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Neuronal activity preceding directional and nondirectional cues in the premotor cortex of rhesus monkeys.

Pre-cue activity, the neuronal modulation that precedes a predictable stimulus, was studied in the premotor cortex of three rhesus monkeys. In one condition, a directional cue dictated the timing and target of a forelimb movement. In another condition, a nondirectional cue provided identical timing information but did not indicate the target. Of 501 task-related neurons recorded in premotor cortex, 168 showed pre-cue activity. The onset time of pre-cue activity varied markedly from trial to trial and cell to cell, ranging from trial initiation to 4.8 sec later. No pre-cue activity reflected the direction of limb movement; thus, the data argue against the hypothesis that pre-cue activity reflects preparation for specific limb movements. A small number of cells showed greater pre-cue activity before directional than before nondirectional cues, and this difference may reflect anticipation of the cue's directional information. However, the vast majority (84%) of neurons lacked such differences. We therefore hypothesize that most pre-cue activity reflects or contributes to a facet of behavior common to the two conditions: anticipation of the time and/or nature of events.

Animals

Perceptual equivalence of acoustic cues that differentiate /r/ and /l/.

The perceptual effects of orthogonal variations in two acoustic parameters which differentiate American English prevocalic /r/ and /l/ were examined. A spectral cue (frequency onset and transition of F2 and F3) and a temporal cue (relative duration of initial steady state and transition of F1) were varied in synthetic versions of "rock" and "lock." Four temporal variations in each of ten stimuli of a spectral-cue continuum were generated. Phonetic identification and oddity discrimination tasks with the four series showed systematic displacement of perceptual boundaries and discrimination peaks, thus reflecting a trading relation between the two cues. The perceptual equivalence of spectral and temporal cues was investigated by comparing the accuracy of discrimination of three types of stimulus comparisons: phonetically facilitating two-cue pairs, one-cue pairs, and phonetically conflicting two-cue pairs. As predicted, discrimination accuracy was ordered: Facilitating cues greater than one-cue greater than conflicting cues, indicating that perceivers discriminated on the basis of an integrated phonetic percept.

Acoustic Stimulation

Function of dog's auditory cortex in tests involving auditory location cues and directional instrumental response.

Twenty one dogs, distributed into four groups, were trained pre-operatively in differentiation of auditory location or frequency cues. In each group instrumental responses, reinforced by food consisted in placing by the animal its right paw on the side levers. The first differentiation, go-left, go-right task with two location cues, required the animal to place its paw on the lever opposite to the source of the cue. The second differentiation task with the same location cues required placing the paw on the lever located close to the cue. The third task, involving 700 Hz vs. 1,000 Hz tone, required responding to one lever to the presentation of one tone and responding to the opposite lever to the presentation of the other. The last task was a symmetrically reinforced go, no-go differentiation with, again, auditory location cues: the animals were trained to place the paw on a lever to one location cue and to withhold this response to the other location cue. Bilateral ablation of the primary auditory cortex produced a considerable impairment of the performance of the two go-left, go-right tasks involving location cues. The go-left, go-right task employing frequency cues, and the symmetrically reinforced go, no-go task with location cues, were only slightly disturbed by this lesion.

Animals

Antagonism of the amphetamine cue by both classical and atypical antipsychotic drugs.

