Testing the contributions of striatal dopamine loss to the genesis of parkinsonian signs

Franco, Vanessa; Turner, Robert S.

doi:10.1016/j.nbd.2012.03.028

Cited by 19 publications

(15 citation statements)

References 121 publications

(167 reference statements)

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“…All procedures were approved by the institutional animal care and use committee. The monkeys performed a unimanual version of a reaching task that has been described in detail previously (Franco and Turner, 2012). In brief, the animal was seated in a primate chair facing a vertical response panel that contained two target LEDs and infrared proximity sensors.…”

Section: Methodsmentioning

confidence: 99%

Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus

et al. 2015

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Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) has largely replaced ablative therapies for Parkinson's disease.Because of the similar efficacies of the two treatments, it has been proposed that DBS acts by creating an "informational lesion," whereby pathologic neuronal firing patterns are replaced by low-entropy, stimulus-entrained firing patterns. The informational lesion hypothesis, in its current form, states that DBS blocks the transmission of all information from the basal ganglia, including both pathologic firing patterns and normal, task-related modulations in activity. We tested this prediction in two healthy rhesus macaques by recording single-unit spiking activity from the globus pallidus (232 neurons) while the animals completed choice reaction time reaching movements with and without STN-DBS. Despite strong effects of DBS on the activity of most pallidal cells, reach-related modulations in firing rate were equally prevalent in the DBS-on and DBS-off states. This remained true even when the analysis was restricted to cells affected significantly by DBS. In addition, the overall form and timing of perimovement modulations in firing rate were preserved between DBS-on and DBS-off states in the majority of neurons (66%). Active movement and DBS had largely additive effects on the firing rate of most neurons, indicating an orthogonal relationship in which both inputs contribute independently to the overall firing rate of pallidal neurons. These findings suggest that STN-DBS does not act as an indiscriminate informational lesion but rather as a filter that permits task-related modulations in activity while, presumably, eliminating the pathological firing associated with parkinsonism.

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Section: Methodsmentioning

confidence: 99%

Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus

et al. 2015

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“…Bilateral intrastriatal infusions of amphetamine post-training have been found to improve retention for certain types of tasks [42]. Unilateral putaminal dopamine receptor blockade in nonhuman primates induces contralateral parkinsonism [43]. Finally, intra-caudate infusion of D1 or D2 antagonists modifies the apparent effects of reward expectation on reaction time (RT) [44].…”

Section: Introductionmentioning

confidence: 99%

Dissociable effects of dopamine on learning and performance within sensorimotor striatum

et al. 2014

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Striatal dopamine is an important modulator of current behavior, as seen in the rapid and dramatic effects of dopamine replacement therapy in Parkinson Disease (PD). Yet there is also extensive evidence that dopamine acts as a learning signal, modulating synaptic plasticity within striatum to affect future behavior. Disentangling these “performance” and “learning” functions is important for designing effective, long-term PD treatments. We conducted a series of unilateral drug manipulations and dopamine terminal lesions in the dorsolateral striatum of rats highly-trained to perform brief instructed head/neck movements (two-alternative forced choice task). Reaction times and accuracy were measured longitudinally to determine if task behavior changed immediately, progressed over time, and/or persisted after drug withdrawal. Enhanced dopamine signaling with amphetamine caused an immediate, nonprogressive, and bilateral decrease in reaction times (RT). The altered RT distributions were consistent with reduced distance to threshold in the linear approach to threshold with ergodic rate (LATER) model of decision-making. Conversely, the dopamine antagonist flupenthixol caused experience-dependent, persistent changes in RT and accuracy indicative of a “learning” effect. These RT distributions were consistent with a slowed rate of approach to decision threshold. Our results show that dopaminergic signaling makes dissociable contributions to current and future behavior even within a single striatal subregion, and provide important clues for both models of normal decision-making and the design of novel drug therapies in PD.

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“…Interestingly, several clinical studies have reported an increased DT in sequential and repeated movements in Parkinson's disease patients compared with control subjects (Agostino et al 2003;Brontë-Stewart et al 2000;Jones et al 1992;Onla-or and Winstein 2001). Franco and Turner (2012) have shown that the selective blockage of dopamine transmission in monkey sensorimotor striatum leads to increased waiting times in the transition between cued reaching movements and selfinitiated, return movements. No similar result has been reported for cerebellar disorders, suggesting that the proposed analysis of finger tapping can lead to clean-cut functional dissociation between both areas putatively contributing to time prediction and control.…”

Section: Discussionmentioning

confidence: 99%

Balancing out dwelling and moving: optimal sensorimotor synchronization

Cos

Girard

Guigon

2015

Journal of Neurophysiology

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Cos I, Girard B, Guigon E. Balancing out dwelling and moving: optimal sensorimotor synchronization. J Neurophysiol 114: 146 -158, 2015. First published April 15, 2015 doi:10.1152/jn.00175.2015.-Sensorimotor synchronization is a fundamental skill involved in the performance of many artistic activities (e.g., music, dance). After a century of research, the manner in which the nervous system produces synchronized movements remains poorly understood. Typical rhythmic movements involve a motion and a motionless phase (dwell). The dwell phase represents a sizable fraction of the rhythm period, and scales with it. The rationale for this organization remains unexplained and is the object of this study. Twelve participants, four drummers (D) and eight nondrummers (ND), performed tapping movements paced at 0.5-2.5 Hz by a metronome. The participants organized their tapping behavior into dwell and movement phases according to two strategies: 1) Eight participants (1 D, 7 ND) maintained an almost constant ratio of movement time (MT) and dwell time (DT) irrespective of the metronome period. 2) Four participants increased the proportion of DT as the period increased. The temporal variabilities of both the dwell and movement phases were consistent with Weber's law, i.e., their variability increased with their durations, and the longest phase always exhibited the smallest variability. We developed an optimal statistical model that formalized the distribution of time into dwell and movement intervals as a function of their temporal variability. The model accurately predicted the participants' dwell and movement durations irrespective of their strategy and musical skill, strongly suggesting that the distribution of DT and MT results from an optimization process, dependent on each participant's skill to predict time during rest and movement. motor control; optimality; psychophysics; rhythmic movements; synchronization MANY BEHAVIORS such as singing or playing music require internal estimates of elapsed time from a past event or of remaining time to a future event (e.g., the beats of a metronome) to timely generate our actions (e.g., to tap on beat). This ability to produce movements synchronously with temporal events, called sensorimotor synchronization (Repp and Su 2013), either can occur spontaneously as during a synchronous applause at a concert hall or may result from long practice as in musical ensemble performance.Sensorimotor synchronization faces two constraints. First, processes involved in time production and perception tasks are governed by a form of Weber's law (Ivry and Hazeltine 1995;Merchant et al. 2008;Wing and Kristofferson 1973), i.e., variability increases with the duration of temporal intervals. Second, movements take time to be prepared and executed and are variable in space and time (Hancock and Newell 1985). How the brain actually predicts time between external events and produces synchronized motor behaviors remains poorly understood.Current theories of sensorimotor synchronization focus either on the prod...

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Testing the contributions of striatal dopamine loss to the genesis of parkinsonian signs

Cited by 19 publications

References 121 publications

Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus

Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus

Dissociable effects of dopamine on learning and performance within sensorimotor striatum

Balancing out dwelling and moving: optimal sensorimotor synchronization

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