Effects of dopaminergic and subthalamic stimulation on musical performance.

Although subthalamic-deep brain stimulation (STN-DBS) is an efficient treatment for Parkinson's disease (PD), its effects on fine motor functions are not clear. We present the case of a professional violinist with PD treated with STN-DBS. DBS improved musical articulation, intonation and emotional expression and worsened timing relative to a timekeeper (metronome). The same effects were found for dopaminergic treatment. These results suggest that STN-DBS, mimicking the effects of dopaminergic stimulation, improves fine-tuned motor behaviour whilst impairing timing precision.

Separate and combined effects of the GABA(B) agonist baclofen and Δ9-THC in humans discriminating Δ9-THC.

BACKGROUND: Our previous research with the GABA reuptake inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABA(B) receptor subtype by assessing the separate and combined effects of the GABA(B)-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures. METHODS: Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received baclofen (25 and 50mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. RESULTS: Δ9-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50 mg) substituted for the Δ9-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ9-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ9-THC-like subjective responses when administered alone. CONCLUSIONS: These results suggest that the GABA(B) receptor subtype is involved in the abuse-related effects of Δ9-THC, and that GABA(B) receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABA(A)) to determine the contribution of the different GABA receptors in the effects of Δ9-THC, and by extension cannabis, in humans.

Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task.

The study examined the effects of a norepinephrine transporter (NET) inhibitor reboxetine (RBX) on an attentional performance test. Adult SD rats trained with five-choice serial reaction time task (5-CSRTT) were administered with RBX (0, 3.0 and 10 mg/kg) in the testing day. Alpha-1 adrenergic receptor antagonist PRA and alpha-2 adrenergic receptor antagonist RX821002 were used to clarify the RBX effect. Results revealed that rat received RBX at 10 mg/kg had an increase in the percentage of the correct response and decreases in the numbers of premature response. Alpha-1 adrenergic receptor antagonist Prazosin (PRA) at 0.1 mg/kg reversed the RBX augmented correct responding rate. However, alpha-2 adrenergic receptor antagonist RX821002 at 0.05 and 0.1 mg/kg dose dependently reversed the RBX reduced impulsive responding. Our results suggested that RBX as a norepinephrine transporter inhibitor can be beneficial in both attentional accuracy and response control and alpha-1 and alpha-2 adrenergic receptors might be involved differently.

[Different effect of eleuterococcus on various psychophysiological parameters of healthy humans depending on their chronotype and the day time].

The administration of a liquid extract of eleuterococcus as a psychotonic drug by young healthy humans leads to changes in some psychophysiological parameters, including an increase in the aural memory volume, decrease in reactive anxiety, and shortening of individual minute. These effects were dependent on the daytime (morning versus evening) and the individual chronotype (circadian features) of each volunteer.

Prenatal choline supplementation increases sensitivity to contextual processing of temporal information.

The effects of prenatal choline availability on contextual processing in a 30-s peak-interval (PI) procedure with gaps (1, 5, 10, and 15 s) were assessed in adult male rats. Neither supplementation nor deprivation of prenatal choline affected baseline timing performance in the PI procedure. However, prenatal choline availability significantly altered the contextual processing of gaps inserted into the to-be-timed signal (light on). Choline-supplemented rats displayed a high degree of context sensitivity as indicated by clock resetting when presented with a gap in the signal (light off). In contrast, choline-deficient rats showed no such effect and stopped their clocks during the gap. Control rats exhibited an intermediate level of contextual processing in between stop and full reset. When switched to a reversed gap condition in which rats timed the absence of the light and the presence of the light served as a gap, all groups reset their clocks following a gap. Furthermore, when filling the intertrial interval (ITI) with a distinctive stimulus (e.g., sound), both choline-supplemented and control rats rightward shifted their PI functions less on trials with gaps than choline-deficient rats, indicating greater contextual sensitivity and reduced clock resetting under these conditions. Overall, these data support the view that prenatal choline availability affects the sensitivity to the context in which gaps are inserted in the to-be-timed signal, thereby influencing whether rats run, stop, or reset their clocks.

Basal ganglia, dopamine and temporal processing: performance on three timing tasks on and off medication in Parkinson's disease.

A pervasive hypothesis in the timing literature is that temporal processing in the milliseconds and seconds range engages the basal ganglia and is modulated by dopamine. This hypothesis was investigated by testing 12 patients with Parkinson's disease (PD), both 'on' and 'off' dopaminergic medication, and 20 healthy controls on three timing tasks. In a seconds range (30-120 s) time production task, patients tested 'on' medication showed a significantly different accuracy profile compared to controls and when tested 'off' medication. However, no group or on vs off medication differences in accuracy were found on a time reproduction task and a warned reaction time task requiring temporal processing within the 250-2000 ms range. Variability was measured using the coefficient of variation, with the performance of the patient group on the time reproduction task violating the scalar property, suggesting atypical temporal processing mechanisms. The data suggest that the integrity of the basal ganglia is necessary for 'typical' time production in the seconds range as well as for time reproduction at shorter intervals. Exploratory factor analysis suggested that the time production task uses neural mechanisms distinct from those used in the other two timing tasks. The dissociation of the effects of dopaminergic medication and nature of task on performance in PD raises interesting questions about the pharmacological mediation and task-specificity of deficits in temporal processing.

