From anticipation to impulsivity in Parkinson's disease

Anticipatory actions require to keep track of elapsed time and inhibitory control. These cognitive functions could be impacted in Parkinson's disease (iPD). To test this hypothesis, a saccadic reaction time task was used where a visual warning stimulus (WS) predicted the occurrence of an imperative one (IS) appearing after a short delay. In the implicit condition, subjects were not informed about the duration of the delay, disfavoring anticipatory behavior but leaving inhibitory control unaltered. In the explicit condition, delay duration was cued. This should favor anticipatory behavior and perhaps alter inhibitory control. This hypothesis was tested in controls (N = 18) and age-matched iPD patients (N = 20; ON and OFF L-DOPA). We found that the latency distribution of saccades before the IS was bimodal. The 1st mode weakly depended on temporal information and was more prominent in iPD. Saccades in this mode were premature and could result of a lack of inhibition. The 2nd mode covaried with cued duration suggesting that these movements were genuine anticipatory saccades. The explicit condition increased the probability of anticipatory saccades before the IS in controls and iPDON but not iPDOFF patients. Furthermore, in iPD patients the probability of sequences of 1st mode premature responses increased. In conclusion, the triggering of a premature saccade or the initiation of a controlled anticipatory one could be conceptualized as the output of two independent stochastic processes. Altered time perception and increased motor impulsivity could alter the balance between these two processes in favor of the latter in iPD, particularly OFF L-Dopa

A subanesthetic dose of ketamine in the Rhesus monkey reduces the occurrence of anticipatory saccades

RATIONALE: It has been shown that antagonism of the glutamatergic N-methyl-D-aspartate (NMDA) receptor with subanesthetic doses of ketamine perturbs the perception of elapsed time. Anticipatory eye movements are based on an internal representation of elapsed time. Therefore, the occurrence of anticipatory saccades could be a particularly sensitive indicator of abnormal time perception due to NMDA receptors blockade. OBJECTIVES: To determine whether the occurrence of anticipatory saccades could be selectively altered by a subanesthetic dose of ketamine. METHODS: Three Rhesus monkeys were trained in a simple visually-guided saccadic task with a variable delay. Monkeys were rewarded for making a visually-guided saccade at the end of the delay. Premature anticipatory saccades to the future position of the eccentric target initiated before the end of the delay were not rewarded. A sub-anesthetic dose of ketamine (0.25 mg/kg) or a saline solution of the same volume was injected i.m. during the task. RESULTS: We found that the injected dose of ketamine did not induce sedation or abnormal behavior. However, in ~4 minutes, ketamine induced a strong reduction of the occurrence of anticipatory saccades but did not reduce the occurrence of visually-guided saccades. CONCLUSION: This unexpected reduction of anticipatory saccade occurrence could be interpreted as resulting from an altered use of the perception of elapsed time during the delay period induced by NMDA receptors antagonism

Ketamine reduces temporal expectation in the rhesus monkey.

Ketamine, a well-known general dissociative anesthetic agent that is a non-competitive antagonist of the N-methyl-D-aspartate receptor, perturbs the perception of elapsed time and the expectation of upcoming events. The objective of this study was to determine the influence of ketamine on temporal expectation in the rhesus monkey. Two rhesus monkeys were trained to make a saccade between a central warning stimulus and an eccentric visual target that served as imperative stimulus. The delay between the warning and the imperative stimulus could take one of four different values randomly with the same probability (variable foreperiod paradigm). During experimental sessions, a subanesthetic low dose of ketamine (0.25-0.35 mg/kg) was injected i.m. and the influence of the drug on movement latency was measured. We found that in the control conditions, saccadic latencies strongly decreased with elapsed time before the appearance of the visual target showing that temporal expectation built up during the delay period between the warning and the imperative stimulus. However, after ketamine injection, temporal expectation was significantly reduced in both subjects. In addition, ketamine also increased average movement latency but this effect could be dissociated from the reduction of temporal expectation. In conclusion, a subanesthetic dose of ketamine could have two independent effects: increasing reaction time and decreasing temporal expectation. This alteration of temporal expectation could explain cognitive deficits observed during ketamine use

Implicit and explicit timing in oculomotor control.

