Table 4 Summary of the selected auditory stimulation studies

Lee et al. [48]

40 Hz

2 h/day over 2 weeks

5xFAD mice

(5 months old)

Molecular and cellular readouts

 Reduced Aβ plaque number in the prelimbic and infralimbic cortices and HPC (IHC)

 Reduced soluble and insoluble Aβ_1-40 and Aβ_1-42 species in the prelimbic and infralimbic regions (ELISA)

 Increased microglia number in the HPC and prelimbic and infralimbic cortices (IHC)

Brain function readouts

 Exaggerated increase of evoked gamma band oscillations in the day after stimulation, decreased over the treatment (wavelet analysis of EEG)

 Increased resting-spontaneous gamma power on days 7 and 14 (EEG)

 Evoked gamma oscillation in the brain facilitates microglial aggregation in 5xFAD mice and their wild-type littermates (EEG and IHC)

 Enhanced brain connectivity, with frontal gamma rhythms coupling with parietal delta at baseline; and to parietal theta brainwaves after stimulation (EEG)

Martorell et al. [30]

- 8, 40, 80 Hz and random tone stimulation

(AS)

- 40 Hz and random tone stimulation

(AS + VS)

20 min/session (1–10 min intervals) 1 h/day (5 sessions) over 7 days

5xFAD

(6 months old)

C57BL/6 J

(3–8 months old)

APP/PS1

(6 months old)

Tau P301S mice

(6 months old)

Molecular and cellular readouts

 Reduced soluble Aβ levels and Aβ plaque area and number in the AC and HPC of 5xFAD and APP/PS1 mice after 40-Hz AS (ELISA and IHC)

 Increased microglia response in the AC and HPC of 5XFAD and APP/PS1 mice after 40-Hz AS, reversed at the 1-week follow-up, except for microglia number in the AC of 5xFAD mice (IHC)

 Increased astrocyte reactivity and vascular dilation in the AC and HPC of 5XFAD mice after 40-Hz AS (IHC)

 Reduced Tau hyperphosphorylation and seeding in the AC and HPC of Tau P301S mice after 40-Hz AS (IHC, WB, and FRET)

 Increased microglial activity displaying an encapsulating effect around Aβ aggregates in the AC, HPC, and mPFC after 40-Hz AS + VS (IHC and 3D reconstruction using IMARIS)

 Reduced Aβ plaque area and number in the AC, VC, HPC, and mPFC of 5XFAD mice after 40-Hz AS + VS (IHC and SHIELD processing)

 Decreased soluble and insoluble Aβ_1-42 levels in the AC, VC, HPC, and mPFC of 5XFAD mice after 40-Hz AS + VS (ELISA and IHC)

Behavioral and brain function readouts:

 Improved spatial and recognition memory after 40-Hz AS in 5xFAD mice (MWM, novel object recognition, and novel object location tasks)

 Gamma brainwave entrainment in the AC and HPC after 40-Hz AS (electrophysiology)

 Gamma brainwave entrainment in the AC, HPC, and mPFC after 40-Hz AS + VS (electrophysiology)

 Greater entrainment and therapeutic effects after combined AS + VS compared to AS alone

Clements-Cortes et al. [83]

40 Hz

(VS + VAS)

30 min/session, 2 sessions/week over 6 weeks (6 VS and 6 VAS sessions)

AD patients

(mild to severe AD)

(age: 59–93)

Behavioral readouts

 Increased cognitive function after 40-Hz VAS, but not after VS (Saint Louis University mental status)

 No significant changes in mood and anxiety (observed emotion rating scale)

 Increased awareness of surroundings, increased interaction, stimulation of discussion/story telling, and increased alertness after 40-Hz VAS (researcher observation)

Calomeni et al. [49]

8, 10, 12, 14, and 15 Hz

(AS + VS)

3 min for each frequency/day, 10 sessions on alternate days over 20 days

AD patients and healthy non-demented older adults

(age: 76 ± 8)

Behavioral and brain function readouts

 Gains in memory function associated with brain wave modulation (EEG)

 Enhanced alpha brainwave activity in AD patients, but not in non-demented elderly (EEG)

 Tendency for improved working memory function in AD patients (Digit Span Test)

Papalambros et al. [70]

20 Hz

Five 50-ms pulses (1.2-s interval) over one night during sleep

Healthy non-demented older adults

(age: 60–84)

Behavioral and brain function readouts

 Increased slow-wave activity and tendency for improved theta and fast spindle power during stimulation (EEG)

 Enhanced amplitude during stimulation for all potentials and larger slow-waves (EEG)

 Increased spindle density and amplitude during stimulation (EEG)

 Increased slow-wave activity during stimulation was associated with improved memory function (cued-recall tests)

 Mean phase stimulation was positively correlated with recall enhancement

 No significant differences in self-reported sleep quality, mood, and alertness between stimulated and sham-treated subjects (sleep-quality, mood and alertness questionnaires)

Papalambros et al. [31]

20 Hz

Five 50-ms pulses (1.2-s interval) over one night during sleep

Amnestic mild cognitive impaired patients

(age: 72 ± 8.7)

Behavioral and brain function readouts

 Increased slow oscillations, slow-wave, and sigma activities during stimulation (EEG)

 No significant differences in theta and beta activities during stimulation (EEG)

 Tendency for improved overnight word recall after stimulation (cued-recall tests)

 Alterations in slow-wave, slow oscillations, and sigma activities during stimulation were positively correlated with overnight word recall

 Increased slow-wave activity during stimulation was associated with improved cognition (verbal paired-associates task and NIH Toolbox Cognition Battery)

 Improved memory in 5 out of 9 patients (cued-recall tests)

 No significant differences in self-reported sleep quality (sleep quality and alertness questionnaires) and sleep-staging features between stimulated and sham (polysomnography)