Search

Background: There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder., Methods: This is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18-65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine-negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles., Discussion: This trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine., Trial Registration: Australian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022., (© 2024. The Author(s).)

Background: Commonly prescribed antidepressants (paroxetine, fluoxetine, duloxetine, bupropion) inhibit bioconversion of several prodrug opioid medications to their active metabolite, potentially decreasing analgesic effect. There is a paucity of studies assessing the risk-benefit of concomitant administration of antidepressants and opioids., Research Design and Methods: Observational study of adult patients taking antidepressants prior to scheduled surgery using 2017-2019 electronic medical record data to assess perioperative use of opioids and to determine the incidence and risk factors for developing postoperative delirium. We conducted a generalized linear regression with the Gamma log-link to assess the association between use of antidepressants and opioids and a logistic regression to assess the association between antidepressants use and the likelihood of developing postoperative delirium., Results: After controlling for patient demographic and clinical characteristics, and postoperative pain, use of inhibiting antidepressants was associated with 1.67 times greater use of opioids per hospitalization day (p = 0.00154), a two-fold increase in the risk for developing postoperative delirium (p = 0.0224), and an estimated average of four additional days of hospitalization (p < 0.00001) compared to use of non-inhibiting antidepressants., Conclusions: Careful consideration to drug-drug interactions and risk of related adverse events remains critical in the safe and optimal management of postoperative pain in patients taking concomitantly antidepressants.

The hypothalamic tuberoinfundibular dopaminergic (TIDA) neurones are critical with respect to regulating prolactin secretion from the anterior pituitary. Under most physiological conditions, they are stimulated by prolactin to release dopamine into the median eminence which subsequently suppresses further prolactin secretion from the lactotrophs. During lactation, the TIDA neurones are known to undergo both electrophysiological and neurochemical changes that alleviate this negative-feedback, thus allowing circulating prolactin levels to rise. The present study aimed to determine whether TIDA neurone morphology, most notably spine density, is also modified during lactation. This was achieved by stereotaxically injecting the arcuate nucleus of female, tyrosine hydroxylase-promoter driven Cre-recombinase transgenic rats with Cre-dependent adeno-associated virus-expressing Brainbow. This resulted in the highly specifici transfection of between 10% and 30% of the TIDA neurones, thus allowing the morphologies on multiple individual neurones to be examined in a single hypothalamic slice. The transfected neurones exhibited a range of complex forms, including a diversity of soma and location of axonal origin. Neuronal spine counting showed that the density of somatic, but not dendritic, spines was significantly higher during lactation than at any other reproductive stage. There was also a significant fall in somatic spine density across the oestrous cycle from dioestrus to oestrus. Although the functional characteristics of the additional somatic spines have not been determined, if, as might be expected, they represent an increased excitatory input to the TIDA neurones, this could have important physiological implications by perhaps supporting altered neurotransmitter release at their neuroendocrine terminals. Enhanced excitatory input may, for example, favour the release of the opioid peptide enkephalin rather than dopamine, which is potentially significant because the expression of the peptide is known to increase in the TIDA neurones during lactation and, in contrast to dopamine, it stimulates rather than inhibits prolactin secretion from the pituitary., (© 2020 British Society for Neuroendocrinology.)

Drug losses and theft from the healthcare system are accelerating; hospitals are pressured to implement safeguards to prevent drug diversion. Thus far, no reviews summarize all known risks and potential safeguards for hospital diversion. Past incidents of hospital drug diversion have impacted patient and staff safety, increased hospital costs, and resulted in infectious disease outbreaks. We searched MEDLINE, Embase, PsycINFO, CINAHL, Scopus, and Web of Science databases and the gray literature for articles published between January 2005 and June 2018. Articles were included if they focused on hospital settings and discussed either: (1) drug security or accounting practices (any drug) or (2) medication errors, healthcare worker substance use disorder, or incident reports (only with reference to controlled drugs). We included 312 articles and extracted four categories of data: (1) article characteristics (eg, author location), (2) article focus (eg, clinical areas discussed), (3) contributors to diversion (eg, factors enabling drug theft), and (4) diversion safeguards. Literature reveals a large number of contributors to drug diversion in all stages of the medication-use process. All health professions and clinical units are at risk. This review provides insights into known methods of diversion and the safeguards hospitals must consider to prevent them. Careful configuration of healthcare technologies and processes in the hospital environment can reduce the opportunity for diversion. These system-based strategies broaden the response to diversion beyond that of individual accountability. Further evidence is urgently needed to address the vulnerabilities outlined in this review and prevent harm.

