In Parkinson's disease on a probabilistic Go/NoGo task deep brain stimulation of the subthalamic nucleus only interferes with withholding of the most prepotent responses.

The evidence on the impact of subthalamic nucleus deep brain stimulation (STN-DBS) on action restraint on Go/NoGO reaction time (RT) tasks in Parkinson's disease (PD) is inconsistent; with some studies reporting no effect and others finding that STN stimulation interferes with withholding of responses and results in more commission errors relative to STN-DBS off. We used a task in which the probability of Go stimuli varied from 100% (simple RT task) to 80, 50 and 20% (probabilistic Go/NoGo RT task), thus altering the prepotency of the response and the difficulty in withholding it on NoGo trials. Twenty PD patients with STN-DBS, ten unoperated PD patients and ten healthy controls participated in the study. All participants were tested twice; the order of on versus off stimulation for STN-DBS PD patients was counterbalanced. Both STN-DBS and unoperated PD patients were tested on medication. The results indicated that STN-DBS selectively decreased discriminability when the response was most prepotent (high--80%, as compared to low Go probability trials--50 and 20%). Movement times were faster with STN stimulation than with DBS off across different Go probability levels. There was neither an overall nor a selective effect of STN-DBS on RTs depending on the level of Go probability. Furthermore, compared to healthy controls, both STN-DBS and unoperated PD patients were more prone to making anticipatory errors; which was not influenced by STN stimulation. The results provide evidence for 'load-dependent' effects of STN stimulation on action restraint as a function of the prepotency of the Go response.

Neural correlates of executive dysfunction in schizophrenia: failure to modulate brain activity with task demands.

In schizophrenia, executive functions are impaired and are associated with altered activation of prefrontal areas. We used H2[15]O PET to examine patients with schizophrenia and matched controls on a random number generation (RNG) task and a control counting (COUNT) task. To assess the effects of increasing task demand, both tasks were performed at three different rates (intervals 1, 2 or 3 s). Both groups showed a significant increase in the nonrandomness of responses at faster rates of RNG. Despite similar performances, patients but not controls showed higher activation of the right dorsolateral prefrontal cortex (DLPFC) and atypically reduced activation of the right anterior cingulate gyrus and the right medial frontal gyrus in RNG compared with COUNT, whereas only for controls, activation of the left DLPFC was increased and activation of the right superior temporal gyrus and the right superior frontal gyrus was reduced in the same comparison. Whereas for the controls several cortical areas including the bilateral superior temporal gyrus and the bilateral DLPFC, together with the right cerebellum, showed significant changes in regional cerebral blood flow with faster or slower rates, patients with schizophrenia showed rate-dependent changes only in the left cerebellum. In conclusion, the patients' failure to modulate cortical activation with changing demands of rate, particularly in prefrontal areas and in the cerebellum, and even when performance is similar to that in healthy controls, is a characteristic of their abnormal pattern of executive processing.

Executive dysfunction in Parkinson's disease: a review.

Executive dysfunction can be present from the early stages of Parkinson's disease (PD). It is characterized by deficits in internal control of attention, set shifting, planning, inhibitory control, dual task performance, and on a range of decision-making and social cognition tasks. Treatment with dopaminergic medication has variable effects on executive deficits, improving some, leaving some unchanged, and worsening others. In this review, we start by defining the specific nature of executive dysfunction in PD and describe suitable neuropsychological tests. We then discuss how executive deficits relate to pathology in specific territories of the basal ganglia, consider the impact of dopaminergic treatment on executive function (EF) in this context, and review the changes in EFs with disease progression. In later sections, we summarize correlates of executive dysfunction in PD with motor performance (e.g., postural instability, freezing of gait) and a variety of psychiatric (e.g., depression, apathy) and other clinical symptoms, and finally discuss the implications of these for the patients' daily life.

Perceptual sequence learning is more severely impaired than motor sequence learning in patients with chronic cerebellar stroke.