Rats were trained to discriminate the stimulus properties of 1 mg/kg of d-amphetamine sulphate (AMPH) from saline in a two-lever task in which correct responding was reinforced with water under a fixed ratio (FR 32) schedule. Classical antipsychotic drugs from different chemical classes were all able to block the AMPH cue. Doses (mg/kg) inhibiting the cueing effect to 50% (ID50) were 0.035 (haloperidol), 0.04 (spiroperidol), 0.09 (cis(Z)-flupenthixol), 0.12 (trifluperazine), 0.15 (perphenazine), 0.92 (chlorpromazine) and 1.40 (pimozide). The AMPH cue was also antagonized by antipsychotic drugs that are considered atypical due to their relative lack of activity in conventional animal models or inability to produce extrapyramidal symptoms in the clinic. The following ID50 values were obtained: 0.88 (molindone), 1.22 (clozapine), 5.48 (metoclopramide), 15.4 (thioridazine) and 52.8 [-)-sulpiride). In addition, the AMPH cue was blocked by the D-1 selective dopamine (DA) antagonist, SCH 23390 (ID50 = 0.014 mg/kg). The abilities of these drugs to block the AMPH cue were unrelated to the drugs' effect upon the rate of responding. For example, some drugs (e.g. haloperidol, spiroperidol and SCH 23390) blocked the AMPH cue completely without any effect on the response rate. Furthermore, the non-antipsychotic phenothiazine, promethazine (2.5-12.5 mg/kg) failed to affect the AMPH cue although the drug strongly suppressed the response rate. However, the potent DA agonists, apomorphine (0.05-0.33 mg/kg) and lisuride (0.02-0.08 mg/kg), and the DA and norepinephrine agonist, DPI (0.4 and 0.8 mg/kg), did not mimic the AMPH cue or did so only partially. These results suggest that the 1 mg/kg AMPH cue depends on (DA) systems other than those involved in the stereotyped motor behavior commonly produced by high doses of AMPH or DA agonists. Low-dose AMPH discrimination may thus serve as a new model for studying antipsychotic drug action.

Animals

Effect of external cues for pedal pacing on breathing pattern during cycle exercise.

Fourteen subjects performed cycle exercise at work loads of 0 and 1 kp, each for 3 min, during which the pedal rate was kept constant by various external cues. Six cues were used in order: no cue (N1), a speedometer dial (S), a flashing light (F), a verbal command (V), a metronome sound (M) and no cue, again (N2). An attempt was to study the effect of these cues on breathing pattern in a lower tidel volume (VT) range during exercise, actually VT increasing to 2 times the resting levels. In N1 and N2, exercise was performed at preferred pedal rates, which were 40 +/- 4 (mean +/- S.E.)rpm and 52 +/- 2 rpm, respectively. Pedaling to other four cues was kept at 50 rpm. Ventilatory responses during exercise were similar in all conditions of cue except N1. Increases in respiratory frequency (f) during exercise were similar in S but greater in F at 0-kp load and in V and M at 1-kp load, compared with N2. The greater increases in f in F, V and M were due to greater shortening in inspiratory (T1) and expiratory (TE) durations. In any conditions of cue, T1 and TE decreased with increasing VT in response to exercise. The present study indicates that (1) breathing pattern during rhythmic exercise is affected by external rhythmic stimuli like F, V and M, and (2) there is no such a VT range that TI and TE remain constant in the VT-TI and VT-TE relations during exercise. cycle exercise: rhythmic cue during exercise; breathing pattern.

Adult

Development of knowledge about the use of cues to aid prospective retrieval.

Retrieval cues can be used to help one remember to perform tasks in the future and to relocate objects in the environment. However, in both tasks there are requirements for a retrieval cue to be effective as a mnemonic aid. For example, the cue must be associated with the target item, but it must not be ambiguous, and it must be appropriately placed. 2 studies assessed children's ability to evaluate the communicative quality of retrieval cues. In Study 1, 5-9-year-old children and adults evaluated the potential effectiveness of cues to remind themselves. In Study 2, 4-9-year-olds evaluated the potential effectiveness of cues for relocating hidden objects. Patterns of results were similar in both studies: young children first learned that the retrieval cue should be associated with the target and should be encountered for retrieval to occur. However, children often overlooked problems with the potential informativeness of the cues, such as ambiguity, and did not anticipate that such cues might be misinterpreted in the future. Children's difficulty in estimating their information needs may be related to their difficulty in monitoring their current comprehension state.

Adult

The involvement of the nucleus accumbens in the ability of rats to switch to cue-directed behaviours.