Co-localization of the expression of the dopamine transporter (DAT) with the catecholamine synthesising enzyme tyrosine hydroxylase (TH) has been investigated using transgenic mice expressing Cre recombinase (Cre) dependent green fluorescent protein (GFP) under the control of the DAT promoter (DAT IREScre /GFP). Brain sections from adult female mice were stained for Cre-induced GFP and TH using immunohistochemistry, revealing a high degree of co-expression in the midbrain dopaminergic neurons (A8-10) with the exception of the periaqueductal and dorsal raphe nuclei where dual-labelling was notably lower. In contrast, most of the rostral groups of TH-expressing neurons in the forebrain (A11, A13 - A15) showed little or no co-localization with Cre-induced GFP. Interestingly, a subpopulation of about 30% of the TH-immunoreactive neurons in the arcuate nucleus (A12) also express GFP staining. This observation supports the proposal that this hypothalamic cluster of dopaminergic neurons is neurochemically, and thus potentially functionally, heterogeneous. This study extends earlier literature focusing primarily on DAT expression in midbrain structures to demonstrate a heterogeneity of DAT and TH co-localization in forebrain neurons, particularly those in the hypothalamus. It also highlights the importance of carefully selecting and validating transgenic mouse lines when studying dopaminergic neurons., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this Letter, we describe theoretical modeling of an experimentally realized nanoscale system that exhibits the general universal behavior of a nonlinear dynamical system. In particular, we consider the description of voltage-induced current fluctuations through a single nanopore from the perspective of nonlinear dynamics. We briefly review the experimental system and its behavior observed and then present a simple phenomenological nonlinear model that reproduces the qualitative behavior of the experimental data. The model consists of a two-dimensional deterministic nonlinear bistable oscillator experiencing both dissipation and random noise. The multidimensionality of the model and the interplay between deterministic and stochastic forces are both required to obtain a qualitatively accurate description of the physical system.

High-frequency stimulation of around 130 Hz delivered to the subthalamic nucleus (STN-DBS [deep brain stimulation]) is an effective treatment of Parkinson's disease (PD), but the mechanisms of its therapeutic effect remain obscure. Recently, it has been shown in anaesthetized rats that STN-DBS antidromically activates cortical neurons with coincident reduction of the cortical slow wave oscillations that occur in this preparation. Here we extend this work; recording the effect of STN-DBS upon cortical EEG and akinesia, in unanesthetized rats rendered cataleptic by acute dopaminergic blockade. STN-DBS-like stimulation resulted in a short latency, presumed antidromic, evoked potential in the cortex. In cataleptic animals, there was a significant increase in the power of beta oscillations in the electroencephalography which was reversed by stimulation that evoked the cortical response. We also observed a significant rescue of motor function, with the level of akinesia (bar test score) being inversely correlated to the amplitude of the evoked potential (R2 = 0.84). These data confirm that (probably antidromic) short latency cortical responses occur in the awake animal and that these are associated with reductions in abnormal cortical oscillations characteristic of PD and with improvements in akinesia. Our results raise the possibility that STN-DBS reduces PD oscillations and symptoms through antidromic cortical activation.

The use of cables for recording neural activity limits the scope of behavioral tests used in conscious free-moving animals. Particularly, cable attachments make it impossible to record in three-dimensional (3D) mazes where levels are vertically stacked or in enclosed spaces. Such environments are of particular interest in investigations of hippocampal place cells, in which neural activity is correlated with spatial position in the environment. We developed a flexible miniaturized Bluetooth-based wireless data acquisition system. The wireless module included an 8-channel analogue front end, digital controller, and Bluetooth transceiver mounted on a backpack. Our bidirectional wireless design allowed all data channels to be previewed at 1 kHz sample rate, and one channel, selected by remote control, to be sampled at 10 kHz. Extracellular recordings of neuronal activity are highly susceptible to ambient electrical noise due to the high electrode impedance. Through careful design of appropriate shielding and hardware configuration to avoid ground loops, mains power and Bluetooth hopping frequency noise were reduced sufficiently to yield signal quality comparable to those recorded by wired systems. With this system we were able to obtain single-unit recordings of hippocampal place cells in rats running an enclosed vertical maze, over a range of 5 m.

