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Anticipatory symptoms and anticipatory immune responses in pediatric cancer patients receiving chemotherapy: features of a classically conditioned response?

UNLABELLED: There is considerable evidence from studies in adult patients that classical conditioning contributes to anticipatory nausea and/or vomiting (ANV) in cancer chemotherapy: The stimuli predicting the infusion serve as conditioned stimuli (CS). When reexposed to the CS, some patients experience ANV prior to infusion onset. In adult patients, anticipatory immunomodulation (AIM) has also been observed. The present study examines whether ANV and AIM occur in pediatric cancer patients and whether they show features of a conditioned response. METHODS: Nineteen pediatric cancer patients (M = 10.1 years, > 2 previous chemotherapies) were studied over two consecutive cycles (A, B). In both cycles, self-reported symptoms, for example nausea and vomiting, were recorded from two days prior to the onset (Day -2), during infusion, and two days after the end of the infusion (Day +2). In Cycle B, blood was drawn at home at Day -2, and at Day 0 in the hospital prior to infusion onset, thus using a quasi-experimental variation of the CS content of the environment. Immune parameters valid for tumor defense and cytotoxic competence (natural killer cell activity [NKCA], plasma interleukin [IL]-1beta, IL-2, IL-10, interferon [IFN]-gamma, tumor necrosis factor [TNF]-alpha) and cortisol were measured. RESULTS: ANV was reported by 7 patients in at least one cycle. In Cycle A, ANV was positively associated with emetogenity of chemotherapy. Features of ANV-duration and occurrence-tended to be positively associated with those of posttreatment nausea and vomiting. AN increased as infusion onset time approached. NKCA and IFN-gamma increased from home to hospital, independent from cortisol level. The NKCA increase was predominantly observed in patients with ANV. CONCLUSIONS: ANV in pediatric patients showed features of a CR. Immune parameters were sensitive to the CS content of the environment, predominantly in patients with ANV. This is consistent with the manifestation of multiple CRs.

Adolescent↗

Cellular correlates of classical conditioning in identified light responsive pedal neurons of Hermissenda crassicornis.

Cellular correlates of classical conditioning were examined in two recently identified light responsive pedal neurons. The correlates of conditioning consisted of significant decreases in the pedal cells' responses to light (conditioned stimulus) recorded from conditioned animals compared to random controls. Pedal cell P7, which exhibits an inhibitory response to light in naive animals, showed significantly less inhibition during a 5 min light step in conditioned animals as compared to random controls. Pedal neuron P9, which exhibits an excitatory response to light in naive animals, showed significantly less excitation during a 10 s light step in conditioned animals as compared to random controls. The changes in the response to light recorded from pedal neurons P7 and P9 in conditioned animals were not accompanied by any significant changes in membrane potential, action potential amplitude or dark-adapted spike frequency.

Animals↗

Effects of LSD on classical conditioning as a function of CS-UCS interval: relationship to reflex facilitation.

Classical conditioning of the rabbit nictitating membrane response was accomplished by presenting a 100-msec tone CS at intervals 0, 100, 200, 400 and 800 msec before the presentation of a 100-msec shock UCS. In addition, tone-alone trials were used to monitor CR acquisition and shock-alone trials to measure facilitation of the nictitating membrane reflex by the tone CS at the various CS-UCS intervals. LSD at a dose of 13 micrograms/kg (30 nmol/kg) increased the excitatory effects of the shock UCS as measured by a greater frequency and amplitude of UCRs elicited across a wide range of UCS intensities and by the ability of a low intensity shock to produce reflex facilitation. Consequently, LSD produced a higher amplitude of UCRs on UCS-alone trials and on paired trials across all CS-UCS intervals during measurement of tone-induced reflex facilitation. LSD also enhanced CR acquisition across all CS-UCS intervals. Because LSD produced larger amplitude reference UCRs on the UCS-alone trials as compared with controls, calculations of reflex facilitation as a percentage change from these reference amplitudes led to an artifactually smaller effect for the LSD group as compared with controls. Nevertheless, both reflex facilitation as measured prior to CR acquisition on the first day of conditioning and CR acquisition across 10 conditioning sessions were a function of CS-UCS intervals and these two measures were highly correlated in the LSD (+0.94) and vehicle control (+0.85) groups. It was concluded that LSD enhances CR acquisition by enhancing the excitatory effects of both the CS and UCS and thus increasing their ability to enter into associative learning.

Animals↗

Classical conditioning of the flexion reflex in spinal cat: features of the reflex circuitry.

