Ursula Stockhorst

Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans

Insulin is mainly known for its peripheral effects on the metabolism of glucose, fats, and proteins. However, insulin also exerts important actions within the brain, and functions as a neuropeptide. The brain can thus be regarded as both an insulin-sensitive and a glucose-sensitive organ. Its neuroanatomical basis is the localization of insulin receptors, predominantly in the olfactory bulbs, hypothalamus, and hippocampus. Data obtained in animal experiments reveal an interesting insulin profile in the brain. Central insulin affects glucoregulation. As long as peripheral euglycemia is maintained, it was shown to reduce food intake and body weight and to improve learning and memory. Cognitive dysfunctions in dementia of the Alzheimer type (DAT) are associated with insulin deficiency within the brain, and memory improves in DAT patients when insulin levels increase. After describing these actions of insulin in the brain, we address here the transport of insulin into the brain. Insulin can either be transported from the periphery to the brain, or be administered directly into the brain. To reach insulin receptors directly, animals are typically administered insulin via the cerebral ventricles. For humans, the intranasal route is a practicable way to reach the brain while maintaining euglycemia. Additionally, the localization of insulin receptors in the olfactory bulb makes insulin interesting for the nose-to-brain pathway. Promising initial results have been reported with intranasally administered insulin corresponding to the diverse actions of insulin in the brain. Interestingly, initial data indicate that states of central insulin deficiencies (DAT and obesity) are accompanied by olfactory deviations. Thus, the nose-to-brain pathway deserves further attention.

Olfactory perception, communication, and the nose-to-brain pathway.

Abstract The present papers aim is of to give an overview about the basic knowledge as well as actual topics of olfaction—with a special regard on behavior. We summarize different functions of the nose and the olfactory system in human physiology and psychology. We will first describe the functional anatomy of the olfactory system in man. Afterwards, the function of the olfactory system will be viewed from an evolutionary and phylogenetic perspective. We will further outline the main features of olfactory perception, and will show how olfactory perception is influenced by learning. Olfactory signals are relevant stimuli that affect communication. Consequently, the role of the olfactory system in social interaction and mood will be described and gender differences will be addressed. Finally, the function of the nose as an interface to the brain, including implications for pharmacology, will be discussed.

Effects of overshadowing on conditioned nausea in cancer patients: an experimental study

The infusion of cytotoxic drugs in cancer patients is often accompanied by posttreatment nausea (PN). In addition, patients complain about nausea prior to an infusion [i.e., anticipatory nausea (AN)]. AN is mainly explained by classical conditioning, with the infusion as the unconditioned stimulus (US) and with the stimuli signaling the infusion as conditioned stimuli (CS). Despite this conditioning etiology, a specifically derived therapy to attenuate the CS-US contingency is missing. The purpose of this study is to develop and to test an overshadowing procedure for prevention of AN, and also for the modification of PN intensity. Sixteen cancer patients were assigned to one of two groups: Overshadowing+ (OV+) and Overshadowing- (OV-). At the start of all infusions of two consecutive chemotherapy cycles A and B (acquisition), OV+ subjects drank a saliently tasting beverage (the overshadowing CS), whereas group OV- drank water. All patients received water in cycle C (test). Self-reported symptoms and heart rates were recorded. As expected, in cycle C (test), no patient of group OV+ showed AN, whereas two patients of group OV- developed AN. There was a tendency for a reduction of the intensity of PN, in terms of duration and latency after overshadowing, in cycle C: OV+ patients tended to show a shorter duration and a longer latency between end of infusion and PN onset. In OV-, there was a significantly larger heart rate deceleration in both measurement periods, in the anticipatory and the posttreatment measurement period. Data suggest to apply overshadowing for prevention of AN and modification of PN. Physiological markers of conditioned nausea are revealed. After its procedural implementation, the technique can be used in larger samples now.