A high-precision branching ratio measurement for the superallowed beta+ decay of 62Ga was performed at the Isotope Separator and Accelerator radioactive ion beam facility. Nineteen gamma rays emitted following beta+ decay of 62Ga were identified, establishing the dominant superallowed branching ratio to be (99.861+/-0.011)%. Combined with recent half-life and Q-value measurements, this branching ratio yields a superallowed ft value of 3075.6+/-1.4 s for 62Ga decay. These results demonstrate the feasibility of high-precision superallowed branching ratio measurements in the A>or=62 mass region and provide the first stringent tests of the large isospin-symmetry-breaking effects predicted for these decays.

Three rotational bands in 74Kr were studied up to (in one case one transition short of) the maximum spin I(max) of their respective single-particle configurations. Their lifetimes have been determined using the Doppler-shift attenuation method. The deduced transition quadrupole moments reveal a modest decrease, but far from a complete loss of collectivity at the maximum spin I(max). This feature, together with the results of mean field calculations, indicates that the observed bands do not terminate at I = I(max).

Objective: To examine the attitudes and practices of case managers working in Area Mental Health Services (AMHS) towards the physical health of people with chronic mental illness., Method: Case managers at four AMHS in Melbourne participated in focus groups and completed a survey questionnaire., Results: Case managers generally believed that mental illness, psychotropic medication and lifestyle factors contributed to the poor physical health status of their patients. Although many case managers attempted interventions aimed at improving physical health, there was inconsistency regarding the areas targeted. Preventive health measures were often neglected. Overall, there was a sense of pessimism around whether improved physical health was possible for people with chronic mental illness., Conclusions: Lack of coordination among health professionals and the health system may contribute to the poor general health of people with mental illness. Patients often have difficulty accessing general practitioners and the culture within the AMHS can exclude considerations of physical health. Case management should include aspects addressing the physical health issues of AMHS clients.

It has been established that 5-HT(1A) receptors are expressed both presynaptically as autoreceptors by 5-HT containing neurones, and postsynaptically by a variety of other neurones. Activation of either somatodendritic 5-HT(1A) autoreceptors or postsynaptic 5-HT(1A) receptors induces hyperpolarisation and inhibition of action potential discharge of the neurones, but it is unclear whether 5-HT(1A) receptors are under a general tonic influence by 5-HT. In the present study, using single unit recordings from both anesthetized and non-anesthetized rats, we show that the activity of neurones in the medial prefrontal cortex is not altered by systemic administration of the selective 5-HT(1A) receptor antagonist, WAY 100635. In contrast, WAY 100635 increased the firing rate of 5-HT neurones in the dorsal raphe nucleus. Our findings indicate a tonic activation of presynaptic somatodendritic but not postsynaptic cortical 5-HT(1A) receptors.

Objective: The objective of this study was to document the prevalence of risk factors for HIV/AIDS and hepatitis C among people with chronic mental illness treated in a community setting., Method: 234 patients attending four community mental health clinics in the North-western Health Care Network in Melbourne, Australia, completed an interviewer-administered questionnaire which covered demographics, risk behaviour and psychiatric diagnosis., Results: The sample was 58% male, and 79% of the sample had a primary diagnosis of schizophrenia. Forty-three per cent of mentally ill men and 51% of mentally ill women in the survey had been sexually active in the 12 months preceding the survey. One-fifth of mentally ill men and 57% of mentally ill women who had sex with casual partners never used condoms. People with mental illness were eight times more likely than the general population to have ever injected illicit drugs and the mentally ill had a lifetime prevalence of sharing needles of 7.4%., Conclusions: The prevalence of risk behaviours among the study group indicate that people with chronic mental illness should be regarded as a high-risk group for HIV/AIDS and hepatitis C. It is essential that adequate resources and strategies are targeted to the mentally ill as they are for other high-risk groups.