Previous studies have shown that the dorsal striatum is involved in switching arbitrarily behaviour (switching to non cue-directed behaviours). These experiments also revealed that switching behaviour with the help of currently available sensory information (switching to cue-directed behaviours) was not influenced when striatal function was blocked. A number of studies suggested that the nucleus accumbens could mediate the latter type of switching. For testing this hypothesis we used the swimming-test as it allows for studying separately both cue-directed and non cue-directed behaviours. Rats with cannulae aimed at the nucleus accumbens were forced to swim after injection of distilled water (AD) or d-amphetamine (1-10 micrograms/0.5 microliter) in a circular water-tank from which there was no escape. Their behaviour was recorded and analysed according to the presence of cue-directed and non cue-directed behaviours. After six minutes a rope was introduced into the water-tank to determine whether the rats were able to change their behaviour with the help of this external stimulus as well. Rats treated with d-amphetamine showed an enhanced ability to switch to cue-directed behaviours in comparison with rats treated with AD. There was no effect on the ability to switch to non cue-directed behaviours. Furthermore there was a dose-dependent increase in the ability to escape along the rope. The results are taken as evidence that the nucleus accumbens is involved in switching to cue-directed behaviours.

Amphetamine

Pioneer growth cone steering along a series of neuronal and non-neuronal cues of different affinities.

We have analyzed the morphology of over 5000 Ti1 pioneer growth cones labeled with anti-HRP, which reveals the disposition of axons, growth cone branches, and filopodia. Ti1 axon pathways typically consist of a sequence of 7 characteristically oriented segments, with a single, distinct reorientation point between each segment. Growth cones exhibit the same orientations and reorientations in a given region as do axon segments at later stages. The single, distinct reorientations suggest that growth cones make discrete switches between guidance cues as they grow. Ti1 growth cones are guided by various types of cues. A set of 3 immature identified neurons serves as nonadjacent guidepost cells and lies at the proximal end of 3 of the axon segments. To form another segment, growth cones reorient along a limb segment boundary within the epithelium. Growth cones also respond consistently to, and orient toward, a specific mesodermal cell, which may be a muscle pioneer. Thus, growth cones respond to at least 3 different types of cells in the leg. Ti1 growth cones exhibit a hierarchy of affinity for these cues. Guidepost neurons are the dominant cues in that contact with them reorients growth cones from guidance by the other types of cues. Growth cone branches are exclusively oriented to specific cues. Growth cones reorient by extending a branch directly to the cue of highest affinity and by withdrawing any branches that are extended to a cue of lesser affinity. A single filopodium in direct contact with a guidepost neuron can reorient a growth cone that still has multiple filopodia or even prominent branches specifically oriented to a previous cue of lesser affinity. These observations suggest that growth cone steering may not result simply from passive adhesion and filopodial traction, but may involve more active processes.

Axons

The effects of scopolamine and cues to forget on pigeons' memory for time.

Pigeons were trained with a 0-s delayed symbolic matching-to-sample procedure to indicate whether a houselight sample stimulus was short (2 s) or long (8 s) by pecking a red or a green comparison stimulus. In Experiment 1, the pigeons received injections of scopolamine hydrobromide (0.015 mg/kg), or saline, and the delay interval was manipulated (0, 1, 3, and 9 s). Memory for time was significantly poorer following scopolamine injections than following saline injections. A significant choose-short bias was observed under scopolamine at delays as brief as 3 s, but not under saline. In Experiment 2, a brief postsample cue (a vertical or horizontal line) signaled whether the comparison stimuli would be presented or omitted on each trial. During training, comparison stimuli were always presented following the remember (R) cue, but never following the forget (F) cue. During testing, memory for time was significantly poorer on F-cue trials than on R-cue trials. A significant choose-short bias was observed on F-cue trials at the 5- and 10-s delays, but not on R-cue trials. The results suggest that anticholinergic blockade accelerates the rate at which memory for temporal events is foreshortened in working memory. This effect is similar to that produced by an explicit cue to forget the temporal sample.

Animals

Age differences in using source-relevant cues.

Subjects heard words originating from 2 speakers and later decided which of the 2 speakers said the words. Older adults had difficulty with source monitoring when perceptual cues from 2 sources were similar (2 female speakers), but this difficulty was overcome when perceptual cues were distinctive (a male and a female speaker) and were the only salient cues to source. Older adults also benefited from distinctive spatial cues when these were the only salient cues to source. Older adults, however, experienced difficulties in using multiple cues (both perceptual and spatial) to source effectively, whereas younger adults were able to use multiple cues to enhance their source-monitoring performance. It is suggested that age differences in source monitoring result from differential cue utilization.