Classically conditioned facilitation of the flexor withdrawal reflex of spinal cat occurs in knee and ankle flexor muscles but not in a flexor muscle of the toes. Furthermore, the spinal circuitry activated by a component of the conditioned stimulus (A alpha cutaneous fibers) is not by itself involved in the reflex conditioning. The results suggest that increases in both cutaneous afferent output and motoneuron excitability may be eliminated as mechanisms contributing to conditioning and point to certain interneuronal pools as the locus of learning in this preparation.

Animals↗

Effects of drug-induced changes in resting blood pressure on classically conditioned heart rate and blood pressure in restrained rats.

Subsequent to receiving aversive classical conditioning, which led to a decelerative heart rate (HR) conditioned response (CR) and a pressor-depressor blood pressure (BP) CR, three separate groups of restrained rats received intravenous infusion of sodium nitroprusside (40 micrograms/mg/min) to lower baseline BP, phenylephrine (17 micrograms/mg/min) to raise baseline BP, or an equivalent volume of saline. Conditioning test trials during infusion revealed that hypotension produced by sodium nitroprusside eliminated the HR CR and transformed the BP CR into a pressor-only reaction. Hypertension produced by phenylephrine facilitated the HR CR and changed the BP CR to a pressor-only response on selected trials in which baseline BP increases and baseline HR decreases were within restricted limits. Following drug withdrawal, the HR CRs of both drug groups and the BP CR of the phenylephrine group were attenuated. The unconditioned responses to the shock unconditioned stimulus under phenylephrine were exaggerated and consisted of tachycardias and depressor BP changes, whereas under sodium nitroprusside reduced tachycardias and depressor activity occurred. The results suggested that the loss of the vagally mediated HR CR under sodium nitroprusside was due to baroreceptor-controlled inhibition of vagal discharge and that the enhancement of the HR CR under phenylephrine was due to baroreceptor-influenced facilitation of vagal discharge.

Animals↗

Classically conditioned changes of blood glucose level.

This paper reviews the literature dealing with classically conditioned changes of blood glucose level. When conditioning procedures are employed, the repeated administration of large amounts of insulin, or of glucose, leads to a conditioned decrease of blood glucose whereas the repeated administration of smaller amounts of insulin leads to a conditioned increase of glucose. These responses are interpreted as instances of reflex compensation by the central nervous system for rapid alterations of glucose availability. Instances of more naturally occurring changes of glucose levels, which appear to be under the control of the nervous system and to be conditionable, are also discussed. A model that accounts for the observed responses has been formulated and is presented.

Animals↗

Autonomic classical conditioning as a function of awareness of stimulus contingencies.

Two groups of 32 college students were presented compound CSs (lights and tones presented simultaneously) during a classical conditioning paradigm. By means of a masking task and verbal instructions, a partially informed group was made aware of only the visual CS's contingency with the UCS, while a fully informed group was made aware of both the visual and auditory contingencies. Autonomic indices of conditioning (electrodermal responses, heart rate, and digital pulse volume) were later measured to the individual component CSs and to various compound CSs. It was found that: (1) the partially informed group exhibited conditioning exclusively to the visual CS+ and to compounds which included the visual CS+, while (2) the fully informed group exhibited conditioning to both visual and auditory CS+s. The results confirm the importance of awareness in human autonomic discrimination classical conditioning. It is suggested that human autonomic conditioning may be usefully conceptualized as an information processing task with the autonomic indices of conditioning reflecting central cognitive processes.

Acoustic Stimulation↗

[Is there a feature-positive effect in classical conditioning in humans?].

Jenkins and Sainsbury (1969, 1979) first described an asymmetry in pigeon's operant discrimination learning which they called a feature-positive effect. Subsequent studies demonstrated that other animals as well as humans also show a similar asymmetry. The effect is often explained as being caused by a bias in information processing which results from the neglect of negative information as a discriminative cue. The effect has also been observed in classical conditioning experiments, but not yet with human subjects. Sometimes, however, a reversal of the asymmetry, i.e., a feature-negative effect, has been observed. The experiment reported here primarily intended to demonstrate a feature-positive effect in a classical conditioning procedure with human subjects. Secondly, we also wanted to test an alternative explanation of the feature-positive effect. We found that a substantial feature-positive effect does indeed occur during classical conditioning in human subjects. Our results, however, did not fully support the alternative explanation based on rule learning.

Adult↗

Eyeblink classical conditioning in H.M.: delay and trace paradigms.