Objective: The objective of this study was to document the prevalence of risk factors for cardiovascular disease among people with chronic mental illness., Method: A cross-sectional survey was conducted of 234 outpatients attending a community mental health clinic in the North-western Health Care Network in Melbourne, Australia. Prevalence of smoking, alcohol consumption, body mass index, hypertension, salt intake, exercise and history of hypercholesterolemia was assessed., Results: Compared with a community sample, the mentally ill had a higher prevalence of smoking, overweight and obesity, lack of moderate exercise, harmful levels of alcohol consumption and salt intake. No differences were found on hypertension. Men, but not women, with mental illness were less likely to undertake cholesterol screening., Conclusions: Psychiatric outpatients have a high prevalence of cardiovascular risk factors which may account for the higher rate of cardiovascular mortality among the mentally ill. Further research is needed to trial and evaluate interventions to effectively modify risk factors in this vulnerable population.

The performance of freely moving rats (n=18) in a decision-making reaction time task was analyzed to provide data that can be compared with noise-compatibility paradigms previously obtained in humans. Rats were first trained in an auditory pitch discrimination task involving a Go/Nogo response choice. In a subsequent phase, the two tones used in the previous phase were simultaneously presented in different combinations from two locations. Only the presence of the correct tone from the correct location was predictive of the reward. The observed behavioral strategies suggest a competition between two processes: one involving stimulus evaluation, response preparation and execution, the other involving recognition of the stimulus features associated with inhibition of the Go-response. The reaction times in the most adopted strategies towards the end of the experiment suggest an effect of stimulus congruence. Perceptual processes are affected by the congruence of 'pitch' and 'location' stimulus dimensions and the duration of the response may, but need not, be affected by overlapping dimensions. The analysis of error and aborted trials also suggest that subject's reaction and subsequent motor action may depend on whether stimulus identification processes can pass information to the response activation system prior to completion of sensory processing. The data are discussed in the framework of processing stages theory and dimensional overlap model.

A chronic single-unit study of motor cortical activity was undertaken in two monkeys trained to perform a bimanually coordinated task. The hypothesis was tested that the supplementary motor area plays a specific role in coordinating the two hands for common goal-oriented actions. With this objective, a special search was made for neurons that might exhibit properties exclusively related to bimanual task performance. Monkeys learned to reach for and to pull open a spring-loaded drawer with one hand, while the other hand reached out to grasp food from the drawer recess. The two hands were precisely coordinated for achievement of this goal. Monkeys also performed, in separate blocks of trials, only the pulling or grasping movements, using the same hands as in the bimanual task. Task-related activity of 348 neurons from the supplementary motor area and 341 neurons from the primary motor area, each examined in the bimanual and in both unimanual tasks, was recorded in the two hemispheres. Most neurons from the supplementary motor area were recorded within its caudal microexcitable portion. Contrary to expectation, the proportion of neurons with activity patterns related exclusively to the bimanual task was small, but somewhat higher in the supplementary motor area (5%) than in the primary motor cortex (2%). Another group of neurons that were equally modulated during the bimanual as well as to both unimanual task components might also contribute in controlling bimanual actions. Such "task-dependent" rather than "effector-dependent" activity patterns were more common in neurons of the supplementary motor area (19%) than of the primary motor cortex (5%). Bilateral receptive fields were also more numerous among the supplementary motor area neurons. However, a large majority of neurons from primary and supplementary motor areas had activity profiles clearly related only to contralateral hand movements (65% in the primary motor and 51% in the supplementary motor area). A similar group of neurons showed an additional slight modulation with ipsilateral movements; they were equally common in the two areas (14% and 16%, respectively) and their significance for bimanual coordination is questionable. Summed activity profiles of all neurons recorded in the primary and supplementary motor areas of the same hemisphere were compared. The modulations of the three histograms, corresponding to the two unimanual and the bimanual tasks, were similar for the two motor areas, i.e. prominent with bimanual and contralateral movements and weak with ipsilateral movements. It is concluded that the supplementary motor area is likely to contribute to bimanual coordination, perhaps more than the primary motor cortex, but that it is not a defining function for the former cortical area. Instead, it is suggested that the supplementary motor area is part of a callosally interconnected and distributed network of frontal and parietal cortical areas that together orchestrate bimanual coordination.

