Lee Sela

Human vulnerability to stress depends on amygdala's predisposition and hippocampal plasticity

Variations in peoples vulnerability to stressful life events may rise from a predated neural sensitivity as well as from differential neural modifications in response to the event. Because the occurrence of a stressful life event cannot be foreseen, characterizing the temporal trajectory of its neural manifestations in humans has been a real challenge. The current prospective study examined the emotional experience and brain responses of 50 a priori healthy new recruits to the Israeli Defense Forces at 2 time points: before they entered their mandatory military service and after their subsequent exposure to stressful events while deployed in combat units. Over time, soldiers reported on increase in stress symptoms that was correlated with greater amygdala and hippocampus responsiveness to stress-related content. However, these closely situated core limbic regions exhibited different temporal trajectories with regard to the stress effect; whereas amygdalas reactivity before stress predicted the increase in stress symptoms, the hippocampal change in activation over time correlated with the increase in such symptoms. Hippocampal plasticity was also reflected by a modification over time of its functional coupling with the ventromedial prefrontal cortex, and this coupling magnitude was again predicted by predated amygdala reactivity. Together, these findings suggest that variations in humans likelihood to develop symptomatic phenomena following stressful life events may depend on a balanced interplay between their amygdalas predisposing reactivity and hippocampal posteriori intra- and interregional plasticity. Accordingly, an individually tailored therapeutic approach for trauma survivors should target these 2 neural probes while considering their unique temporal prints.

Human olfaction: a constant state of change-blindness

Paradoxically, although humans have a superb sense of smell, they don’t trust their nose. Furthermore, although human odorant detection thresholds are very low, only unusually high odorant concentrations spontaneously shift our attention to olfaction. Here we suggest that this lack of olfactory awareness reflects the nature of olfactory attention that is shaped by the spatial and temporal envelopes of olfaction. Regarding the spatial envelope, selective attention is allocated in space. Humans direct an attentional spotlight within spatial coordinates in both vision and audition. Human olfactory spatial abilities are minimal. Thus, with no olfactory space, there is no arena for olfactory selective attention. Regarding the temporal envelope, whereas vision and audition consist of nearly continuous input, olfactory input is discreet, made of sniffs widely separated in time. If similar temporal breaks are artificially introduced to vision and audition, they induce “change blindness”, a loss of attentional capture that results in a lack of awareness to change. Whereas “change blindness” is an aberration of vision and audition, the long inter-sniff-interval renders “change anosmia” the norm in human olfaction. Therefore, attentional capture in olfaction is minimal, as is human olfactory awareness. All this, however, does not diminish the role of olfaction through sub-attentive mechanisms allowing subliminal smells a profound influence on human behavior and perception.

Sniffing enables communication and environmental control for the severely disabled

Paradoxically, improvements in emergency medicine have increased survival albeit with severe disability ranging from quadriplegia to “locked-in syndrome.” Locked-in syndrome is characterized by intact cognition yet complete paralysis, and hence these individuals are “locked-in” their own body, at best able to communicate using eye blinks alone. Sniffing is a precise sensory-motor acquisition entailing changes in nasal pressure. The fine control of sniffing depends on positioning the soft palate, which is innervated by multiple cranial nerves. This innervation pattern led us to hypothesize that sniffing may remain conserved following severe injury. To test this, we developed a device that measures nasal pressure and converts it into electrical signals. The device enabled sniffs to control an actuator with speed similar to that of a hand using a mouse or joystick. Functional magnetic resonance imaging of device usage revealed a widely distributed neural network, allowing for increased conservation following injury. Also, device usage shared neural substrates with language production, rendering sniffs a promising bypass mode of communication. Indeed, sniffing allowed completely paralyzed locked-in participants to write text and quadriplegic participants to write text and drive an electric wheelchair. We conclude that redirection of sniff motor programs toward alternative functions allows sniffing to provide a control interface that is fast, accurate, robust, and highly conserved following severe injury.

The Influence of Odorants on Respiratory Patterns in Sleep

To assess the feasibility of using odors as a potential mechanism for treating sleep apnea, we set out to test the hypothesis that odorants delivered during sleep would modify respiratory patterns without inducing arousal or wake in healthy sleepers. We used 2 mildly trigeminal odorants: the pleasant lavender and unpleasant vetiver oil and 2 pure olfactory odorants: the pleasant vanillin and unpleasant ammonium sulfide. During sleep, an olfactometer delivered a transient odorant every 9, 12, or 15 min (randomized), providing 21-37 odorant presentations per night. Each of 36 participants was studied for 1 night and with 1 of the 4 different odorants tested. In addition to standard overnight polysomnography, we employed highly accurate measurements of nasal and oral respiration. Odorants did not increase the frequency of arousals or wake but did influence respiration. Specifically, all 4 odorants transiently decreased inhalation and increased exhalation for up to 6 breaths following odor onset. This effect persisted regardless of odorant valence or stage of sleep. These results suggest that the olfactory system may provide a path to manipulate respiration in sleep.

