist, on both the initiation and maintenance of ethanol consumption in isolation-reared Fawn-Hooded rats. Here we demonstrate that whilst both antalarmin and diazepam can decrease the acquisition of an ethanol-preferring phenotype by Fawn-Hooded rats, only antalarmin can alter established, volitional ethanol consumption. This ability of antalarmin to reduce established ethanol consumption is apparently unrelated to changes in ingestive behaviour, or a generalised anxiolytic action. For these reasons, such drugs may provide a new therapeutic approach for the treatment of alcoholism; however, this requires further investigation.

It is hypothesized that although the overall metabolism of ethanol in the brain is very limited, a very small percentage of the brain tissue may carry out that little amount of metabolism. Specifically, hydrogen peroxide may be used as a co-substrate for the metabolism of ethanol to acetaldehyde by catalase and the action of monoamine oxidase in the monoaminergic neurons would supply the hydrogen peroxide. This production of acetaldehyde may result in the formation of novel metabolites that provide the rewarding stimulus for the consumption of ethanol. To test this hypothesis, a reversible inhibitor of the A-isoform of monoamine oxidase, BW A616U, was compared to irreversible inhibitors of one or both MAO-A and B isoenzymes. Doses of 12.5-75 mg/kg p.o. BW A616U reduced the behavioral effects, ptosis and catalepsy, due to monoamine depletion by 2.5 mg/kg reserpine, but these signs of monoamine depletion were evident 24 h after injection. In the cyanamide-induced drinking rat, 50 mg/kg BW A616U reduced consumption of ethanol by 37%. Phenylzine, an irreversible MAO-A and B inhibitor, reduced consumption of ethanol by 67%, but also food consumption; however, the intake of both increased during the post-treatment period. The MAO-B inhibitor, R(-)-deprenyl, was without effect. Both BW A616U, 50 mg/kg and 75 mg/kg, and 2.0 mg/kg i.p. clorgyline reduced the consumption of ethanol in the genetic drinking Myers high-ethanol preferring (mHEP) rat and reduced the proportion of ethanol consumed to total fluids by over 50%. Again, R(-)-deprenyl was without effect. Clorgyline also markedly reduced the intake of food during the 3-day treatment period, only. However, the consumption of ethanol remained depressed during the 4 days after either 75 mg/kg BW A616U or clorgyline. These data demonstrate that inhibition of MAO-A, but not MAO-B, reduces the volitional consumption of ethanol probably by preventing the formation of both biogenic aldehydes and acetaldehyde so that rewarding alkaloidal products cannot be formed.

The mechanism of action underlying the ergogenic effect of caffeine is still unclear. Caffeine increases the force of muscular contraction during low-frequency stimulation by potentiating calcium release from the sarcoplasmic reticulum. Studies have also suggested an enhancement of lipid oxidation and glycogen sparing as potential mechanisms. Given that several studies have found an ergogenic effect of caffeine with no apparent metabolic effects, it is likely that a direct effect upon muscle is important. Twelve healthy male subjects were classified as habitual (n = 6) or nonhabitual (n = 6) caffeine consumers based on a 4-day diet record analysis, with a mean caffeine consumption of 771 and 14 mg/day for each group, respectively. Subjects were randomly allocated to receive caffeine (6 mg/kg) and placebo (citrate) in a double-blind, cross-over fashion approximately 100 min before a 2-min tetanic stimulation of the common peroneal nerve in a custom-made dynamometer (2 trials each of 20 and 40 Hz). Tetanic torque was measured every 30 s during and at 1, 5, and 15 min after the stimulation protocol. Maximal voluntary contraction strength and peak twitch torque were measured before and after the stimulation protocol. Caffeine potentiated the force of contraction during the final minute of the 20-Hz stimulation (P<0.05) with no effect of habituation. There was no effect of caffeine on 40-Hz stimulation strength nor was there an effect on maximal voluntary contraction or peak twitch torque. These data support the hypothesis that some of the ergogenic effect of caffeine in endurance exercise performance occurs directly at the skeletal muscle level.