Precise and repeated spike-train timings within and across neurons define spatiotemporal patterns of activity. Although the existence of these patterns in the brain is well established in several species, there has been no direct evidence of their influence on behavioral output. To address this question, up to 15 neurons were recorded simultaneously in the auditory cortex of freely moving rats while animals waited for acoustic cues in a Go/NoGo task. A total of 235 significant patterns were detected during this interval from an analysis of 13 hr of recording involving over 1 million spikes. Of particular interest were 129 (55%) patterns that were significantly associated with the type of response the animal made later, independent of whether the response was that prompted by the cue because the response occurred later and the cue was chosen randomly. Of these behavior-predicting patterns, half (59/129) were associated with an enhanced tendency to go in response to the stimulus, and for 11 patterns of this subset, trials including the pattern were followed by significantly faster reaction time than those lacking the pattern. The remaining behavior-predicting patterns were associated with an enhanced NoGo tendency. Overall mean discharge rates did not vary across trials. Hence, these data demonstrate that particular spatiotemporal patterns predict future behavioral responses. Such presignal activity could form templates for extracting specific sensory information, motor programs prespecifying preference for a particular act, and/or some intermediate, associative brain process.

The activity of 259 task-related red nucleus neurons was recorded using chronic electrophysiological methods in free moving rats. Modulations in activity were analysed in relation to onset (first detected wrist movement) and end (arrival of the paw over the food) of a reach-to-grasp movement. Excitatory peaks were found to begin before, during and after the reach, but there were clear peaks in the distribution of onset times after reach-onset and before reach-end, reflecting the fact that one third of all peaks began specifically during the reach, although this occupied only a small fraction of the analysis time. Both excitations and inhibitions showed a strong tendency to end in close temporal association with reach-end. Analysis of excitatory modulation amplitudes showed that the largest peaks were formed when data was aligned to reach-end, and that these largest peaks nearly all began during the reach and ended precisely at the time the paw would have been about to grasp the food. The spread of neural activation onset times throughout the course of the complex reach-to-grasp movement is consistent with a relationship of individual neurons in the rat red nucleus with movements of all parts of the forelimb, as would be expected if all limb muscle groups are represented in the nucleus. On the other hand the disproportionate number of modulations that occur during the reach and their strong alignment with time of reach-end suggests there is a bias in red nucleus function towards the control of distal motions associated with accurate grasp, consistent with the result of recent lesion studies. This provides indirect evidence that functionally the rat red nucleus may be organized in a similar way to that of monkeys, in which an important role in control of accurate distal movements is well established. The possibility is discussed that red nucleus offers a timing signal for co-ordination of movements across joints, in particular the precise distal-proximal binding normally seen in accurate reach-to-grasp movements.

Simultaneous single unit spike trains were recorded in the auditory cortex of freely moving rats performing a complex cognitive task. The experimental paradigm is based on a two-choice task (Go/Nogo) with a two-component (pitch and location) auditory stimulus lasting 500 ms. We report evidence that firstly functional interactions, measured by cross-correlation analysis, between single units in the auditory cortex are dynamically modified in the period preceding the onset of the auditory stimulation, referred to as the 'waiting period'. We secondly observed that spatio-temporal firing patterns both within, and across cell spike trains also tended to appear in the waiting period, several seconds before the actual stimulus delivery. These patterns indicate a very precise repetition of spike discharges separated by long intervals (up to several hundreds of milliseconds). No consistent changes in mean rate were observed. These results suggest that network activity in the auditory cortex is selectively modified in rate independent ways before the actual sensory stimulation. These modifications may reflect participation of recurrent neuronal networks in processes anticipating the expected sensory input.

The objective of this study was to assess the relation of motor cortical neural activity in the rat to self-paced reach-to-grasp movements. Overall, around 40% of excitatory and 60% of inhibitory modulations in neuronal activity began prior to reach onset. These data are consistent with a role for rat motor cortex in the initiation and control of the reaching movement. In addition, although the reach only lasted a short time, 30% of excitations and inhibitions began while it was in progress. The existence of such modulations occurring during the reach is consistent with previous data showing activity of cortical neurons late in the reach, and suggests a heavy involvement of cortical neurons in controlling the recently described, complex movements associated with grasping that are seen in the rat. These features were broadly similar in neurones from both the caudal and rostral subdivisions of rat motor cortex.