Spared and impaired olfactory abilities after thalamic lesions.

Olfactory information reaches olfactory cortex without a thalamic relay. This neuroanatomical substrate has combined with functional findings to suggest that, in olfaction, the typical thalamic role in sensory processing has shifted to the olfactory bulb or olfactory cortex. With this in mind, we set out to ask whether the thalamus at all plays a significant functional role in human olfaction. We tested olfactory function in 17 patients with unilateral focal thalamic lesions and in age-matched healthy controls. We found that thalamic lesions did not significantly influence olfactory detection but significantly impaired olfactory identification, and only right lesions altered olfactory hedonics by reducing the pleasantness of pleasant odors. An auditory control revealed that this shift in pleasantness was olfactory specific. These olfactory impairments were evident in explicit measures of perception, as well as in patterns of sniffing. Whereas healthy subjects modulated their sniffs in accordance with odorant content, thalamic patients did not. We conclude that, although the thalamus is not in the path of olfactory information from periphery to cortex, it nevertheless plays a significant functional role in human olfaction.

A social chemosignaling function for human handshaking

Social chemosignaling is a part of human behavior, but how chemosignals transfer from one individual to another is unknown. In turn, humans greet each other with handshakes, but the functional antecedents of this behavior remain unclear. To ask whether handshakes are used to sample conspecific social chemosignals, we covertly filmed 271 subjects within a structured greeting event either with or without a handshake. We found that humans often sniff their own hands, and selectively increase this behavior after handshake. After handshakes within gender, subjects increased sniffing of their own right shaking hand by more than 100%. In contrast, after handshakes across gender, subjects increased sniffing of their own left non-shaking hand by more than 100%. Tainting participants with unnoticed odors significantly altered the effects, thus verifying their olfactory nature. Thus, handshaking may functionally serve active yet subliminal social chemosignaling, which likely plays a large role in ongoing human behavior. DOI: http://dx.doi.org/10.7554/eLife.05154.001

Detection of response to command using voluntary control of breathing in disorders of consciousness

Background: Detecting signs of consciousness in patients in a vegetative state/unresponsive wakefulness syndrome (UWS/VS) or minimally conscious state (MCS) is known to be very challenging. Plotkin et al. (2010) recently showed the possibility of using a breathing-controlled communication device in patients with locked in syndrome. We here aim to test a breathing-based “sniff controller” that could be used as an alternative diagnostic tool to evaluate response to command in severely brain damaged patients with chronic disorders of consciousness (DOC). Methods: Twenty-five DOC patients were included. Patients’ resting breathing-amplitude was measured during a 5 min resting condition. Next, they were instructed to end the presentation of a music sequence by sniffing vigorously. An automated detection of changes in breathing amplitude (i.e., >1.5 SD of resting) ended the music and hence provided positive feedback to the patient. Results: None of the 11 UWS/VS patients showed a sniff-based response to command. One out of 14 patients with MCS was able to willfully modulate his breathing pattern to answer the command on 16/19 trials (accuracy 84%). Interestingly, this patient failed to show any other motor response to command. Discussion: We here illustrate the possible interest of using breathing-dependent response to command in the detection of residual cognition in patients with DOC after severe brain injury.

Odors enhance slow-wave activity in non-rapid eye movement sleep

Most forms of suprathreshold sensory stimulation perturb sleep. In contrast, presentation of pure olfactory or mild trigeminal odorants does not lead to behavioral or physiological arousal. In fact, some odors promote objective and subjective measures of sleep quality in humans and rodents. The brain mechanisms underlying these sleep-protective properties of olfaction remain unclear. Slow oscillations in the electroencephalogram (EEG) are a marker of deep sleep, and K complexes (KCs) are an EEG marker of cortical response to sensory interference. We therefore hypothesized that odorants presented during sleep will increase power in slow EEG oscillations. Moreover, given that odorants do not drive sleep interruption, we hypothesized that unlike other sensory stimuli odorants would not drive KCs. To test these hypotheses we used polysomnography to measure sleep in 34 healthy subjects (19 women, 15 men; mean age 26.5 ± 2.5 yr) who were repeatedly presented with odor stimuli via a computer-controlled air-dilution olfactometer over the course of a single night. Each participant was exposed to one of four odorants, lavender oil (n = 13), vetiver oil (n = 5), vanillin (n = 12), or ammonium sulfide (n = 4), for durations of 5, 10, and 20 s every 9-15 min. Consistent with our hypotheses, we found that odor presentation during sleep enhanced the power of delta (0.5-4 Hz) and slow spindle (9-12 Hz) frequencies during non-rapid eye movement sleep. The increase was proportionate to odor duration. In addition, odor presentation did not modulate the occurrence of KCs. These findings imply a sleep-promoting olfactory mechanism that may deepen sleep through driving increased slow-frequency oscillations.