Patients with cerebellar stroke are impaired in procedural learning. Several different learning mechanisms contribute to procedural learning in healthy individuals. The aim was to compare the relative share of different learning mechanisms in patients and healthy controls. Ten patients with cerebellar stroke and 12 healthy controls practiced a visuomotor serial reaction time task. Learning blocks with high stimulus-response compatibility were exercised repeatedly; in between these, participants performed test blocks with the same or a different (mirror-inverted or unrelated) stimulus sequence and/or the same or a different (mirror-inverted) stimulus-response allocation. This design allowed to measure the impact of motor learning and perceptual learning independently and to separate both mechanisms from the learning of stimulus-response pairs. Analysis of the learning blocks showed that, as expected, both patients and controls improved their performance over time, although patients remained significantly slower. Analysis of the test blocks revealed that controls showed significant motor learning as well as significant visual perceptual learning, whereas cerebellar patients showed only significant motor learning. Healthy participants were able to use perceptual information for procedural learning even when the rule linking stimuli and responses had been changed, whereas patients with cerebellar lesions could not recruit this perception-based mechanism. Therefore, the cerebellum appears involved in the accurate processing of perceptual information independent from prelearned stimulus-response mappings.

Motor and perceptual sequence learning: different time course of parallel processes.

The aim was to determine the extent and time course of motor and perceptual learning in a procedural learning task, and the relation of these two processes. Because environmental constraints modulate the relative impact of different learning mechanisms, we chose a simple learning task similar to real-life exercise. Thirty-four healthy individuals performed a visuomotor serial reaction time task. Learning blocks with high stimulus-response compatibility were practiced repeatedly; in between these, participants performed test blocks with the same or a different (mirror-inverted, or new) stimulus sequence and/or with the same or a different (mirror-inverted) stimulus-response allocation. This design allowed us to measure the progress of motor learning and perceptual learning independently. Results showed that in the learning blocks, a steady reduction of the reaction times indicated that - as expected - participants improved their skills continuously. Analysis of the test blocks indicated that both motor learning and perceptual learning were significant. The two mechanisms were correlated (r=0.62, P<0.001). However, their time course was different: the impact of motor learning increased strongly from earlier to later intervals, whereas the progress of perceptual learning was more stable but slower. In conclusion, in a simple visuomotor learning task, participants can learn the motor sequence and the stimulus sequence in parallel. The positive correlation of motor and perceptual learning suggests that the two mechanisms act in synergy and are not alternative opposing strategies. The impact of these two learning mechanisms changes over time: motor learning sets in later and becomes relevant only in the course of training.

Deciphering the impact of cerebellar and basal ganglia dysfunction in accuracy and variability of motor timing.

Studies in motor timing have shown that the basal ganglia and cerebellum play an important role in temporal processing. Timing studies in Cerebellar/ataxic Disorders (CD) and Parkinson's disease (PD) patients contrast the roles of the cerebellum and basal ganglia in motor timing. Here, we used a synchronization-continuation task to compare accuracy and variability of motor timing during repetitive tapping. We compared data collected for the present study - from patients with CD and healthy controls - to data from a previous study with patients with PD. We asked participants to tap at Inter-stimulus Intervals (ISIs) of 250, 500, 1000, and 2000 ms. Using Linear Mixed Models (LMMs), we explored how ISI, Task Phase, and Diagnosis interacted to determine the (i) the accuracy and (ii) the variability of tapping. In our analysis of accuracy, we found evidence that during the synchronization phase, at ISI=250 ms, CD patients lagged 'behind the beat'; whereas our previous work has suggested that medicated PD patients hasten 'ahead of the beat'. In our analysis of variability, we observed that at ISIs below 1000 ms, CD patients showed greater variability in motor timing than the healthy controls, while PD patients showed less variability than CD patients and healthy controls during the synchronization phase at the 1000 ms ISI. These results highlight the differential performance on explicit motor timing between patients with disorders of the cerebellum and basal ganglia. Our results illustrate a novel approach to discerning cognitive control of motor timing.

Give it time: neural evidence for distorted time perception and enhanced memory encoding in emotional situations.

