High-frequency oscillations of the frontal cortex are involved in functions of the brain that fuse processed data from different sensory modules or bind them with elements stored in the memory. These oscillations also provide inhibitory connections to neural circuits that perform lower-level processes. Deficit in the performance of these oscillations has been examined as a marker for Alzheimer’s disease (AD). Additionally, the neurodegenerative processes associated with AD, such as the deposition of amyloid-beta plaques, do not occur in a spatially homogeneous fashion and progress more prominently in the medial temporal lobe in the early stages of the disease. This region of the brain contains neural circuitry involved in olfactory perception. Several studies have suggested that olfactory deficit can be used as a marker for early diagnosis of AD. A quantitative assessment of the performance of the olfactory system can hence serve as a potential biomarker for Alzheimer’s disease, offering a relatively convenient and inexpensive diagnosis method. This study examines the decline in the perception of olfactory stimuli and the deficit in the performance of high-frequency frontal oscillations in response to olfactory stimulation as markers for AD. Two measurement modalities are employed for assessing the olfactory performance: 1) An interactive smell identification test is used to sample the response to a sizable variety of odorants, and 2) Electroencephalography data are collected in an olfactory perception task with a pair of selected odorants in order to assess the connectivity of frontal cortex regions. Statistical analysis methods are used to assess the significance of selected features extracted from the recorded modalities as Alzheimer’s biomarkers. Olfactory decline regressed to age in both healthy and mild AD groups are evaluated, and single- and multi-modal classifiers are also developed. The novel aspects of this study include: 1) Combining EEG response to olfactory stimulation with behavioral assessment of olfactory perception as a marker of AD, 2) Identification of odorants most significantly affected in mild AD patients, 3) Identification of odorants which are still adequately perceived by mild AD patients, 4) Analysis of the decline in the spatial coherence of different oscillatory bands in response to olfactory stimulation, and 5) Being the first study to quantitatively assess the performance of olfactory decline due to aging and AD in the Iranian population.

Mild cognitive impairment (MCI) is known as an early stage of cognitive decline. Amnestic MCI (aMCI) is considered as the preliminary stage of dementia which may progress to Alzheimer’s disease (AD). While some aMCI patients may stay in this condition for years, others might develop dementia associated with AD. Early detection of MCI allows for potential treatments to prevent or decelerate the process of developing dementia. Standard methods of diagnosing MCI and AD employ structural (imaging), behavioral (cognitive tests), and genetic or molecular (blood or CSF tests) techniques. Our study proposes network-level neural synchronization parameters as topographical markers for diagnosing aMCI and AD. We conducted a pilot study based on EEG data recorded during an olfactory task from a group of elderly participants consisting of healthy individuals and patients of aMCI and AD to assess the value of different indicators of network-level phase and amplitude synchronization in differentiating the three groups. Significant differences were observed in the percent phase locking value, theta-gamma phase-amplitude coupling, and amplitude coherence between the groups, and classifiers were developed to differentiate the three groups based on these parameters. The observed differences in these indicators of network-level functionality of the brain can help explain the underlying processes involved in aMCI and AD.

Background Impairment of gamma oscillations has been observed in cognitive disorders like Alzheimer’s disease (AD). Gamma entrainment using 40Hz auditory or visual stimulation has been proposed as a potential treatment for AD (Adaikkan et al., Trends in Neuroscience 2020; Sedghizadeh et al. Alzheimer’s and Dementia 2020), while simultaneous use of both modalities has been reported to show superior therapeutic results (Martorell et al., Cell 2019; Suk et al. Alzheimer’s and Dementia 2020). Gamma and theta oscillations are both produced in the hippocampal area and interact with each other. Evidence shows that the interaction between these bands leads to their phase‐amplitude coupling (PAC) in the frontal cortex (Amemiya et al., Cell Reports 2018). The current study assesses the effects of 40Hz auditory and visual stimulation on the theta‐gamma PAC, and suggests that the superior performance of multimodal entrainment can be explained by this marker. Method 10 cognitively healthy participants were included in this study. Each participant was seated in a dark and quiet room and underwent three sessions of sensory stimulation (visual, auditory, and simultaneous (multimodal) visual and auditory) in a randomized order. Each session consisted of 60 trials of 5s stimulation and 5s rest. The auditory stimulation consisted of a 40Hz clicking sound modulated with a career frequency of 5kHz. The visual stimulation was generated using white LEDs flickering at 40Hz. EEG data were acquired and the theta‐gamma PAC was calculated using the time‐frequency mean vector length (tf‐MVL) method (Munia et al., Scientific Reports 2019). Result The PAC value for theta (4‐8Hz) and gamma oscillations near the stimulation frequency (39‐41Hz) on the Fz channel showed a significant increase during the multimodal stimulation intervals compared to the resting state, whereas the increase was not significant during the single‐modal stimulations compared to rest. The multimodal stimulation also involved more brain areas and resulted in a higher PAC compared to single‐modal stimulation. Conclusion Entraining gamma oscillations using simultaneous auditory and visual stimulation results in markedly superior theta‐gamma PAC compared to entrainment with single modalities. This superiority can explain the advantages reported for multimodal entrainment in AD therapy experiments.

Background High‐level cognitive processes such as binding the processed data from sensory modules with elements stored in the memory involve the activity of long‐range pyramidal cells. These excitatory neuronal populations also provide input to a population of GABAAergic inhibitory interneurons, which in turn recruit feedback links to suppress the activity of the pyramidal cells. Interneuron networks generate rhythmic synchronization in the Gamma band driven by the time constant of the GABA receptors. Disrupted or desynchronized Gamma oscillations have been observed in patients of Alzheimer’s disease (AD). Earlier works have proposed the deficit in coherence between oscillations measured by EEG electrodes across the frontal lobe in the Gamma band in response to olfactory stimulation as a diagnostic marker of AD. This study examines the strength and spatial spread of Gamma band activity induced by auditory chirp stimulation as a marker for AD. The chirp signal is designed to entrain a target frequency of 40Hz at which the populations of inhibitory interneurons are known to operate. Method A session comprising 11 interleaved periods of 40sec ON and 20sec OFF auditory stimuli of 5kHz tone modulated by a 40Hz chirp at 0.1 duty cycle was administered to mild AD patients and non‐AD elderly participants with memory complaints, and EEG data were collected by a 10/20 system. Magnitude of 40Hz oscillations at different scalp positions during the ON cycles was measured as an indicator of the entrained Gamma oscillations. Result While 40Hz oscillations were recorded across a majority of electrodes in non‐AD demented participants with particular strengths in the temporal and frontal areas, the 40Hz entrainment occurred for a limited number of electrodes in AD patients. Conclusion Auditory chirp stimulation at 40Hz results in spatially distinguishable patterns of entrained Gamma oscillations in AD patients and non‐AD demented participants, and hence suggests a marker for AD. Despite this difference, the fact that 40Hz entrainment still occurs in regions of the brain in AD patients offers a positive indication for the possibility to employ such stimulation to reinvigorate the operation of the involved neural circuitry in therapy campaigns. Further studies are needed to assess such possibility.

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