H.M., a well-known subject with bilateral removal of medial-temporal-lobe structures and profound amnesia, performed eyeblink classical conditioning (EBCC) for 21 90-trial sessions in the 400-ms delay and 900-ms trace paradigms. A 2nd amnesic subject with temporal lobe lesions and 2 normal control subjects (NCSs) were also conditioned. Acquisition occurred in both paradigms for all subjects. Acquisition in the delay paradigm was prolonged in H.M. (perhaps because of his cerebellar degeneration in the vermis and hemispheres), but not in the 2nd amnesic subject. Amnesic subjects and NCSs showed more rapid acquisition in the trace than in the delay paradigm. Two years after initial EBCC, H.M. attained learning criterion in the trace paradigm in 1/10th as many trials. No recollection of the experimenters, apparatus, instructions, or procedure was manifested by H.M. Results suggest that humans can condition in the 400-ms delay and 900-ms trace EBCC paradigms with the hippocampus radically excised.

Aged↗

Neuronal unit activity in the abducens nucleus during classical conditioning of the nictitating membrane response in the rabbit (Oryctolagus cuniculus).

Neuronal unit activity was recorded from the abducens (6th nerve) nucleus, the "final common path," during classical conditioning of the nictitating membrane (NM) response in the rabbit, with the use of a tone conditioned stimulus, an air puff unconditioned stimulus (UCS), 250-msec interstimulus interval, and 60-sec intertrial interval. Animals were given 2 days of conditioning training (104 trials in eight blocks per day) and 1 day of extinction. Control animals were given comparable periods of stimulus presentations, explicitly unpaired. Activity of small clusters of units--"multiple unit" recording--was compared with the amplitude-time course of the NM response. Between-blocks comparisons of neural and behavioral responses indicated an essentially perfect correlation during acquisition of the conditioned response (Day 1, r = .99; Day 2, r = .98) and a slightly lower correlation during extinction (r = .93) for the conditioning animals. Within-blocks comparisons indicated a close correspondence between the histograms of unit activity and the amplitude-time course of the NM response for the conditioning animals in all phase of training and for the control animals in the UCS trial blocks.

Abducens Nerve↗

Classical conditioning of activities of salivary neurones in the cockroach.

Secretion of saliva to aid swallowing and digestion is a basic physiological function found in many vertebrates and invertebrates. For mammals, classical conditioning of salivation in dogs was reported by Pavlov a century ago. However, conditioning of salivation or of related neural activities in non-mammalian species has not been reported. In many species of insects, salivation is regulated by salivary neurones. In this study, we found that salivary neurones of the cockroach Periplaneta americana exhibited a strong response to sucrose solution applied to the mouth and a weak response to odours applied to an antenna, and we studied the effect of conditioning on the activities of salivary neurones. After three sets of differential conditioning trials in which an odour was presented just before the presentation of sucrose solution and the other odour was presented alone, the response of salivary neurones to sucrose-associated odour significantly increased but that to the odour presented alone was unchanged. Backward pairing trials in which an odour was presented after the presentation of sucrose solution were not effective in achieving conditioning. Our study of the change in the level of saliva secretion in response to electrical stimulation of salivary neurones suggested that the magnitude of increase in odour response of salivary neurones by conditioning is sufficient to lead to an increased level of salivation. This study suggests classical conditioning of salivation in an insect.

Animals↗

Red nucleus lesions impair acquisition of the classically conditioned nictitating membrane response but not eye-to-eye savings or unconditioned response amplitude.

Following a single electrocoagulating RF lesion aimed at left red nucleus, rabbits received classical conditioning of the nictitating membrane (NM) response. A tone was the conditioned stimulus (CS) and electrostimulation of the eye was the unconditioned stimulus (US). The US was applied to the right eye during the initial phase of training. It was then switched to the left eye to assess transfer of learning and ultimately switched back to the right eye. NM responses were recorded simultaneously from both eyes during each phase of training. Consistent with reports implicating a cerebellar-rubro circuit in this behavior, RN lesions disrupted acquisition of CRs in the eye contralateral to the lesion. Animals with disrupted NM CRs of the right eye resembled controls in showing transfer of conditioning to the left eye. CR-disrupting lesions did not affect UR amplitude.

Animals↗

Classical conditioning of the rabbit eyelid response increases glutamate receptor binding in hippocampal synaptic membranes.

Hippocampal pyramidal neurons exhibit a rapid within-trial increase in firing frequency during classical conditioning of the rabbit eyelid response. It has been proposed that the cellular mechanisms responsible for hippocampal long-term potentiation (LTP) may also mediate this learning-dependent increase in neuronal activity. The induction of LTP in rat hippocampal slices results in an increase in the number of [3H]glutamate-binding sites in the potentiated region. The present study investigates the kinetics of [3H]glutamate binding to hippocampal synaptic membranes after eyelid conditioning in the rabbit. We report that the regional distribution of [3H]glutamate binding across the layers of rabbit hippocampus is compatible with a dendritic localization. The pharmacological and ionic properties of the binding suggest that it is associated with an excitatory amino acid receptor. After eyelid conditioning, the maximal number of hippocampal [3H]glutamate-binding sites is increased in animals receiving paired presentations of the tone conditioned stimulus and corneal air-puff unconditioned stimulus relative to that found in naive or unpaired control animals. These results strengthen the hypothesis that an LTP-like mechanism underlies the increase in hippocampal firing frequency during rabbit eyelid conditioning.