Auditory temporal processing in Parkinson's disease.

Previous research has suggested that Parkinson's disease (PD) impairs perceptual acuity in the temporal domain. In the present study, psychophysical tests assessing several aspects of auditory temporal processing were administered to a group of PD patients treated with bilateral subthalamic nucleus (STN) stimulation and to a normal control group. Each patient was tested in three clinical conditions: without treatment, with levodopa therapy, and during STN stimulation. In all three conditions, the patients showed a significant deficit in the detection of very short temporal gaps within noise bursts and in the discrimination between the durations of two well-detectable time intervals (circa 50ms) bounded by two temporally non-contiguous pairs of clicks. However, the patients showed no deficit in the detection of a temporal break produced by a local interval change in an otherwise isochronous sequence of 10 clicks spaced by 50-ms intervals. The latter result contradicts previous suggestions that PD slows down an internal clock or pacemaker involved in the perception of short durations. In this regard, we reinterpret previous evidence. Remarkably, the patients' deficits were not diminished by levodopa therapy; in contrast, STN stimulation slightly improved performance, overall. We tentatively ascribe the deficit observed in the gap-detection test to a dysfunctioning of the auditory cortex, impairing its ability to track rapid fluctuations in sound intensity. We argue that the deficit in the duration-discrimination test is the consequence of an impairment in memory and/or attention rather than in the perception of time per se.

The effect of methylphenidate on auditory information processing in healthy volunteers: a combined EEG/MEG study.

INTRODUCTION: The psychomotor stimulant methylphenidate (MPH) has been shown to improve attentional processes, reflected in behavioural measures such as vigilance, reaction time and visual attention tasks. The neural mechanisms of MPH action on sensory information processing, however, remain poorly understood. To the authors' knowledge, this present study is the first to investigate whether a single dose of MPH affects neural substrates of passive attention in healthy adults studied with simultaneous whole-head magnetoencephalography (MEG) and electroencephalography (EEG). METHODS: Monaural left-ear auditory stimuli were presented in an oddball paradigm with infrequent deviant tones differing in frequency and duration. Neuronal activity was recorded with simultaneous whole-head MEG and EEG in 13 healthy subjects (five females; aged 27 +/- 5 years) after oral administration of 40 mg MPH or placebo in a randomised, double-blind, cross-over design. We analysed both electric and magnetic N100, P200 and mismatch negativity (MMN) components. RESULTS: MPH increased arousal levels in visual analogue scales. MPH had no effect on the dipole strength of MMN or MMNm in either frequency or duration deviations. MPH did, however, reduce P200 amplitudes in EEG. CONCLUSIONS: The lack of effect of MPH on either MMN or MMNm suggests no association between catecholaminergic activities and MMN generation. However, our findings imply that MPH may change the neural bases of auditory information processing such as the early stimulus evaluation reflected in the P200 component. Dopamine and noradrenaline neurotransmitter systems could be responsible for the modulation of these processes. The exclusive effect of MPH on the P200 component could have a clinical application.

Neural representation of spectral and temporal features of song in the auditory forebrain of zebra finches as revealed by functional MRI.

Song perception in songbirds, just as music and speech perception in humans, requires processing the spectral and temporal structure found in the succession of song-syllables. Using functional magnetic resonance imaging and synthetic songs that preserved exclusively either the temporal or the spectral structure of natural song, we investigated how vocalizations are processed in the avian forebrain. We found bilateral and equal activation of the primary auditory region, field L. The more ventral regions of field L showed depressed responses to the synthetic songs that lacked spectral structure. These ventral regions included subarea L3, medial-ventral subarea L and potentially the secondary auditory region caudal medial nidopallium. In addition, field L as a whole showed unexpected increased responses to the temporally filtered songs and this increase was the largest in the dorsal regions. These dorsal regions included L1 and the dorsal subareas L and L2b. Therefore, the ventral region of field L appears to be more sensitive to the preservation of both spectral and temporal information in the context of song processing. We did not find any differences in responses to playback of the bird's own song vs other familiar conspecific songs. We also investigated the effect of three commonly used anaesthetics on the blood oxygen level-dependent response: medetomidine, urethane and isoflurane. The extent of the area activated and the stimulus selectivity depended on the type of anaesthetic. We discuss these results in the context of what is known about the locus of action of the anaesthetics, and reports of neural activity measured in electrophysiological experiments.

alpha7 Nicotinic acetylcholine receptors and temporal memory: synergistic effects of combining prenatal choline and nicotine on reinforcement-induced resetting of an interval clock.