Prior research showed that attentional deficits are observed in Alzheimer's disease (AD). These deficits can further impair other cognitive processes. The present experiment was designed to study the shifts in attention induced by a noradrenergic drug (S 12024-2) through their electrophysiological correlates in 12 outpatients with mild AD, using an auditory oddball paradigm. The P3a component, known to be related to automatic attentional processing, was increased by the drug, whereas no changes occurred either in PN or in P3b, which are considered to reflect conscious processing. These results point to an involvement of the noradrenergic system in the modulation of automatic attentional processing, and provide evidence for weakening of the orienting reflex in AD, due to a possible noradrenergic deficit in patients with mild AD.

Fourteen children with attention-deficit hyperactivity disorder (ADHD) and 14 normal control children were compared with respect to stimulus- and response-related processes. Subjects with ADHD took part in two additional sessions under methylphenidate or placebo. In both experiments, performance and electrophysiological measures such as the P2, N2, and P3 components of event-related potential and electromyogram (EMG) activity were measured during an Eriksen flanker task. In both groups of children, reaction times (RTs) to arrow stimuli incongruent with the target were longer than those to neutral stimuli (response interference), which were again slower than RTs to target-alone stimuli (perceptual interference). Children with ADHD made more errors to incongruent stimuli and showed more response interference. For correct responses, no differences between the groups in response interference effects on reaction time, P2, N2, and P3 latency, or EMG onset were found. Methylphenidate had a general enhancing effect on accuracy but did not specifically reduce interference from the flanking stimuli. Methylphenidate had no effects on RT, N2 and P2 latency, P3 amplitude or latency, or EMG activity. The conclusion that methylphenidate did not influence response processes contrasts sharply with findings reported by authors using the Sternberg memory search task.

Background: The aim of the present study was to further investigate a previously reported attention-related impairment in dependent amphetamine users using event-related potential (ERP) indices of selective attention., Methods: ERPs were recorded during an auditory selective attention task (SAT) that involved detecting infrequent long-duration target tones presented among short-duration tones that varied in location (left vs. right ear) and pitch (low vs. high). Amphetamine users (n = 19) were divided into two groups, high dependence (n = 10) and low dependence (n = 10), based on amphetamine Severity of Dependence Scale scores, and compared to an age-matched control group (n = 9)., Results: The high-dependence group showed slowed reaction time and reduced early processing negativity and peak N1 amplitude to location-relevant nontarget stimuli. Poor performance on the SAT was highly correlated with deficits in early processing, which were also related to poor performance on the Wechsler Memory Scale Attention/Concentration index., Conclusions: It is suggested that severely dependent users suffer an inability to selectively enhance the sensory processing of relevant auditory information. This may produce poor automatic preferential processing of relevant information and increase load on limited attentional resources.

Background: Substantial evidence now shows that the genetic vulnerability to schizophrenia can be manifested clinically in first-degree relatives of people with schizophrenia, even without the full manifestations of the disorder. One pattern of problems observed involves the combination of negative symptoms and neuropsychological deficits. We have investigated whether a low dose of a novel antipsychotic medication, risperidone, could attenuate these clinical problems in non-psychotic, first-degree relatives, and report here findings from our first 4 cases., Methods: Twelve adults who were first-degree relatives of patients with schizophrenia were evaluated for the presence of negative symptoms and neuropsychological deficits (in attention and working memory, long-term verbal memory and executive functions). Four subjects who met our predetermined criteria, and who did not demonstrate medical contraindications, were enrolled in a 6-week trial of risperidone. Clinical and medical measures were assessed before, during and after treatment. Doses of risperidone started at 0.25 mg and were increased to 1.0-2.0 mg/day., Results: These subjects showed substantial reductions in negative symptoms, and one subject showed modest reductions. All four subjects showed substantial improvements on some tests of attention and working memory. Side effects of risperidone were temporary and mainly mild., Conclusions: These initial findings support two conclusions. First, clinical deficits in non-psychotic first-degree relatives of people with schizophrenia are identifiable, and to a significant extent, reversible. Second, risperidone may eventually serve as an effective treatment for people whose lives are impaired by similar or related problems.