Adult

[Facilitating and inhibiting effects of the orientation of attention using peripheral cues].

The attentional field resulting from the presentation of peripheral cues; which were either informative or non informative about the position of the imperative stimulus, was studied. Different time intervals between cue and stimulus (120, 300, 600 ms) were used. The results showed facilitation of the response with the informative cue and inhibition with the non informative cue. This happened for the longest cue-stimulus intervals and when the position of the cue and the position of the stimulus were congruent. Also order of cue presentation (i.e., either informative followed by the non informative cue or vice versa) proved important in producing facilitatory and inhibitory effects.

Attention

Differential effects of cholinergic drugs on discriminative cues and self-stimulation produced by electrical stimulation of the ventral tegmental area.

Cholinergic receptors have been shown to modulate a subset of discriminative cues produced by electrical stimulation of the ventral tegmental area (VTA) in rats. The present study identified the specific cholinergic receptor type modulating these electrical brain-stimulation (EBS) cues, and assessed whether these receptors also mediated the rewarding effects of VTA EBS. The EBS cues were enhanced by the acetylcholinesterase inhibitor physostigmine and the muscarinic receptor agonists pilocarpine and RS-86, whereas the nicotinic receptor agonist nicotine had no effect. The enhancing effects of pilocarpine or RS-86 were attenuated by the muscarinic antagonist scopolamine. The EBS cues were not affected when scopolamine was injected alone, although high doses disrupted discriminated responses. Intracranial self-stimulation (ICSS) rates were depressed by physostigmine and pilocarpine and increased by nicotine and scopolamine. These results indicated a facilitatory influence of muscarinic receptors on the EBS cues, and an inhibitory role in VTA ICSS. Nicotinic receptor activation did not affect the EBS cues, but facilitated ICSS. These differential effects of cholinergic receptor activation point to a dissociation of the specific EBS cues measured in this study from the rewarding effects of VTA stimulation.

Animals

The effects of smoking-related sensory cues on psychological stress.

Previous studies have shown that the sensory cues of cigarette smoking are important for smoking satisfaction and craving reduction. Sensory cues in the absence of pharmacological doses of nicotine have been found to be moderately satisfying and to reduce craving. The current study was conducted to determine if administration of the sensory cues of cigarette smoking with minimal nicotine would also provide relief from mild anxiety associated with anticipation of a difficult anagram test. This test has previously been shown to be sensitive to the anxiety relieving effects of cigarette smoking. Compared to the placebo control condition, the sensory condition caused a significant alleviation of the stress as measured by components of the Spielberger scale for anxiety. The addition of cigarette smoke containing 0.5 mg of nicotine to the sensory cues caused a slight though nonsignificant enhancement of the stress alleviation. These results demonstrate that sensory cues of smoking can provide similar effects as nicotine containing cigarettes with regard to stress alleviation. Previous studies had shown that sensory cues are important for the consumptive aspects of smoking (i.e., smoking satisfaction and craving reduction). The current study shows that sensory cues are important for other effects of smoking as well.

Adolescent

What is presented, and what prevented, in cue exposure and response prevention with alcohol dependent subjects?

The following questions, pertaining to cue reactivity in alcoholics, are discussed: (a) What cues are relevant to alcoholics' drinking? Previous research has been concerned with the obvious: bottles, glasses, pub/bar environments, and other visual cues. Presumably more potent cues, that is, smell, taste and internal effects, subtle stimuli like social climate, shifts in conversations, also influence drinking. The effects of mood states on alcoholics' urges and behavior are rarely integrated into experimental studies. (b) What is the CR? Given that drinking is a very complex social behavior, "the drug effect" becomes problematic to disentangle from the effects of other factors, such as bio-medical states, social setting and learning history. This is further complicated by the fact that drugs affect physiological and cognitive systems differently at different dose levels and with rising and falling Blood Alcohol Levels. Moreover, it has been found that alcohol cues may elicit responses that are in the same and in the opposite direction to the drug response. (c) If such responses are reliably tied to alcohol cues (as opposed to novelty of the experimental situation), the impact of the conditioned responses on craving for alcohol and relapse becomes an issue. (d) Another question relates to the analogy between fear in phobias and craving in substance abuse since, unlike phobics, substance abusers do not fear the substance they are responding to. (e) A further issue is the effectiveness of extinction procedures, as opposed to changes in efficacy expectations, as a therapeutic mechanism for the cue exposure paradigm. Examples of recent research at the Hjellestad Clinic are presented.