We previously showed that prenatal choline supplementation could increase the precision of timing and temporal memory and facilitate simultaneous temporal processing in mature and aged rats. In the present study, we investigated the ability of adult rats to selectively control the reinforcement-induced resetting of an internal clock as a function of prenatal drug treatments designed to affect the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR). Male Sprague-Dawley rats were exposed to prenatal choline (CHO), nicotine (NIC), methyllycaconitine (MLA), choline + nicotine (CHO + NIC), choline + nicotine + methyllycaconitine (CHO + NIC + MLA), or a control treatment (CON). Beginning at 4-mo-of-age, rats were trained on a peak-interval timing procedure in which food was available at 10-, 30-, and 90-sec criterion durations. At steady-state performance there were no differences in timing accuracy, precision, or resetting among the CON, MLA, and CHO + NIC + MLA treatments. It was observed that the CHO and NIC treatments produced a small, but significant increase in timing precision, but no change in accuracy or resetting. In contrast, the CHO + NIC prenatal treatment produced a dramatic increase in timing precision and selective control of the resetting mechanism with no change in overall timing accuracy. The synergistic effect of combining prenatal CHO and NIC treatments suggests an organizational change in alpha7 nAChR function that is dependent upon a combination of selective and nonselective nAChR stimulation during early development.

Role of GABAergic inhibition in the coding of interaural time differences of low-frequency sounds in the inferior colliculus.

A major cue for the localization of sound in space is the interaural time difference (ITD). We examined the role of inhibition in the shaping of ITD responses in the inferior colliculus (IC) by iontophoretically ejecting gamma-aminobutyric acid (GABA) antagonists and GABA itself using a multibarrel pipette. The GABA antagonists block inhibition, whereas the applied GABA provides a constant level of inhibition. The effects on ITD responses were evaluated before, during and after the application of the drugs. If GABA-mediated inhibition is involved in shaping ITD tuning in IC neurons, then applying additional amounts of this inhibitory transmitter should alter ITD tuning. Indeed, for almost all neurons tested, applying GABA reduced the firing rate and consequently sharpened ITD tuning. Conversely, blocking GABA-mediated inhibition increased the activity of IC neurons, often reduced the signal-to-noise ratio and often broadened ITD tuning. Blocking GABA could also alter the shape of the ITD function and shift its peak suggesting that the role of inhibition is multifaceted. These effects indicate that GABAergic inhibition at the level of the IC is important for ITD coding.

[The role of the epiphysis in forming a conditioned reaction to time in rats]. / Rol' épifiza v formirovanii uslvonoi reaktsii na vremia u krys.

Pinealectomy impeded formation of time-conditioned reflex in the mode of fixed intervals. This was accompanied by a shortening of reaction latency and runs as well as by an increase in the number of intertrial responses. On the contrary, melatonin injection (0.1 mg/kg) facilitated conditioning by restricting the locomotion. It is suggested that pineal compounds have specific chronotropic properties.

[The effect of hippocampectomy on the acquisition and recovery of a conditioned reflex to time in rats]. / Vliianie gippokampéktomii na vyrabotku i vosstanovlenie uslovnogo refleksa na vremia u krys.

The dynamics of time conditioning was studied before and after electrolytic lesions of the dorsal hippocampus in rats. Hippocampectomy disturbed the recovery of time conditioned reflex which was consolidated before surgery. The change depended on the extent of hippocampal lesion. In rats after the limited hippocampectomy the conditioned reflex recovered faster than in sham-operated animals. However, after more extensive lesions the process of conditioning recovery was delayed. In hippocampectomized animals without previous training the time conditioned reflex was not formed irrespective of the volume of brain lesion. Injection of amphetamine (0.05 mg/kg) was ineffective in this case.

The impact of long-term vitamin supplementation on cognitive functioning.

The possibility that the taking of vitamin supplements may influence cognitive functioning was explored. One hundred and twenty-seven young healthy adults took either ten times the recommended daily dose of nine vitamins, or a placebo, under a double-blind procedure, for a year. After 12 months better performance on two measures of attention was found in females who had taken the vitamin supplement, even though the blood status of nine vitamins reached a plateau after 3 months. The use of regression equations demonstrated the association between improved thiamin status and improved performance on a range of measures of cognitive functioning in females rather than males. Although it was not possible to establish the reason for a beneficial response in females rather than males, the evidence that females respond differently to dietary factors was discussed.

Pharmacologic alteration of the perception of being awake or asleep.