The goal of this study was to evaluate the effect of methylphenidate (MPH) and clonidine in comparison with placebo on response inhibition and state regulation in children with Attention Deficit Hyperactivity Disorder (ADHD). The study utilised a double-blind cross-over design in which children were randomly assigned without replacement to placebo, MPH, and clonidine following baseline assessment. The primary dependent measures were derived from children's performance (reaction time and errors) on a GO-NO GO task under three conditions that altered the inter-stimulus interval (ISI) for presented GO-NO GO stimuli: ISI of 1 sec (fast condition), 4 sec (medium condition), and 8 sec (slow condition). Findings indicated no difference in task performance between groups treated for 7 weeks with placebo, MPH, and clonidine. We concluded that the state regulation problem in ADHD is resistant to MPH and clonidine.

Objective: Caffeine is widely consumed by children around the world. The purpose of this study was to determine whether children manifest withdrawal effects after cessation of caffeine intake., Method: Thirty normal children completed the single-blind, within-subjects, repeated-measures study with weekly sessions. Subjects were tested four times: (1) baseline (on regular caffeine diet); (2) on caffeine (approximately 120 to 145 mg/day); (3) during withdrawal (24 hours after discontinuation of caffeine taken for 13 consecutive days); and (4) at return to baseline. Subjects were evaluated with self-report measures of symptoms and objective measures of attention, motor performance, processing speed, and memory., Results: During caffeine withdrawal, there was a significant deterioration on response time of a visual continuous performance test of attention. This finding is consistent with caffeine withdrawal. The deterioration in response time appeared to persist for 1 week., Conclusions: Twenty-four hours after children discontinued caffeine, there was a decrease in performance on reaction time of a task requiring sustained attention. Further work is indicated to determine whether children manifest caffeine withdrawal effects after cessation of caffeine intake.

Some forms of behavioral perseveration may reflect the disruption of specific neurotransmitter systems including mesencephalic dopaminergic projection. We present an open-labeled trial of a dopamine agonist for treating perseveration in dementia. Eight patients with ischemic vascular or degenerative dementia completed a 25-day trial of bromocriptine with a maximum daily dose of 10 mg. Patients were assessed with neuropsychological scales and a test battery for detecting perseveration. Recurrent and stuck-in-set types of perseveration significantly improved during the treatment, whereas measures for general attention and overall cognitive function showed no significant changes. We assume that bromocriptine supplemented the mesolimbocortical or ventral mesostriatal dopamine system ameliorated a certain frontal lobe function such as focused attention or working memory and improved the patients' perseverations. Although this study is preliminary because of the small sample size and open-labeled design, the results underline the possibility of pharmacotherapy for perseveration and recommend a double-blind, placebo-controlled study.

Children with attention-deficit hyperactivity disorder who are categorized as responders or non-responders to methylphenidate (MPH) on the basis of their electrophysiological P3 response in a selective attention task differ in metabolic patterns of the D- and L-threo MPH enantiomers. Non-responders showed significantly higher plasma concentrations of both D- and L-threo MPH enantiomers.

Objective: This study examined the effects of ACTH 4-10, a fragment of adrenocorticotropin (ACTH) with known central nervous system (CNS) activity, on the dimensional complexity of the ongoing electroencephalographic (EEG) activity. Stressful stimuli cause ACTH to be released from the pituitary, and as a neuropeptide ACTH may concurrently exert adaptive influences on the brain's processing of these stimuli. Previous studies have indicated an impairing influence of ACTH on selective attention., Methods: Dimensional complexity of the EEG, which indexes the brain's way of stimulus processing, was evaluated while subjects performed tasks with different attention demands. Sixteen healthy men (23 to 33 years) were tested once after placebo and another time after administration of ACTH 4-10 (1.25 mg intravenously (i.v.), 30 minutes before testing). The EEG was recorded while subjects were presented with a dichotic listening task (consisting of the concurrent presentation of tone pips to the left and right ear). Subjects either a) listened to pips in both ears (divided attention), or b) listened selectively to pips in one ear (selective attention), or c) ignored all pips., Results: Dimensional complexity of the EEG was higher during divided than selective attention. ACTH significantly increased the EEG complexity during selective attention, in particular over the midfrontal cortex (Fz, Cz)., Conclusions: The effects support the view of a de-focusing action of ACTH during selective attention that could serve to improve the organism's adaptation to stress stimuli.