Animals↗

Microinjections of anisomycin into the intermediate cerebellum during learning affect the acquisition of classically conditioned responses in the rabbit.

The purpose of this study was to examine the effects of protein synthesis inhibition in the intermediate cerebellum on the acquisition and expression of classically conditioned nictitating membrane responses in the rabbit. Animals were conditioned for three days in a standard delay paradigm. Before each training session, either a solution of anisomycin (a protein synthesis inhibitor) or vehicle was bilaterally injected into the interposed cerebellar nuclear. Following these three training sessions, rabbits were tested to determine whether the previous training under the influence of anisomycin or vehicle resulted in the acquisition of conditioned responses. In this test, animals that were injected previously with the protein synthesis inhibitor exhibited significantly less retention of conditioned responses than rabbits injected with vehicle. Additional experiments demonstrated that anisomycin does not block the expression of conditioned responses during conditioning or in well-trained animals. Microinjections of muscimol at the same sites of the previous drug infusions suppressed the expression of conditioned responses, indicating that the protein synthesis inhibitor was applied to the eyeblink-related parts of cerebellar circuits. The obtained data are the first to demonstrate that a manipulation of cerebellar circuits, which does not affect the performance of learned behavior, can affect the process of learning. These results suggest that the synthesis of new proteins in the intermediate cerebellum participates in the formation of plastic changes responsible for eyeblink conditioning.

Analysis of Variance↗

Classical conditioning of the rabbit eyelid response with a mossy-fiber stimulation CS: I. Pontine nuclei and middle cerebellar peduncle stimulation.

The nictitating membrane/eyelid responses of 18 rabbits were classically conditioned using cerebellar mossy-fiber stimulation as a conditioned stimulus (CS) and air puff as an unconditioned stimulus (US). The dorsolateral, lateral, and medial pontine nuclei and the middle cerebellar peduncle were effective stimulation-CS sites for training. In one group of rabbits, robust conditioned eyelid responses were produced with paired trials and subsequently extinguished with CS-alone and explicitly unpaired presentation of the CS and US. In a second group of rabbits, no conditioned responses were evident for 4 days of unpaired CS and US presentations. Conditioned responses did develop, however, after paired training was begun. Lesions of the interpositus nucleus of the cerebellum completely abolished the conditioned responses of a third group of rabbits overtrained with the mossy-fiber CS and air-puff US. These results support previous studies which have demonstrated that the cerebellum is critically involved in acquisition and retention of simple learned responses. In addition, the present results support previous theories of cerebellar function which have proposed that mossy fibers supply critical "learning" input to the cerebellum for acquisition and retention of motor skills.

Animals↗

Classical conditioning of a complex skeletal response.

The pigeon's so-called "arbitrary" response of pecking an illuminated disk can be established and maintained by procedures resembling those of classical conditioning. This phenomenon was shown to be independent of the specific signaling relationships between illumination of the pecking disk and presentation of food; it will appear as long as the key is differentially associated with food. When a nondifferential condition is introduced, pecking "extinguishes" even if it has previously been established and even when the new condition involves as much reinforcement as the old one. Reinstating differential conditions reestablishes pecking. The initial conditions determine the speed and apparently the asymptote of pecking rates in the differential condition; initial exposure to a nondifferential procedure retards subsequent acquisition, possibly quite permanently. These findings are discussed in the context of mechanisms of adaptive learning, not involving reward and punishment, which lead to selection of effective behaviors on a nonarbitrary basis.

Animals↗

Classical conditioning with auditory discrimination of the eye blink in decerebrate cats.

Cats were subjected to complete lower brainstem transection, and were then tested for learning ability according to a classical conditioning paradigm. An auditory stimulus was systematically paired with a brief shock to the eyelid. Within a few weeks after the operation, the decerebrate cats could learn the conditioned response with a tone frequency discrimination and then a discrimination reversal. Our results support the notion that the brainstem reticular formation can support a conditioned response which isbehaviorally similar to that obtained in the intact animal.

Acoustic Stimulation↗

Classical conditioning of stress-induced analgesia.

Exposure of mice to a series of inescapable shocks produced analgesic reaction. This type of naloxone reversible, stress-induced analgesia responds to classical conditioning. Stress-induced analgesia involves activation of the opiate system: thus this type of analgesic mechanism responds to classical conditioning.

Animals↗