Endocrine and psychological stress responses in a simulated emergency situation

BACKGROUND Several studies have assessed the effects of training using patient simulation systems on medical skills. However, endocrine and psychological stress responses in a patient simulation situation and the relationship between stress reactivity and medical performance have been studied rarely, so far. METHODS Medical students (18 males and 16 females) who had completed at least two months anaesthesiology training participated in the study. In a counterbalanced cross-over design they were subjected to three conditions: rest, laboratory stress (LS; public speaking), and simulated emergency situation (SIM; myocardial ischemia and ventricular fibrillation). Salivary cortisol and psychological responses (visual analogue scales, VAS) were assessed every 15 min from 15 min prior to until 60 min after intervention. Differences between stress and rest conditions were analysed. Medical performance was assessed according to the European Resuscitation Councils Guidelines for Resuscitation. RESULTS As compared to rest, cortisol increased significantly in both stress conditions with different time courses in LS and SIM. Psychological responses in SIM exceeded those in LS. Cortisol increase in LS (r(s)=.486; p=.019) but not in SIM (r(s)=.106; p=.631) correlated significantly with medical performance. DISCUSSION A simulated emergency situation is a profound stressor. The positive relationship between endocrine stress responsiveness in a standard laboratory situation and medical performance in a simulated emergency situation indicates that high stress responsiveness might be a predictor of good performance. At the same time the high stress response might counteract educational efforts associated with training using high-fidelity patient simulation.

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.

Latent Inhibition of Rotation Chair-Induced Nausea in Healthy Male and Female Volunteers

Objectives: Pre-exposure to an environment in which a nausea-inducing body rotation will subsequently be given constitutes a latent inhibition procedure that might act to reduce anticipatory and postrotation nausea. Methods: This was tested in 24 healthy subjects randomly assigned to receive no pre-exposure (group 0), a single pre-exposure (group 1), or three pre-exposures (group 3). Rotation was standardized as 5 × 1 minute rotation, but the subjects could terminate it on request. Nausea was determined on a 7-item symptom rating scale before, during, and after rotation on days 3 and 4, whereas anticipatory nausea was measured before presumed rotation on day 5. Saliva cortisol and tumor necrosis factor &agr; (TNF-&agr;) levels were determined at baseline before, directly, and 15 and 30 minutes after rotation every day, and before presumed rotation on day 5. Results: Pre-exposure significantly reduced the degree of anticipatory nausea on day 5. Cortisol levels increased with rotation and were higher at baseline on days 4 and 5, but subjects habituated from day 3 to day 4; levels were lower in women than in men. In contrast, TNF-&agr; decreased with rotation but showed no habituation. For both cortisol and TNF-&agr;, no effects on postrotational nausea were found. Conclusion: It is concluded that repetitive pre-exposure (latent inhibition) reduces anticipatory but not postrotation nausea; behavioral measures (rotation time) and measures of acute stress (cortisol, TNF-&agr;) do not respond to latent inhibition. Thus, Pavlovian conditioning rules are effective in healthy humans with anticipatory nausea but not with postrotation nausea. Hormonal responses—TNF-&agr; decrease with stress, compensatory cortisol increase—and gender-related effects on learning and habituation are discussed with regard to psychophysiological and psychoimmunological processes. AN = anticipatory nausea; CS = conditioned stimulus; US = unconditioned stimulus; CR = conditioned response; PN = posttreatment nausea; UR = unconditioned response; TNF-&agr; = tumor necrosis factor &agr;; RT = rotation tolerance; MSSQ = motion sickness susceptibility questionnaire; SR = symptom rating; ANOVA = analysis of variance.

Pavlovian conditioning of nausea and vomiting

Cancer patients undergoing cytotoxic drug treatment often experience side-effects, the most distressing being nausea and vomiting. Despite antiemetic drugs, 25-30% of the chemotherapy patients report these side-effects when being re-exposed to the stimuli that usually signal the chemotherapy session and its drug infusion. These symptoms are called anticipatory nausea and anticipatory vomiting. The present paper summarizes the evidence that anticipatory vomiting is acquired by Pavlovian conditioning, and, consequently, may be alleviated by conditioning techniques. To explore the mechanisms that induce and alleviate conditioned nausea and vomiting further, a conditioned nausea model was established in healthy humans using body rotation as the nausea-inducing treatment. The validity of this motion sickness model to examine conditioning mechanisms in the acquisition and alleviation of conditioned nausea was demonstrated. Cortisol and tumor-necrosis factor-alpha were elevated as endocrine and immunological correlates of nausea. Data in the rotation-induced motion sickness model indicated that gender is an important moderator variable to be considered in further studies. The paper concludes with a review of applications of the demonstrated conditioning principles as interventions to ameliorate distressing anticipatory nausea or anticipatory vomiting in cancer patients undergoing chemotherapy.