Time perception is compromised in emotional situations, yet our ability to remember these events is enhanced. Here we suggest how the two phenomena might be functionally linked and describe the neural networks that underlie this association. We found that participants perceived an emotionally aversive stimulus longer than it was, compared to an immediately following neutral stimulus. These time estimation errors were in the same trials associated with better recognition memory for the emotionally aversive stimuli and poorer memory for the neutral stimuli. Functional imaging revealed that the superior frontal gyrus was activated during time perception with aversive stimuli, and the amygdala, putamen and insula showed activations that are specific to time estimation errors in this aversive context. We further found that activity in the insula and putamen was correlated with memory performance but only during over-estimation of time with the aversive stimuli. We suggest that processing is accelerated during the experience of emotionally aversive events, presumably in the service of memory-related operations, resulting in better encoding but at the expense of time perception accuracy.

Handedness is modulated by sex and self-perception.

The distribution of handedness is different for men and women. Less pronounced right- or left-handedness in men is well established and often attributed to direct effects of genetic factors. Many studies observing this sex difference assessed handedness via questionnaire. It may therefore be influenced by a sex-specific bias in self-perception. Permanent inadequate self-perceptions are key characteristics of hypochondriasis. The study therefore tested 1017 participants (614 females) on two standard questionnaires to assess handedness and hypochondriasis: the Edinburgh Inventory and the Whiteley Index. Effects of sex, hypochondriac traits and the direction of handedness (left-handers; right-handers) on the degree of handedness (DH; the strength of lateralisation) were tested with multivariate linear regression. In confirmation of previous results, the DH is lower (less pronounced) in right-handed males than right-handed females, but is similar across sexes in left-handers. Regression analyses showed that for right-handers, male sex and higher hypochondriac traits are independent predictors of lower DH. For left-handers, main effects of sex and hypochondriac traits are not significant whereas a significant interaction of these two factors indicates that in left-handed men higher hypochondriac traits are associated with a differentially stronger shift towards lower DH compared to left-handed women. In conclusion, the DH is modulated by sex-specific effects of self-perception for left-handers but not right-handers. The implications of this finding on current theories of the inheritance of handedness are discussed. The assessment of hypochondriac traits might be useful to control response bias in questionnaire-based studies of human handedness.

Modeling accuracy and variability of motor timing in treated and untreated Parkinson's disease and healthy controls.

Parkinson's disease (PD) is characterized by difficulty with the timing of movements. Data collected using the synchronization-continuation paradigm, an established motor timing paradigm, have produced varying results but with most studies finding impairment. Some of this inconsistency comes from variation in the medication state tested, in the inter-stimulus intervals (ISI) selected, and in changeable focus on either the synchronization (tapping in time with a tone) or continuation (maintaining the rhythm in the absence of the tone) phase. We sought to re-visit the paradigm by testing across four groups of participants: healthy controls, medication naïve de novo PD patients, and treated PD patients both "on" and "off" dopaminergic medication. Four finger tapping intervals (ISI) were used: 250, 500, 1000, and 2000 ms. Categorical predictors (group, ISI, and phase) were used to predict accuracy and variability using a linear mixed model. Accuracy was defined as the relative error of a tap, and variability as the deviation of the participant's tap from group predicted relative error. Our primary finding is that the treated PD group (PD patients "on" and "off" dopaminergic therapy) showed a significantly different pattern of accuracy compared to the de novo group and the healthy controls at the 250-ms interval. At this interval, the treated PD patients performed "ahead" of the beat whilst the other groups performed "behind" the beat. We speculate that this "hastening" relates to the clinical phenomenon of motor festination. Across all groups, variability was smallest for both phases at the 500-ms interval, suggesting an innate preference for finger tapping within this range. Tapping variability for the two phases became increasingly divergent at the longer intervals, with worse performance in the continuation phase. The data suggest that patients with PD can be best discriminated from healthy controls on measures of motor timing accuracy, rather than variability.

On the regularity of preparatory activity preceding movements with the dominant and non-dominant hand: a readiness potential study.