The hypothesis was tested that the mesial frontal cortex, including the supplementary motor area, is engaged in bimanual co-ordination. Three monkeys, trained in a well-co-ordinated bimanual pull-and-grasp task, were subjected to unilateral or bilateral lesions of the mesial frontal cortex. With unilateral lesions, the deficit consisted in a delay in movement initiation of the contralateral arm. With a bilateral lesion, the deficit was more pronounced with marked bilateral delays in movement onset and slowing in reaching. However, in the three monkeys bimanual co-ordination at the moment of goal achievement remained intact with an excellent temporal co-variation of the two limbs. In the two unilateral cases, an adaptive strategy developed after a few sessions, either by catching up during reaching with the limb contralateral to the lesion (monkey M1) or by delaying movement initiation of the limb ipsilateral to the lesion (monkey M2). This outcome is discussed in terms of Lashley's principle of motor equivalence, i.e. invariant goal achievement with variable means. Bilateral lesions led to a transient and near-total impairment in movement self-initiation when all external cues were absent. It is concluded that in monkeys the mesial frontal cortex does not play a crucial role in bimanual co-ordination but rather in movement initiation, especially when sensory cues are absent.

In the monkey, reaction time in a precued delayed response task was found to be faster when the animals had to remember the precue than when it was continually available (Smyrnis, Taira, Ashe, & Georgopoulos, 1992). We investigated whether this reflects a general principle that applies to all types of precued tasks. However, we found the opposite result in a simpler task in humans. Our findings suggest that the beneficial effect of a memory requirement on reaction time in the monkey may reflect an effect of task difficulty, rather than a fundamental process involved in all precued movement tasks.

The spatial aspect of cooperation between the two upper extremities was investigated using a bimanual task involving drawing simultaneous zig-zag lines on a vertical surface. In 62 trials by 31 strongly right-handed subjects three performance types were identified; Type I involved alternation of dominance in sideways and vertical movement components, in Type II a constant vertical movement was superimposed upon sideways movement, and Type III showed no consistent pattern across the two hands. These performance types differed significantly on the measure of spatial coordination, with Type I having the best, and Type III the poorest. These results suggest that on this bimanual task better spatial symmetry in limb movement is achieved when both hands employ similar within-hand strategies, involving switching between vectors for all muscle groups.

Kinematic characteristics and lateral differences between two upper extremities were investigated in a unimanual graphic task involving fast and precise oscillating movements on the vertical plane. The spatial locations of sequential reversal points were used to calculate the pairs of angles, relative to the horizontal axis. The point biserial coefficient of correlation was used to analyze the difference between big and large angles and their sequence in each pair. Three main groups (A, B, and C) of performance models were distinguished in 132 tests by 33 strongly right-handed male subjects. Group A showed strong variation in vertical movement, Group B covariation in vertical and horizontal vectors, while Group C reflected independent variation of both vertical and horizontal directions. It is suggested that the movement strategies might reflect three different models of motor control involving coupling of an oscillator controlling pools of motoneurons which regulates horizontal movements with an oscillator controlling vertical movement (Groups A + B) or with nonoscillating control signal (Group B). It is argued that Group A represents the simplest strategy and only performance Type A met by the left hand.

The concept of a motor program has been used to interpret a diverse range of empirical findings related to preparation and initiation of voluntary movement. In the absence of an underlying mechanism, its exploratory power has been limited to that of an analogy with running a stored computer program. We argue that the theory of cortical cell assemblies suggests a possible neural mechanism for motor programming. According to this view, a motor program may be conceptualized as a cell assembly, which is stored in the form of strengthened synaptic connections between cortical pyramidal neurons. These connections determine which combinations of corticospinal neurons are activated when the cell assembly is ignited. The dynamics of cell assembly ignition are considered in relation to the problem of serial order. These considerations lead to a plausible neural mechanism for the programming of movements and movement sequences that is compatible with the effects of precue information and sequence length on reaction times. Anatomical and physiological guidelines for future quantitative models of cortical cell assemblies are suggested. By taking into account the parallel re-entrant loops between the cerebral cortex and basal ganglia, the theory of cortical cell assemblies suggests a mechanism for motor plans that involve longer sequences. The suggested model is compared with other existing neural network models for motor programming.

