André Ferrara

Brain Activation Induced by Estimation of Duration: A PET Study

Duration information about a visual stimulus requires processing as do other visual features such as size or intensity. Using positron emission tomography, iterative H215O infusions, and statistical parametric mapping, we investigated the neural correlates of time processing. Nine normal subjects underwent six serial rCBF. Three tasks were studied: (a) A temporal generalization task (D task) in which the subjects had to judge (by pressing one of two keys) whether the duration of the illumination of a green LED was equal to or different from that of a previously presented standard; (b) An intensity generalization task (I task) in which the judgment concerned the intensity of the LED; and (c) A control task (C task) in which the subjects had to press one of the two keys at random in response to LED illumination. A significant increase in rCBF during the D task, compared to that during the C task, was observed in right prefontal cortex, right inferior parietal lobule, anterior cingulate cortex, vermis, and a region corresponding to the left fusiform gyrus. A significant increase in rCBF during the I task, compared to that during the C task, was observed in right prefontal cortex, right inferior parietal lobule, right extrastriate cortex, anterior cingulate cortex, left inferior parietal lobule, vermis, and two symmetrical regions corresponding to the fusiform gyri. No significant activation was observed in the D task when compared to that in the I task. We propose that these cortical maps are best explained by the recruitment of visual attention and memory structures, which play a major role in prospective time judgements as indicated by behavioral studies. The data also suggest that the temporal dimension of a visual stimulus is processed in the same areas as other visual attributes.

Stimulus spacing effects in temporal bisection by humans.

Two experiments with human subjects, using short-duration tones as stimuli to be judged, investigated the effect of the range of the stimulus set on temporal bisection performance. In Experiment 1, six groups of subjects were tested on a temporal bisection task, where each stimulus had to be classified as “short” or “long”. For three groups, the difference between the longest (L) and shortest (S) durations in the to-be-bisected stimulus set was kept constant at 400 msec, and the L / S ratio was varied over values of 5:1 and 2:1. For three other groups, the L/S ratio was kept constant at 4:1 but the L-S difference varied from 300 to 600 msec. The bisection point (the stimulus value resulting in 50% “long” responses) was located closer to the arithmetic mean of L and S than the geometric mean for all groups except that for which the L / S ratio was 2:1, in which case geometric mean bisection was found. In Experiment 2, stimuli were spaced between L and S either linearly or logarithmically, and the L / S ratio took values of either 2:1 or 19:1. Geometric mean bisection was found in both cases when the L / S ratio was 2:1, but effects of stimulus spacing were found only when the L / S ratio was 19:1. Overall, the results supported a previous conjecture that the L / S ratio used in a bisection task played a critical role in determining the behaviour obtained. A theoretical model of bisection advanced by Wearden (1991) dealt appropriately with bisection point shifts discussed above but encountered difficulties with stimulus spacing effects.

Subjective shortening in humans' memory for stimulus duration

Three experiments investigated memory for stimulus duration in humans using a modification of a delayed-matching technique previously used to study event memory in pigeons. In a session of 48 discrete trials subjects were presented with a sample stimulus (a 500-Hz tone with mean duration of 400 msec) then a comparison stimulus (the same duration as the sample, or longer or shorter), after a delay that was 1 to 10 sec in Experiments 1 and 2, and 2 to 16 sec in Experiment 3. After the comparison had been presented, subjects judged whether the sample and comparison had the same duration (a YES/NO decision, Experiment 1), or whether the comparison was longer, shorter, or of the same duration as the sample (Experiments 2 and 3). Overall, mean number of correct responses changed little with increases in the delay, but the change of number of correct responses with delay was markedly different on trials in which the sample and comparison were the same, the comparison was shorter, or the comparison was longer. In general, accuracy declined with increasing delay in the first case, remained constant in the second case, and increased when the comparison was longer than the sample. Examination of the types of errors made on the different sorts of trials (Experiment 3) suggested that the data were produced by two mechanisms: (1) subjective shortening of the sample as the delay between sample and comparison increased, and (2) a time-order error to respond that the sample was longer than the comparison. Overall, it appears that humans’ working memory for duration exhibits a subjective shortening effect similar to that previously found in pigeons.

The basic pattern of activation in motor and sensory temporal tasks: positron emission tomography data

Positron emission tomography (PET) data were obtained from subjects performing a synchronization task (target duration 2700 ms). A conjunction analysis was run to identify areas prominently activated both in this task and in a temporal generalization task (target duration 700 ms) used previously. The common pattern of activation included the right prefrontal, inferior parietal and anterior cingulate cortex, the left putamen and the left cerebellar hemisphere. These areas are assumed to play a major role in time processing, in relation to attention and memory mechanisms.

Changing Sensitivity to Duration in Human Scalar Timing: An Experiment, a Review, and Some Possible Explanations

Evidence from a number of studies of human timing, using temporal generalization and bisection tasks, suggests more sensitive behavioural adjustment to presented durations under conditions in which the timing task demands discriminations between more closely spaced stimuli. An experiment using temporal generalization demonstrated this effect, as discrimination between a 600-msec standard duration and non-standard stimuli both shorter and longer than 600 msec was better when non-standard stimuli were more closely spaced around 600 msec. A review showed similar effects in other temporal generalization tasks and in a number of bisection studies, where time discrimination improved as the ratio of the long and short standards on the bisection task decreased. A standard model of human temporal generalization explained the experimental data in terms of a decrease in the response threshold under more difficult conditions, rather than changes in the representation of the standard duration. On the other hand, data from bisection could be modelled by assuming the contrary; that representations of the short and long standards of the task were more precise under the more difficult conditions. Explanations of some of these effects in terms of attention to duration and/or arousal-induced changes in the speed of an internal clock were discussed.