The readiness potential (RP), a slow negative electroencephalographic pre-movement potential, was reported to commence earlier for movements with the non-dominant left hand than with the dominant right hand. Latencies in these reports were always calculated from averaged RPs, whereas onset times of individual trials remained inaccessible. The aim was to use a new statistical approach to examine whether a few left hand trials with very early pre-movement activity disproportionally affect the onset of the average. We recorded RPs in 28 right-handed subjects while they made self-paced repetitive unilateral movements with their dominant and non-dominant hand. Skewness, a measure of distribution asymmetry, was analysed in sets of single-trial RPs to discriminate between a symmetric distribution and an asymmetric distribution containing outlier trials with early onset. Results show that for right hand movements skewness has values around zero across electrodes and pre-movement intervals, whereas for left hand movements skewness has initially negative values which increase to neutral values closer to movement onset. This indicates a symmetric (e.g., Gaussian) distribution of onset times across trials for simple right hand movements, whereas cortical activation preceding movements with the non-dominant hand is characterised by outlier trials with early onset of negativity. These findings may explain differences in the averaged brain activation preceding dominant versus non-dominant hand movements described in previous electrophysiological/neuroimaging studies. The findings also constrain mental chronometry, a technique that makes conclusions upon the time and temporal order of brain processes by measuring and comparing onset times of averaged electroencephalographic potentials evoked by these processes.

Differential effects of age and executive functions on the resolution of the contingent negative variation: a reexamination of the frontal aging theory.

The "frontal aging theory" assumes the deterioration of executive/inhibitory functions as causal factors for the cognitive decline in human aging. The contingent negative variation resolution (CNV-R) is an electroencephalographic potential elicited after the second (informative) stimulus in warned Go/NoGo tasks requiring a response to one type of stimulus (Go) but not to the other (NoGo). Whereas the CNV-R across conditions is a measure of executive functions, the augmented potential in the NoGo condition is a specific measure of inhibitory processes. The aim was to examine the presumed linkage between executive processes and the CNV-R with special regard to inhibition in the NoGo condition, and to test whether any effects of age on this potential can be explained by a failure of (inhibitory) executive functions. Nineteen young and 15 elderly non-demented healthy volunteers were examined in a Go/NoGo CNV-R paradigm and on a test of executive functions focussed on set shifting (Trail Making test). Results showed: (1) Better executive functions are associated with higher amplitudes of the CNV-R across conditions. (2) The CNV-R is higher for elderly than younger subjects; this increment is much stronger in the NoGo condition. In conclusion, the CNV-R across conditions reflects executive processes such as the shift of motor set. A higher CNV-R for elderly subjects (particularly of the inhibition-related NoGo CNV-R) indicates that this group is not impaired in the available amount of executive control but may exert such control for task demands where young subjects do not require it.

Response selection in dual task paradigms: observations from random generation tasks.

Performance of attention-demanding tasks is worse if two tasks are carried out simultaneously than if each of the tasks is performed alone. Our aim was to determine whether these 'dual task costs' can be attributed to mechanisms on a supra-trial level such as switching of limited resources between trials or concurrent breakdown of supervisory functions, or to mechanisms effective within each trial such as demands of response selection. Twenty healthy volunteers performed verbal random number generation (RNG) and random movement generation (RMG) at three different rates. For each rate, both tasks were examined once in a single task condition and once in a dual task condition. Results showed that performance (quality of randomness) in each random generation task (RNG/RMG) was reduced at faster rates and impaired by concurrent performance of a secondary random generation task. In the dual task condition, transient increase or decrease of bias in one random generation task during any short interval was not associated with concurrent increase or decrease of bias in the other task. In conclusion, the fact that during dual task performance transient bias in one task was not associated with concurrent improvement of performance in the other task indicates that alternation of supervisory control or attentional resources from one to the other task does not mediate the observed dual task costs. Resources of the central executive are not re-allocated or 'switched' from one to the other task. Dual task costs may result from mechanisms effective within each trial such as the demands of response selection.

