Finally, using a human lesion-type model-i.e., an individual born without bilateral OBs-we will determine whether absence of OBs abolishes the EBG signal. This is a hallmark neural signature of the OB commonly reported in animal models 25. Third, we will demonstrate that while participants after long odor exposure perceptually habituate, the EBG signal is insensitive to odor habituation. Second, we will determine whether we can observe an EBG signal on the sensor level that on the source level is located to the OB, with subsequent assessment of reliability of the obtained measure. First, we will optimize the electrode placement by simulating how a potential signal would be manifested on the scalp. To this end, we are addressing the hypothesis that signals from the human OB can be assessed from the scalp using micro-amplified EEG using a four-stage approach. Specifically, this activation should occur within 100–200 ms after odor onset based on the temporal limits given by the biology of the olfactory system (see Supplementary Note 1) and past studies demonstrating that down-stream areas are activated shortly before 300 ms post odor onset 23, 24. Given that gamma and gamma-like oscillations in the OB have been related to odor processing in a range of species 3, 21, 22 and gamma-band responses have been observed in the only study to date where intracranial recordings from the human OB have been collected 12, we hypothesized that non-invasive signals from the OB, a so-called electrobulbogram (EBG), should be detectable within the gamma-band range. However, when centrifugal input to the OB is eliminated, only gamma oscillations remain 19, 20. In sharp contrast, odor processing within the rodent OB has been demonstrated to produce both beta and gamma oscillations 18. Odor-dependent EEG recordings in humans have, by tradition, used low-pass filters at around 30 Hz 16, based partly-on the now disputed assumption-that most human perceptual processes occur in lower frequency bands, and on the observation that human cortical processing of odors mainly operates at around 5 Hz 17. However, until now, no attempts have been made to demonstrate non-invasive recordings of OB function in humans using EEG. Electroencephalogram (EEG) signals do not suffer from interferences from the sinuses and recordings in rabbits demonstrate that OB signals can be obtained from scalp electrodes placed above the OB 14, 15. Attempts to acquire neural signals from the human OB using functional neuroimaging have failed either due to poor spatial resolution of the method (positron emission tomography PET) or, in the case of functional magnetic resonance imaging (fMRI), due to the OB’s proximity to the sinuses where the cavity creates susceptibility artifacts and reduced signal strength in the OB area 13. The only published data of human OB odor responses dates back fifty years and was obtained from electrodes placed directly on the human OB during intracranial surgery 12. Thus, the development of a non-invasive method to assess OB processing in the awake human is a necessary and important step to fully understand the neural mechanisms of human olfactory processing in both health and disease. The OB is the very first cerebral area of insult in Parkinson’s disease 9 which explains why behavioral olfactory disturbances commonly precede the characteristic motor symptoms defining the disease by several years 10 and why early occurrence of olfactory dysfunction is more prevalent (~91%) than motor problems (~75%) 8, 11. The OB is also linked to several disabling neurodegenerative diseases 7 where a strong link to Parkinson’s disease stands out 8. In rodents the relative size of the OB compared to the rest of the brain is very large 6 and as such, it is not surprising that the OB is one of the most well-studied brain areas in the mammalian brain. Critically, all our knowledge about the OB comes from animal studies. Within the olfactory system, the OB has been suggested to fulfill a role comparable to both V1 4 and the thalamus in the visual system 5. Moreover, recent studies demonstrate that the role of the OB is not limited to the olfactory system, but that it impacts many brain functions 2, 3. The OB is the critical first central processing stage of the olfactory system, intimately involved in processing of an ever-increasing list of olfactory tasks: odor discrimination, concentration-invariant odor recognition, odor segmentation, and odor pattern recognition 1, to mention but a few. Measures of neural processing can be obtained using non-invasive methods from all areas of the human brain but one, the olfactory bulb (OB).
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