Objective: The present investigation examined whether increased overtime work predicts impairment in cognitive performance in the domains of attention, executive function, and mood., Methods: The behavioral and cognitive functions of 248 automotive workers were measured by a neurobehavioral test performance. Overtime, defined as number of hours worked greater than 8 h a day or greater than 5 d a week, was calculated from company payroll records for the week before the test day. The number of consecutive days worked before the test day was also determined., Results: Cross-sectional data analysis by multiple linear regression, after adjustment for the effects of age, education, gender, alcohol intake, repeated grade in school, acute petroleum naphtha exposure, shift worked, job type, number of consecutive days worked before the test day, and number of hours worked on the test day before the testing, demonstrated that increased overtime was significantly associated with impaired performance on several tests of attention and executive function. Increased feelings of depression, fatigue, and confusion were also associated with increased overtime work. In addition significant interaction effects were observed for job type but not for naphtha exposure., Conclusions: The findings support the hypothesis that overtime work results in impaired cognitive performance in the areas of attention and executive function and that both overtime hours and the number of consecutive days worked prior to a test day affect mood.

Background: Validation of animal models of hallucinogenic drugs' subjective effects requires human data. Previous human studies used varied groups of subjects and assessment methods. Rating scales for hallucinogen effects emphasized psychodynamic principles or the drugs' dysphoric properties. We describe the subjective effects of graded doses of N,N-dimethyltryptamine (DMT), an endogenous hallucinogen and drug of abuse, in a group of experienced hallucinogen users. We also present preliminary data from a new rating scale for these effects., Methods: Twelve highly motivated volunteers received two doses (0.04 and 0.4 mg/kg) of intravenous (IV) dimethyltryptamine fumarate "nonblind," before entering a double-blind, saline placebo-controlled, randomized study using four doses of IV DMT. Subjects were carefully interviewed after resolution of drug effects, providing thorough and systematic descriptions of DMT's effects. They also were administered a new instrument, the Hallucinogen Rating Scale (HRS). The HRS was drafted from interviews obtained from an independent sample of 19 experienced DMT users, and modified during early stages of the study., Results: Psychological effects of IV DMT began almost immediately after administration, peaked at 90 to 120 seconds, and were almost completely resolved by 30 minutes. This time course paralleled DMT blood levels previously described. Hallucinogenic effects were seen after 0.2 and 0.4 mg/kg of dimethyltryptamine fumarate, and included a rapidly moving, brightly colored visual display of images. Auditory effects were less common. "Loss of control," associated with a brief, but overwhelming "rush," led to a dissociated state, where euphoria alternated or coexisted with anxiety. These effects completely replaced subjects' previously ongoing mental experience and were more vivid and compelling than dreams or waking awareness. Lower doses, 0.1 and 0.05 mg/kg, were primarily affective and somaesthetic, while 0.1 mg/kg elicited the least desirable effects. Clustering of HRS items, using either a clinical, mental status method or principal components factor analysis provided better resolution of dose effects than did the biological variables described previously., Conclusions: These clinical and preliminary quantitative data provide bases for further psychopharmacologic characterization of DMT's properties in humans. They also may be used to compare the effects of other agents affecting relevant brain receptors in volunteer and psychiatric populations.

The effects of the psilocybin, a psychomimetic substance, on mental junctioning were investigated in normal volunteers as well as in schizophrenics. The disturbances induced constitute a psychoneurotoxic syndrome--"a state of drunkenness"--of about four hours duration which develops in three distinct phases. The basic mental symptoms of this syndrome consist of disturbances of the apperception, sensory perception and emotion. A moderate impairment of egofunctioning or reality appraisal and an inability to integrate different mental processes are observed. The psychomotor behavior is mainly harmonized to the prevailing emotional state and to the experiences caused by perceptual alterations, in a lesser degree. These changes, according to our observations, are more severe and more "psychotic-like" in schizophrenics rather than in normals. Psychopathological analysis of these changes proves that the whole syndrome cannot be considered as related to the spontaneously triggered functional psychoses or to the organic ones and, therefore, the term "model-psychosis" according to our opinion, is unsatisfactory.