Separating coordinative and executive dysfunction in cerebellar patients during motor skill acquisition.

OBJECTIVE: Patients with cerebellar stroke are impaired in motor skill acquisition and cognitive/executive performance. The aim was to test whether skill acquisition in cerebellar patients is influenced by executive demands such as the intermittent exercise of a conflicting motor task. METHODS: Patients with cerebellar stroke and healthy controls were tested in two serial reaction time experiments. In Experiment 1, participants performed practice runs (always same sequence) and interference runs (new sequence for each run) in a strictly alternating fashion. In Experiment 2, participants rested between successive practice runs; the duration of rests was adapted to the duration of interference runs in the other experiment. Participants of Experiment 1 were also tested for cognitive-executive functions (Wisconsin Card Sort, Word Fluency, Trail Making, Digit Span backwards). RESULTS: (1) Patients in Experiment 1, although always slower than controls, acquired motor skills in the first run before interference but in contrast to controls failed to improve their performance in subsequent runs. (2) Patients in Experiment 2 improved their performance consistently over several runs. (3) Patients of Experiment 1 were worse than controls in several cognitive-executive functions; however, these deficits did not correlate with the degree of interference in motor skill acquisition. INTERPRETATION: Simple movement coordination and higher order context-related movement organisation are separate cerebellar functions. In cerebellar patients, impaired movement coordination is associated with generally slower reaction times whereas organisational deficits are associated with a specific impairment to change between motor sets. Motor-executive functions responsible for the latter impairment might be independent from cognitive-executive functions.

A new method to determine temporal variability in the period of pre-movement electroencephalographic activity.

The readiness potential (RP), a slow electroencephalographic (EEG) pre-movement potential, was used in earlier studies to determine the onset and order of neural processes preceding voluntary movement. Latencies in these studies were always calculated from the averaged RP, whereas onset times of individual trials remained inaccessible. The aim of this study was to use a different, statistical approach to examine how variable the onset of single-trial RPs within subjects is. We recorded RPs in 15 right-handed healthy subjects while they made self-paced repetitive unilateral button presses with their dominant right hand. Skewness, a measure of distribution asymmetry, was analysed in sets of single-trial RPs to discriminate between fixed onset and variable onset models. Results show that skewness has values around zero across all electrodes and pre-movement intervals without any significant deviation. This result obtained for the original data was replicated using modelled data with fixed onset times, whereas alternative models with variable onset times (i.e., including trials with exceptionally early onset) showed significant deviations of skewness from zero. In conclusion, for simple repetitive movements with the dominant hand these results confirm a fixed onset model of the RP with similar onset times of pre-movement cortical activation across trials. The methodology might be also applicable for other paradigms to test basic assumptions of mental chronometry.

Hypochondriasis and the self-perception of handedness: a critique of the use of hand preference scales.

OBJECTIVE: Previous research reported an association of handedness with a variety of neurologic, psychiatric, and immunologic diseases. Most of these studies assessed handedness via questionnaire. This association might therefore result from response bias. METHODS: Participants (n=422) completed 2 standard questionnaires to assess handedness and hypochondriasis: the Edinburgh Handedness Inventory and the Whiteley Index. Subjects with past or present neurologic, psychiatric, or immunologic disease or any severe disease were excluded. Separate analyses were made for the overall sample and 2 subsamples with and without a reported medical history of nonsevere diseases. RESULTS: The distribution of handedness is different for subjects with lower versus higher hypochondriac traits: higher scores of hypochondriac traits are associated with weaker right or left-handedness. The subsample reporting a history of nonsevere diseases had even stronger hypochondriac traits and less extreme handedness scores compared with the other subsample. CONCLUSIONS: Handedness scores derived from questionnaires are affected by information bias. Future medical and psychologic research on handedness should control for this bias or use empirical methods to assess hand preference.

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.

A preliminary investigation of the running digit span as a test of working memory.