In order to further explore the effects of triazolam on the subjective experience of sleeping, we awakened chronic insomniacs with an electronic tone at five points across the night after having administered placebo and three doses of triazolam (0.125, 0.25 and 0.375 mg). Triazolam reduced the likelihood of subjects reporting that they had been awake by about half. Drug effects were most evident in the period 5 minutes after "lights out", at which time there was a reduction in the certainty of the subjects' response; the investigator's ratings of mental activity on the dream complexity scale rose from a rating of "awake" following placebo to the borderline of sleep following triazolam. After triazolam administration, subjects reported less certainty about their descriptions of mental imagery. These data are consistent with a hypothesis that during sleep, and particularly at the threshold of electroencephalogram (EEG) defined sleep, triazolam induces cognitive changes in which the subjective distinction between waking and sleep becomes less clear. Several approaches are suggested to determine whether these effects are related to retrospective subjective reports of hypnotic efficacy.

Chronic dietary choline enrichment affects DRL responding of old, but not of adult CPBB rats.

Using adult (11-month-old) and aged (22-month-old) inbred female CPBB rats, we tested the hypothesis that chronic dietary choline supplementation affects timing behavior. The rats had received choline chloride in their tap water for about 9 months before they acquired responding on a differential reinforcement of low-rate schedule with a critical delay of 8 s (DRL-8"). One retention session and two extinction sessions were given 4 weeks after the end of acquisition. The treatment had no effect on the timing behavior of the adult rats. Choline-treated old animals made more perservation errors, i.e., responses with interresponse times (IRTs) < 2 s, than the untreated old control rats. Even after correction for burst responses, the frequency of short IRTs was higher in the treated than in the control group, indicating that choline supplementation slightly impaired timing behavior. The mechanisms underlying the action of supplemented choline are still unknown.

Effects of chronic dietary choline on temporal discrimination of BN and WAG rats.

Using rats of the inbred BN and WAG strain, we tested the hypothesis that chronic dietary choline supplementation would especially affect the timing behavior of BN rats because of their lower cholinergic activity and their poor performance in aversively motivated learning and memory tasks. An apparent effect of chronic choline supplementation (2.5 mg choline chloride per ml water) on DRL-8" responding was not confirmed in a second experiment when the choline concentration was doubled. WAG rats treated chronically with choline showed a poorer temporal discrimination performance on a DRL-16" schedule than untreated WAG rats. In contrast, choline supplementation never had an effect on the performance of BN rats. The results of the DRL-16" experiment provide partial support for a hypothesis proposed by Church and Meck that the remembered time of reinforcement is inversely related to the functional activity of brain cholinergic activity: acetylcholine precursor treatment increases memory storage speed, which results in an overestimation of the time elapsed. An alternative explanation, which takes into account the aberrant EEG activities of WAG rats, is also discussed.

Psychopharmacologic analysis of an alleged oneirogenic plant: Calea zacatechichi.

Calea zacatechichi is a plant used by the Chontal Indians of Mexico to obtain divinatory messages during dreaming. At human doses, organic extracts of the plant produce the EEG and behavioral signs of somnolence and induce light sleep in cats. Large doses elicit salivation, ataxia, retching and occasional vomiting. The effects of the plant upon cingulum discharge frequency were significantly different from hallucinogenic-dissociative drugs (ketamine, quipazine, phencyclidine and SKF-10047). In human healthy volunteers, low doses of the extracts administered in a double-blind design against placebo increased reaction time and time-lapse estimation. A controlled nap sleep study in the same volunteers showed that Calea extracts increased the superficial stages of sleep and the number of spontaneous awakenings. The subjective reports of dreams were significantly higher than both placebo and diazepam, indicating an increase in hypnagogic imagery occurring during superficial sleep stages.

Interactions in man of delta-9-tetrahydrocannabinol. II. Cannabinol and cannabidiol.

Oral doses of delta-9-tetrahydrocannabinol (THC) 20 mg, combined with placebo or with 40 mg dses of cannabinol (CBN) and cannabidiol (CBD), were given to volunteers. The combination of THC with CBN produced no detectable changes in the quality, intensity, or duration of the effects of THC alone. The THC-CBD combination tended to delay onset and prolong effects of THC, while making them somewhat more intense. Even this interactive effect was slight, providing no reason to abandon the current practice of basing doses of marihuana for clinical studies solely on THC content.

Dose effects of smoked marihuana on human cognitive and motor functions.

Graded doses of marihuana were administered to five adults in a longitudinal repeated-measurements design. Speed of response was the basic parameter measured accross tests of increasing cognitive involvement. Marihuana produced significant dose-response effects of impaired performance in all test scores. However, single automatic motor abilities demonstrated greater sensitivity than tests of greater complexity. Evidence is presented for tolerance development.