Alcohol Drinking

Cue exposure and relapse prevention in the treatment of addictive behaviors.

Cue exposure techniques have been increasingly applied in the treatment of addictive behaviors. The role of cue exposure in a comprehensive approach to relapse prevention is considered from several theoretical perspectives. Issues discussed include the optimal definition of both cue and response variables in cue exposure, the relation between exposure to drug-taking cues and elicitation of outcome expectancies, and the combination of extinction-based cue exposure methods and skill training in relapse prevention programs. Whether cue exposure effects are mediated by extinction of appetitive craving responses and/or by the modification of efficacy and outcome expectancies is discussed.

Adaptation, Psychological

Ontogeny of spatial navigation behaviors in the rat: dissociation of "proximal"- and "distal"-cue-based behaviors.

Rats can use both "proximal" and "distal" cues to locate goal objects in their environments (Morris, 1981). In the proximal-cue situation, local stimuli that spatially co-occur with the goal are available to guide behavior. In the distal-cue situation, there are no cues that co-occur with the goal object; thus to directly locate the goal, the rat must learn about the spatial location of the goal relative to distal cues. Using the Morris water maze, we found that these two navigation behaviors are dissociated during ontogeny. Rats only 17-days-old are capable of using proximal cues to locate a safe platform. It was not until the rats were 20-days-old, however, that they began to display minimal evidence of distal-cue utilization. Control experiments indicated that the 17-day-old subjects' failure on the distal problem was likely due to their inadequate spatial learning skills. These results were interpreted within a Jacksonian perspective of brain-behavior relations.

Aging

Relative effectiveness of central, peripheral, and abrupt-onset cues in visual attention.

The relative effectiveness of central arrow, peripheral arrow, and abrupt-onset cues was assessed in a character recognition task. On each trial, either a central or a peripheral arrow cue was presented 0, 100, or 200 msec before the appearance of a three-digit display. Two of the digits were "uncamouflaged" from previous figure-eight masks, whereas the third digit appeared abruptly in a previously empty space. Four different groups of subjects were run in factorial combinations of high or low expected validities for arrow and onset cues. In Experiment 1, arrow cues were located centrally, near the fixation point. Abrupt onsets showed larger cost-plus benefits than central arrows, except when subjects expected the central cues to have higher validity than the onsets. In Experiment 2, arrow cues were located peripherally, near the display digits, and abrupt onsets were again more effective in capturing attention except when peripheral cues had higher validity and led the onsets by 100 msec or more. In both experiments, the relative effectiveness of abrupt onsets decreased with arrow SOA. The results were consistent with a model in which automatic and voluntary processes interact in their control of attentional resources.

Adolescent

The cue-responsivity phenomenon in dependent drinkers: 'personality' vulnerability and anxiety as intervening variables.

The cue-responsivity phenomenon to alcohol-associated stimuli in dependent drinkers was examined. In accordance with previous research, significant differences on both physiological and subjective cue-responsivity variables, between dependent and non-dependent drinkers were found. The unique contribution of this paper is two-fold. Firstly, evidence is presented which suggests that the Eysenckian personality traits of introversion and neuroticism are more predictive of cue-responsivity variance in the dependent drinkers than either severity of dependence or number of years' drinking. Secondly, within this dependent group, the relationship between cue-responsivity and 'craving' was seen to be less straightforward than traditionally thought. Specifically, it suggested that it was the extent to which autonomic cue-responsivity elicited increases in self-reported anxiety, which predicted most of the variance on the 'craving' variable. Taken together, these results raise the interesting possibility that a personality disposition akin to trait anxiety, and the degree to which cue exposure elicits state anxiety, mediated the relationship between cue-responsivity and 'craving' in dependent drinkers.

Adult