The objective of this study was to compare performance on different versions of the running span task, and to examine the relationship between task performance and tests of episodic memory and executive function. We found that the average capacity of the running span was approximately 4 digits, and at long sequence lengths, performance was no longer affected by varying the running span window. Both episodic and executive function measures correlated with short and long running spans, suggesting that a simple dissociation between immediate memory and executive processes in short and long running digit span tasks may not be warranted.

The substantia nigra pars compacta and temporal processing.

The basal ganglia and cerebellum are considered to play a role in timing, although their differential roles in timing remain unclear. It has been proposed that the timing of short milliseconds-range intervals involves the cerebellum, whereas longer seconds-range intervals engage the basal ganglia (Ivry, 1996). We tested this hypothesis using positron emission tomography to measure regional cerebral blood flow in eight right-handed males during estimation and reproduction of long and short intervals. Subjects performed three tasks: (1) reproduction of a short 500 ms interval, (2) reproduction of a long 2 s interval, and (3) a control simple reaction time (RT) task. We compared the two time reproduction tasks with the control RT task to investigate activity associated with temporal processing once additional cognitive, motor, or sensory processing was controlled. We found foci in the left substantia nigra and the left lateral premotor cortex to be significantly more activated in the time reproduction tasks than the control RT task. The left caudate nucleus and right cerebellum were more active in the short relative to the long interval, whereas greater activation of the right putamen and right cerebellum occurred in the long rather than the short interval. These results suggest that the basal ganglia and the cerebellum are engaged by reproduction of both long and short intervals but play different roles. The fundamental role of the substantia nigra in temporal processing is discussed in relation to previous animal lesion studies and evidence for the modulating influence of dopamine on temporal processing.

Random number generation as an index of controlled processing.

Random number generation (RNG) is a functionally complex process that is highly controlled and therefore dependent on Baddeley's central executive. This study addresses this issue by investigating whether key predictions from this framework are compatible with empirical data. In Experiment 1, the effect of increasing task demands by increasing the rate of the paced generation was comprehensively examined. As expected, faster rates affected performance negatively because central resources were increasingly depleted. Next, the effects of participants' exposure were manipulated in Experiment 2 by providing increasing amounts of practice on the task. There was no improvement over 10 practice trials, suggesting that the high level of strategic control required by the task was constant and not amenable to any automatization gain with repeated exposure. Together, the results demonstrate that RNG performance is a highly controlled and demanding process sensitive to additional demands on central resources (Experiment 1) and is unaffected by repeated performance or practice (Experiment 2). These features render the easily administered RNG task an ideal and robust index of executive function that is highly suitable for repeated clinical use.

Executive dysfunction in Parkinson's disease is associated with altered pallidal-frontal processing.

Executive dysfunction in Parkinson's disease is well documented, but it is still unclear whether this results from (i) prefrontal dysfunction, (ii) striatal dysfunction, or (iii) altered striatal outflow to the prefrontal cortex. To clarify this issue, we used H(2)(15)O PET to asses six nondemented and nondepressed patients with Parkinson's disease and six matched controls while they performed a task involving executive function, random number generation (RNG), and a control counting task. To assess the effect of increasing task demands, each task was performed at three rates. Both groups showed significant increase in nonrandomness of responses during RNG at faster rates, which was differentially greater for the patients at the faster rate. The controls showed significant activation of the lateral and medial prefrontal cortex and superior and medial parietal cortex during RNG relative to counting. For the same comparison, the patients did not show any activity in medial frontal structures. The controls showed significantly greater mesial frontotemporal activation during counting than RNG, whereas the patients did not show any modulation of regional cerebral blood flow (rCBF) in these areas with task. With faster rates of RNG, the controls showed rCBF increase in the right internal segment of globus pallidus (GPi) and a decrease in frontal cortex. The patients showed the opposite pattern of subcortical and frontal rCBF change with faster rates. The results suggest that executive dysfunction in Parkinson's disease is associated with a failure to modulate frontal activation with increased task demands (nature of task or rate), a deficit associated with altered rCBF in the GPi, the final basal ganglia output pathway to frontal cortex rather than any intrinsic prefrontal dysfunction.