Adjusting to changes in the time of reinforcement: peak-interval transitions in rats.

Thirty rats received training on a peak-interval procedure, where a baseline with a 20-s time of reinforcement was interspersed among cyclic transitions to other reinforcement time values (10, 20, 30, or 40 s), each of which was either in force for only a single session or for 3 sessions. Peak times were close to the time of reinforcement on the 20-s baseline and tracked the new reinforcement times both closely (but not exactly) and very rapidly. Peak time during transitions was affected by the criterion value in force on the previous session, exhibiting a proactive interference effect. Analysis of individual peak times during a session showed that transitions from lower to higher reinforcement time values were usually characterized by abrupt jumps in peak time, whereas descending transitions were mostly smooth but rapid.

The usefulness of operant conditioning procedures to assess long-lasting deficits following transient focal ischemia in mice.

In this study, we examined a number of short and long-term sensorimotor, behavioural and cognitive consequences of an experimental ischemia induced by a 60-min right middle cerebral artery occlusion (MCAO) in 129S2 mice. During 14 days after surgery, a classical sensorimotor assessment was conducted using hanging wire test, negative geotaxis test, grip strength test, accelerated rotarod test and locomotor activity-meter. In order to provide a technique for the assessment of more resistant consequences of ischemia on fine psychomotor control, the peak procedure (a modified version of the operant fixed-interval schedule of reinforcement) was used. This procedure also helped to objectify temporal perception in mice five weeks following surgery. On several sensorimotor tests, ischemic mice showed some degree of impairment which rapidly tended to improve after stroke, a profile of results substantially consistent with previous studies. Five weeks post-surgery, ischemic mice tested with the peak procedure exhibited a moderate but yet significant temporal regulation impairment along with a reduced response rate compared to control mice. The present results suggest that the peak procedure and other derived operant schedules of reinforcement may provide useful and sensitive tools for the long-term assessment of both behavioural and cognitive aspects of the consequences of an experimental ischemia.

Assessment of behavioral flexibility after middle cerebral artery occlusion in mice.

Middle cerebral artery occlusion (MCAO) is the most common animal model of cerebral ischemia and induces various functional impairments. Long-lasting deficits resulting from MCAO however, remain insufficiently characterized, especially regarding cognition. Yet, behavioral flexibility, a prominent cognitive process is found impaired after stroke in humans. We thus used an operant-based task to assess behavioral flexibility in mice after MCAO. Three weeks after 30 min MCAO surgery, mice were subjected to a battery of sensorimotor tests (rotarod, vertical pole test, spontaneous locomotion and grip-strength test). Behavioral flexibility was then assessed in an operant task, in which mice, rewarded according to a FR5 schedule of reinforcement, had to alternate their operant responses between two levers from trial to trial. Regarding sensory and motor functioning, only the pole test yielded a significant difference between MCAO and sham mice. In the operant flexibility task, results showed a behavioral flexibility deficit in MCAO mice; neither the operant response acquisition nor the appeal for food rewards was altered. In conclusion, our operant-based task revealed a long-lasting behavioral flexibility deficit after MCAO in mice.

Do excitatory and inhibitory conditioning processes underlie psychomotor sensitization to amphetamine? An analysis using simple and multiple regressions

Excitatory or inhibitory conditioning processes have been proposed to account for the context-dependent establishment of amphetamine psychomotor sensitization in rodents. The purpose of this study was to test the predictions of these theories in mice. We first assessed the consequence of the extinction of post-sensitization conditioned activity (CR) on the ulterior expression of sensitization. We also assessed the relations between several measures of sensitization and conditioned hyperactivity revealed on a saline challenge using simple and multiple regression analyses. Context-dependent sensitization was induced via 7 amphetamine injections in the test context given alternately with 7 saline injections in another context in paired mice, unpaired mice receiving the converse pretreatment. Context-dependent sensitization (drug challenge) and the CR (saline challenge) were revealed subsequently. After CR extinction (over 7 every-other-day repetition of the saline challenge), mice were tested again for context-dependent sensitization. Against the excitatory conditioning model, CR extinction spared context-dependent sensitization in paired mice, and regression analyses revealed no significant correlations between the size of the CR and several measures of sensitization. In apparent agreement with the inhibitory conditioning model, unpaired mice expressed higher levels of sensitization in the test context after extinction than before. However, regression analyses did not indicate that activity on the saline challenge was related to measures of sensitization in unpaired mice. Therefore, the present results support neither the excitatory nor the inhibitory conditioning models of context-dependent sensitization, but remain compatible with theories proposing that other inhibitory mechanisms modulate sensitization.

Procedural learning as a measure of functional impairment in a mouse model of ischemic stroke

Basal ganglia stroke is often associated with functional deficits in patients, including difficulties to learn and execute new motor skills (procedural learning). To measure procedural learning in a murine model of stroke (30min right MCAO), we submitted C57Bl/6J mice to various sensorimotor tests, then to an operant procedure (Serial Order Learning) specifically assessing the ability to learn a simple motor sequence. Results showed that MCAO affected the performance in some of the sensorimotor tests (accelerated rotating rod and amphetamine rotation test) and the way animals learned a motor sequence. The later finding seems to be caused by difficulties regarding the chunking of operant actions into a coherent motor sequence; the appeal for food rewards and ability to press levers appeared unaffected by MCAO. We conclude that assessment of motor learning in rodent models of stroke might improve the translational value of such models.