Odor Sensitivity After Intranasal Insulin Application Is Modulated by Gender.

Obesity constitutes a global health care problem, and often eating habits are to blame. For intervention, a thorough understanding of energy intake and expenditure is needed. In recent years, the pivotal role of insulin in connection to energy intake was established. Olfactory sensitivity may be a target of cerebral insulin action to maintain body weight. With this experiment, we aimed to explore the influence of intranasal insulin on olfactory sensitivity for the odors n-butanol and peanut in a placebo-controlled, double-blind setting in a within-subject design. All subjects participated in two experimental sessions on separate days and received either intranasal insulin or placebo in a pseudorandomized order. Application was followed by two olfactory threshold tests for n-butanol and peanut in a pseudorandomized order. After a single dose of intranasal insulin (40 IU) or placebo (0.4 ml), olfactory sensitivity for the odorants n-butanol and peanut were examined in 30 healthy normosmic participants (14 females). Measured blood parameters revealed no decrease in plasma glucose, however, insulin, leptin and cortisol levels were affected following intranasal application. Females' but not males' olfactory sensitivity for n-butanol was lower after intranasal insulin administration vs. placebo. In contrast, olfactory sensitivity for peanut was not influenced by intranasal insulin application. Our results indicate that the effects of cortical insulin levels on processing of specific odors is likely modulated by gender, as central increase of insulin concentration led to a reduced olfactory sensitivity for n-butanol in women only, which might be due to differentially regulated insulin and leptin signaling in men and women.

Chemosensory danger detection in the human brain: Body odor communicating aggression modulates limbic system activation.

Although the sense of smell is involved in numerous survival functions, the processing of body odor emitted by dangerous individuals is far from understood. The aim of the study was to explore how human fight chemosignals communicating aggression can alter brain activation related to an attentional bias and danger detection. While the anterior cingulate cortex (ACC) was seen involved in processing threat-related emotional information, danger detection and error evaluation, it still remains unknown whether human chemosignals communicating aggression can potentially modulate this activation. In the fMRI experiment, healthy male and female normosmic odor recipients (n=18) completed a higher-order processing task (emotional Stroop task with the word categories anger, anxiety, happiness and neutral) while exposed to aggression and exercise chemosignals (collected from a different group of healthy male donors; n=16). Our results provide first evidence that aggression chemosignals induce a time-sensitive attentional bias in chemosensory danger detection and modulate limbic system activation. During exposure to aggression chemosignals compared to exercise chemosignals, functional imaging data indicates an enhancement of thalamus, hypothalamus and insula activation (p<.05, FWE-corrected). Together with the thalamus, the ACC was seen activated in response to threat-related words (p<.001). Chemosensory priming and habituation to body odor signals are discussed.

Neural correlates of olfactory and visual memory performance in 3D-simulated mazes after intranasal insulin application.

This fMRI study intended to establish 3D-simulated mazes with olfactory and visual cues and examine the effect of intranasally applied insulin on memory performance in healthy subjects. The effect of insulin on hippocampus-dependent brain activation was explored using a double-blind and placebo-controlled design. Following intranasal administration of either insulin (40IU) or placebo, 16 male subjects participated in two experimental MRI sessions with olfactory and visual mazes. Each maze included two separate runs. The first was an encoding maze during which subjects learned eight olfactory or eight visual cues at different target locations. The second was a recall maze during which subjects were asked to remember the target cues at spatial locations. For eleven included subjects in the fMRI analysis we were able to validate brain activation for odor perception and visuospatial tasks. However, we did not observe an enhancement of declarative memory performance in our behavioral data or hippocampal activity in response to insulin application in the fMRI analysis. It is therefore possible that intranasal insulin application is sensitive to the methodological variations e.g. timing of task execution and dose of application. Findings from this study suggest that our method of 3D-simulated mazes is feasible for studying neural correlates of olfactory and visual memory performance.

You Smell Dangerous: Communicating Fight Responses Through Human Chemosignals of Aggression.

The ability to detect conspecifics that represent a potential harm for an individual represents a high survival benefit. Humans communicate socially relevant information using all sensory modalities, including the chemosensory systems. In study 1, we investigated whether the body odor of a stranger with the intention to harm serves as a chemosignal of aggression. Sixteen healthy male participants donated their body odor while engaging in a boxing session characterized by aggression-induction methods (chemosignal of aggression) and while performing an ergometer session (exercise chemosignal). Self-reports on aggression-related physical activity, motivation to harm and angry emotions selectively increased after aggression induction. In study 2, we examined whether receivers smelling such chemosignals experience emotional contagion (e.g., anger) or emotional reciprocity (e.g., anxiety). The aggression and exercise chemosignals were therefore presented to 22 healthy normosmic participants in a double-blind, randomized exposure during which affective/cognitive processing was examined (i.e., emotion recognition task, emotional stroop task). Behavioral results indicate that chemosignals of aggression induce an affective/cognitive modulation compatible with an anxiety reaction in the recipients. These findings are discussed in light of mechanisms of emotional reciprocity as a way to convey not only affective but also motivational information via chemosensory signals in humans.