The aim of the present investigation was to assess a bimanual goal-oriented movement sequence with particular emphasis on its temporal structure. The three monkeys (Macaca fascicularis) used in this study chose the left arm as the leading and more postural arm to reach out and pull back a spring-loaded drawer containing a food morsel. The right arm followed the left and picked up the food with a precision grip. Video recordings, trajectory recordings of the two index fingers, drawer displacement and the measurements of discrete events of the left and right hand revealed a considerable trial-by-trial variability in the temporal and spatial domain. The variability of latencies progressively increased from the initiation of the bimanual sequence to the left-hand and right-hand events defining goal achievement. The main result was that, in spite of this variability in each of the two limbs, there was an invariant left-right goal-related synchronization. The timing of the goal-related event pairs covaried and showed high correlation coefficients. Covariation of the two hands resulting in an invariant synchronization was particularly striking when monkeys performed the task without vision, and timing of right and left movement components was delayed with further increase in variability. The results indicate that, in the present bimanual skill, kinaesthetic signals may be sufficient to coordinate the two limbs in a goal-oriented unitary action in accord with a memorized plan.

Neuronal activity recorded from the primary motor cortex (MI) and from the supplementary motor area (SMA) was compared in two monkeys trained to perform conditioned arm movements. A handle had to be held in a central waiting position until a visual go and cueing signal indicated to the monkey to move the handle either to a medial or to a lateral target zone (choice reaction time paradigm). Unit and representative electromyographic data were analyzed in relation either to the go signal or to movement onset. In 240 penetrations, 431 SMA neurons and 353 MI neurons were found with activity related to the task. The majority of neurons (303 in MI, 290 in SMA) displayed activity changes after the go signal and before movement onset. Of these "short-lead neurons", 71% in MI and 41% in SMA were clearly related to movement execution. The distribution of lead times in MI and SMA neurons was completely overlapping without any statistical difference among subgroups. The remaining neurons were as well related to the go signal as to movement onset, or were better related to the visual go signal. The response latencies to this signal were not statistically different in SMA and MI neurons. Activity changes during the waiting period was observed more frequently in SMA (47%) than in MI (32%); modulations restricted to the waiting period occurred in 14% of SMA neurons, but were exceptional in MI neurons (3%). It is concluded from these experiments that a surprisingly large proportion of SMA neurons have "MI-like" properties, in that they are temporally recruited together with MI neurons, with similar patterns of discharges during the task. This then suggests that the two interconnected areas operate in parallel. A population of SMA neurons is involved in some processing that is not as predominantly expressed in MI. This activity could relate to sensory, timing, or other higher-order aspects of response preparation, and/or motor functions such as postural stabilization.

Recent work on the supplementary motor area (SMA) in Macaca fascicularis led to the conclusion that this area is involved mainly in the preparation of self-paced movements. Results are presented indicating that the posterior portion of the SMA is also directly involved in movement execution and that it receives various sensory inputs. The main results are as follows: (1) The SMA has direct access to the spinal cord by way of corticospinal neurons, but the density of these neurons is lower than in the primary motor cortex (MI). (2) Intracortical microstimulation effects can be elicited in the SMA. Facilitatory effects on ongoing EMG activity can even be produced by single micropulses (8/s). The shortest latencies are compatible with an oligosynaptic or monosynaptic transmission. (3) SMA neurons respond (as do MI neurons) to external perturbations. (4) Anatomical tracing studies revealed that basal ganglia outflow to the SMA via the thalamus is important; our results suggest that dentate outflow contributes as well. (5) Many cells of the SMA may covary with conditioned movements in the same way as MI neurons do. It is argued that it is difficult to compare the lead-time of MI and SMA neurons since 'early' discharges may be coupled with anticipatory postural events.

The hierarchical position of the supplementary motor area (SMA) relative to the primary motor cortex is discussed on the basis of neurological observations and of animal experiments. In the last 10 years evidence has accumulated, especially from studies on the human brain, that the supplementary motor area is a hierarchically superior structure involved in the processes of movement initiation. Single unit studies in subhuman primates also revealed neuronal populations related to aspects of movement preparation rather than to the movement per se. However, we report that a surprisingly large subpopulation of SMA neurones has features classically found in the primary motor cortex (MI). These MI-like neurones precede movement onset by a relatively short interval. The occurrence of such "short-lead neurones" was somewhat higher in MI, but the histograms of lead-times were completely overlapping in the two areas. Taken together with the fact that the SMA is microexcitable and is part of the origin of the pyramidal tract, these findings suggest that the SMA functions also in parallel with MI as concluded by Woolsey and coworkers (1952). Finally, the SMA and MI are reciprocally interconnected, a situation which is not unlike that of the cortical visual areas.