Pavlovian conditioning of immune function: animal investigation and the challenge of human application

Pavlovian conditioning of immune functions provided early impetus to the rapidly expanding knowledge of bi-directional communication among the immune, endocrine, and central nervous systems. Since these early investigations, the phenomenology of this response has been well characterized. However the neural mechanisms and biological relevance of conditioned immunomodulation remain unclear. To this end, we present here data from our laboratories that have: (1) revealed some of the neural mechanisms and biological relevance of an animal model of conditioned immunomodulation; (2) demonstrated the conditionability and potential mechanisms of conditioned immune responses in healthy humans, and (3) investigated conditioned immunomodulation in a clinical sample. Together, these data demonstrate that animal models provide a basis for investigating mechanisms whereby conditioned changes in immune function may modulate health status in a clinical realm.

Anticipatory nausea in cancer patients receiving chemotherapy: Classical conditioning etiology and therapeutical implications

The delivery of cytotoxic drugs in cancer treatment is often accompanied by posttreatment side effects (e.g., nausea). Moreover, there is evidence that cancer patients are at risk to develop these side effects in anticipation of chemotherapy (i.e., anticipatory nausea [AN]). AN can be explained as the result of a classical conditioning process with the cytotoxic drug as the unconditioned stimulus (US). Stimuli paired with the US (e.g., smells, tastes) can become conditioned stimuli (CSs) eliciting AN as the conditioned response (CR). The present study was conducted to test whether AN shows characteristics of a CR. Fifty-five ambulatory cancer patients were asked to record nine kinds of physical symptoms (e.g., nausea, vomiting, sweating) on time-scheduled symptom lists: after an infusion (indicating posttreatment symptoms) and prior to their next infusion (indicating anticipatory symptoms). Each measurement period covered a maximum of 48 hours. AN was reported by ten patients (18.08%). Data revealed (a) a statistically significant association between posttreatment nausea and vomiting, respectively, and AN; (b) the occurrence of AN increased with drug emetogenity (i.e., US-intensity); and (c) the duration of AN increased with temporal proximity to the infusion. The results support the conditioning model. Thus, it is proposed to prevent AN by classical conditioning techniques (e.g., overshadowing).

Classically conditioned responses following repeated insulin and glucose administration in humans

This paper describes the neural basis and the role of Pavlovian conditioning in the modification of blood glucose and related endocrine parameters after repeated insulin and glucose administration. Pavlovian conditioning requires that conditioned stimulus (CS) and unconditioned stimulus (US) are both detected in the central nervous system (CNS), where the CS-US association takes place. We will therefore elucidate the detectability of insulin and glucose in the CNS. Since current data focus almost exclusively on animals, we conducted a placebo-controlled insulin conditioning experiment in humans (Experiment 1). Compared with the control group with CS-placebo pairings throughout, the experimental group with previous CS-insulin pairings in the acquisition phase showed a conditioned decrease in blood glucose and a trend for a conditioned baseline insulin increase, and an increase in cortisol levels relative to baseline and cumulative number of neuroglycopenic symptoms in the CS-placebo test session. The conditionability of glucose administration also had to be examined; experiments using an arbitrary CS and glucose are extremely rare, even in animals. Glucose is the natural stimulus for endogenous insulin secretion, so studies on cephalic-phase insulin release (CPIR) will be reviewed in this paper. We implemented a placebo-controlled three-group design (Experiment 2): Subjects received either CS-insulin, CS-glucose or CS-placebo pairings during the acquisition. Together, our results demonstrate the conditionability mainly of insulin, but also of glucose effects in healthy humans. The clinical relevance and future research perspectives are outlined with an emphasis on insulin in the brain and its role in learning and memory.