The passage of time can be estimated either explicitly, e.g. before leaving home in the morning, or implicitly, e.g. when catching a flying ball. In the present study, the latency of saccadic eye movements was used to evaluate differences between implicit and explicit timing. Humans were required to make a saccade between a central and a peripheral position on a computer screen. The delay between the extinction of a central target and the appearance of an eccentric target was the independent variable that could take one out of four different values (400, 900, 1400 or 1900 ms). In target trials, the delay period lasted for one of the four durations randomly. At the end of the delay, a saccade was initiated by the appearance of an eccentric target. Cue&target trials were similar to target trials but the duration of the delay was visually cued. In probe trials, the duration of the upcoming delay was cued, but there was no eccentric target and subjects had to internally generate a saccade at the estimated end of the delay. In target and cue&target trials, the mean and variance of latency distributions decreased as delay duration increased. In cue&target trials latencies were shorter. In probe trials, the variance increased with increasing delay duration and scalar variability was observed. The major differences in saccadic latency distributions were observed between visually-guided (target and cue&target trials) and internally-generated saccades (probe trials). In target and cue&target trials the timing of the response was implicit. In probe trials, the timing of the response was internally-generated and explicitly based on the duration of the visual cue. Scalar timing was observed only during probe trials. This study supports the hypothesis that there is no ubiquitous timing system in the brain but independent timing processes active depending on task demands

Short-term temporal memory in idiopathic and Parkin-associated Parkinson's disease.

In a rapidly changing environment, we often know when to do something before we have to do it. This preparation in the temporal domain is based on a 'perception' of elapsed time and short-term memory of previous stimulation in a similar context. These functions could be perturbed in Parkinson's disease. Therefore, we investigated their role in eye movement preparation in sporadic Parkinson's disease and in a very infrequent variant affecting the Parkin gene. We used a simple oculomotor task where subjects had to orient to a visual target and movement latency was measured. We found that in spite of an increased average reaction time, the influence of elapsed time on movement preparation was similar in controls and the two groups of PD patients. However, short-term temporal memory of previous stimulation was severely affected in sporadic PD patients either ON or OFF dopaminergic therapy. We conclude that the two different contributions to temporal preparation could be dissociated. Moreover, a short-term temporal memory deficit might underlie temporal cognition deficits previously observed in PD

Nmda antagonists for the treatment of mental disorders with occurrence of aggressive and/or impulsive behavior

The present invention relates to the use of N-Methyl-D-aspartate (NMDA) antagonists at sub-anesthetic doses for the treatment of mental disorders with occurrence of aggressive and/or impulsive behavior

Histograms of absolute saccadic latencies in <i>cue&target</i> trials.

<p>The ordinate represents the percentage of saccades in the 100-ms bins for each of the 4 delay durations independently. The abscissa represents the time elapsed until the appearance of the eccentric target (<i>vertical dashed lines</i>).</p

Comparison of variable and fixed foreperiods.

<p>Mean latency (±2 SE) as a function of delay duration in <i>target</i> trials. Variable foreperiod (<i>Variable</i>) and fixed foreperiod blocks of trials (<i>Fixed</i>). In the variable foreperiod condition, mean latencies were longer for 400 ms delay duration. An opposite trend was found in the fixed foreperiod condition. Group data from 6 subjects (6/9) who participated in this control experiment.</p

Summary of descriptive statistics.

<p>Group data of all subjects. <i>N</i>, sample size; <i>STD</i>, standard deviation, <i>CV</i>, coefficient of variation (STD/mean absolute latency); <i>(r)</i>, randomized durations blocks of trials, variable foreperiod; <i>(b)</i>, single duration blocks of trials, fixed foreperiod. <b>Bold type</b> is used to indicate trials collected in blocks with P(<i>probe</i>) = 0.5.</p

Histograms of saccadic absolute latencies in the <i>probe</i> trials.

<p>X-axis: saccadic absolute latencies; Y-axis: number of saccades in the 100-ms bins. Note the increasing spread of the latencies with increasing delay duration. Vertical dashed lines: time of target appearance in cue&target trials.</p