Central insulin administration improves odor-cued reactivation of spatial memory in young men.

CONTEXT: Insulin receptors are ubiquitously found in the human brain, comprising the olfactory bulb, essential for odor processing, and the hippocampus, important for spatial memory processing. OBJECTIVE: The present study aimed at examining if intranasal insulin, which is known to transiently increase brain insulin levels in humans, would improve odor-cued reactivation of spatial memory in young men. DESIGN: We applied a double-blind, placebo-controlled, counterbalanced within-subject design. SETTING: The study was conducted at the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: Following intranasal administration of either insulin (40 I.U.) or placebo, male subjects (n = 18) were exposed to eight odors. During each odor exposure, a green-colored field was presented on a 17-in. computer screen. During immediate recall (comprising 3 runs), the participants were re-exposed to each odor cue, and were asked to select the corresponding field (with visual feedback after each response). The delayed recall was scheduled ∼10 min later (without feedback). To test if insulin's putative effect on odor-place memory would be domain-specific, participants also performed a separate place and odor recognition task. RESULTS: Intranasal insulin improved the delayed but not immediate odor-cued recall of spatial memory. This effect was independent of odor type and in the absence of systemic side effects (eg, fasting plasma glucose levels remained unaltered). Place and odor recognition were unaffected by the insulin treatment. CONCLUSIONS: These findings suggest that acute intranasal insulin improves odor-cued reactivation of spatial memory in young men.

Depicting the inner and outer nose: the representation of the nose and the nasal mucosa on the human primary somatosensory cortex (SI).

The nose is important not only for breathing, filtering air, and perceiving olfactory stimuli. Although the face and hands have been mapped, the representation of the internal and external surface of the nose on the primary somatosensory cortex (SI) is still poorly understood. To fill this gap functional magnetic resonance imaging (fMRI) was used to localize the nose and the nasal mucosa in the Brodman areas (BAs) 3b, 1, and 2 of the human postcentral gyrus (PG). Tactile stimulation during fMRI was applied via a customized pneumatically driven device to six stimulation sites: the alar wing of the nose, the lateral nasal mucosa, and the hand (serving as a reference area) on the left and right side of the body. Individual representations could be discriminated for the left and right hand, for the left nasal mucosa and left alar wing of the nose in BA 3b and BA 1 by comparing mean activation maxima and Euclidean distances. Right-sided nasal conditions and conditions in BA 2 could further be separated by different Euclidean distances. Regarding the alar wing of the nose, the results concurred with the classic sensory homunculus proposed by Penfield and colleagues. The nasal mucosa was not only determined an individual and bilateral representation, its position on the somatosensory cortex is also situated closer to the caudal end of the PG compared to that of the alar wing of the nose and the hand. As SI is commonly activated during the perception of odors, these findings underscore the importance of the knowledge of the representation of the nasal mucosa on the primary somatosensory cortex, especially for interpretation of results of functional imaging studies about the sense of smell.

Intranasal insulin reduces olfactory sensitivity in normosmic humans.

CONTEXT: High densities of insulin receptors are found throughout the human brain, including the olfactory bulb, an essential brain area for odor processing. This brain region is the phylogenetically oldest part of the olfactory central nervous system. OBJECTIVE: We hypothesized that enhanced brain insulin signaling would modulate olfactory processing in humans. DESIGN: We applied a double-blind, placebo-controlled, balanced within-subject design. SETTING: This study was conducted in the research unit of a university hospital. INTERVENTIONS/PARTICIPANTS/MAIN OUTCOME MEASURES: A single dose of either insulin (40 IU) or placebo was intranasally administered to 17 normal-weight normosmic participants (7 women). Subjects' olfactory abilities were examined by means of an olfactory threshold test (odorant n-butanol) and an olfactory discrimination test. In addition, circulating concentrations of glucose, insulin, and cortisol levels were measured. RESULTS: After intranasal insulin administration, subjects' sensitivity for the odorant n-butanol was significantly decreased compared with that for the placebo condition (-13%; P = .025), whereas olfactory discrimination ability was not (P = .841). While serum insulin and serum cortisol were not altered after intranasal insulin administration, there was a small but significant drop in plasma glucose levels. Importantly, a correlational analysis demonstrated that this treatment-induced drop in plasma glucose was not related to the effects of intranasal insulin on olfactory sensitivity. CONCLUSIONS: These findings suggest that intranasal insulin impairs olfactory sensitivity for a nonfood odorant, whereas no such effects were found for olfactory discrimination. Thus, variations in brain insulin signaling most likely have implications for the olfactory threshold of normosmic humans. Bearing in mind the fact that insulin acts as an anorexigenic signal in the human brain, further studies are needed to test whether intranasal insulin also impairs the ability of humans to perceive food-related odors.

Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence.

Research in animals and humans has associated Alzheimer's disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism--such as insulin resistance in obesity, type 2 diabetes and AD--and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy.