Georg Dirnberger

The Role of the Dorsolateral Prefrontal Cortex in Random Number Generation: A Study with Positron Emission Tomography

Random number generation (RNG) engages a number of executive processes. We used positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) in six volunteers who performed RNG and a control counting (COUNT) task at six rates paced by a tone. This provided a systematic variation of difficulty of RNG. Relative to COUNT, RNG was associated with significant activation of the left dorsolateral prefrontal cortex (DLPFC), the anterior cingulate, the superior parietal cortex bilaterally, the right inferior frontal cortex, and the left and right cerebellar hemispheres. Faster rates of RNG were associated with a significant decrease in regional cerebral blood flow (rCBF) in the left and right DLPFC and the right superior parietal cortex. rCBF in the left DLPFC was significantly and negatively associated with count score 1, a measure of habitual counting during RNG. These results are discussed in relation to the network modulation model of RNG developed on the basis of our previous studies using transcranial magnetic stimulation and dual task paradigms. This suggests that during RNG, suppression of habitual counting is achieved through the modulatory (inhibitory) influence of the left DLPFC over a number associative network distributed in the superior temporal cortex. At faster rates of RNG the synchronization demands of paced RNG result in the breakdown of this modulatory influence, which is evident from decreased rCBF in the left DLPFC and increased habitual counting at faster rates.

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.

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 Parkinsons 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.

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

Executive dysfunction in Parkinsons 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 Parkinsons 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 Parkinsons 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.

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 Baddeleys 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.

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 Parkinsons 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.

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 2000u2009ms. 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.

Does the Pre-frontal Cortex Contribute to Movement-related Potentials? Recordings from Subdural Electrodes

The contribution of the pre-frontal cortex to movement-related potentials (MRPs) subdural electrode strips placed over the frontal cortex in a 13-year-old girl being monitored prior to surgery for intractable epilepsy. MRPs were recorded prior to two types of movement: self-paced random joystick movements which involve ‘what to do’ and ‘when to do’ decision making on every trial and prior to joystick movements in a fixed forward direction triggered by a tone which does not involve any trial-by-trial decision making. Self-paced random joystick movements were associated with an increased subdural positivity starting from 1000 ms prior to onset of joystick movement at electrodes over the pre-motor cortex (BA 6) and dorsolateral and inferior pre-frontal cortex (BA 46/45/10), as evident from a magnetic resonance imaging scan. These results suggest that in addition to the pre-motor area, the pre-frontal cortex also contributes to the generation of MRPs in conditions involving decision making about the precise nature (‘what to do’) and timing (‘when to do’) of the movement. These preliminary results require replication in a larger series of patients.

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.