Abstract

Dementia causes a substantial global economic burden, but effective treatment is lacking. Recently, studies have revealed that gamma-band waves of electrical brain activity, particularly 40 Hz oscillations, are closely associated with high-order cognitive functions and can activate microglia to clear amyloid-β deposition. Here, we found that compared with sham stimulation, applying 40-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) over the bilateral angular gyrus in patients with probable Alzheimer’s disease (AD; n = 37) resulted in up to 8 weeks of significantly improved cognitive function. Power spectral density analysis of the resting-state electroencephalography (EEG) demonstrated that 40-Hz rTMS modulated gamma-band oscillations in the left posterior temporoparietal region. Further testing with magnetic resonance imaging and TMS-EEG revealed the following: 40-Hz rTMS 1) prevented gray matter volume loss, 2) enhanced local functional integration within bilateral angular gyrus, as well as global functional integration in bilateral angular gyrus and the left middle frontal gyrus, 3) strengthened information flow from the left posterior temporoparietal region to the frontal areas and strengthened the dynamic connectivity between anterior and posterior brain regions. These findings demonstrate that modulating gamma-band oscillations effectively improves cognitive function in patients with probable AD by promoting local, long-range, and dynamic connectivity within the brain.

cognitive impairment, fMRI, gamma oscillations, rTMS, TMS-EEG
Issue Section:
Original Article

Introduction

Dementia is a growing global health problem that has created heavy social and economic burdens (Jia et al. 2020). Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by significant cognitive decline. Its pathogenesis involves the extracellular accumulation of amyloid-β (Aβ) plaques and intracellular tau protein aggregates called neurofibrillary tangles (Ittner and Gotz 2011). Current medications for these targets are not always beneficial and have failed to hinder disease progression (Doody et al. 2014; Salloway et al. 2014). Increasing evidence suggests that Aβ plaques aggravate synapse loss and the depression of synaptic activity (Li et al. 2009; Forner et al. 2017). Specially, even soluble Aβ oligomers appearing in the very early stage of AD are toxic for synapses and impair synaptic plasticity (Querfurth and LaFerla 2010). The synaptic dysfunction and pathology that result from disturbed neurotransmission might lead to deficits in functional integration within the cognitive neural network of the brain and thus in cognition itself (Tamura et al. 2018).

Neuronal oscillations play an essential role in efficient neural communication during cognitive processing. Specifically, they facilitate the transient coupling of synchronously firing neurons that form functional neural networks (Nyhus and Curran 2010). Among all oscillation frequencies, gamma-band oscillations (30–80 Hz) are most closely associated with high-order cognitive function (Jadi et al. 2016). Previous studies have shown that gamma oscillations provide a unique and robust mechanism for effectively modulating perceptual feature binding and the encoding and retrieval of episodic memories (Hanslmayr et al. 2009; Nyhus and Curran 2010). Studies of synaptic plasticity based on spike timing showed that gamma oscillations accurately and rapidly established synchronous neuronal activity between presynaptic and postsynaptic neurons within intervals of 10–30 ms (Axmacher et al. 2006; Jutras and Buffalo 2010), which are enough to strengthen the connections between neurons and promote information transmission through Hebbian long-term potentiation (Dan and Poo 2004; Wespatat et al. 2004). Reduced gamma power accompanied by spontaneous gamma synchronization has been observed in both patients with AD and rodent models (Verret et al. 2012; Gillespie et al. 2016). A recent study has shown that 40-Hz gamma oscillations can activate microglia that clear Aβ deposition (Iaccarino et al. 2016). Furthermore, increasing the power of these oscillations can enhance attention, memory, and other cognitive functions (Jensen et al. 2007). Therefore, modulating 40-Hz gamma oscillations in the brain might constitute a promising therapy for improving cognitive function in patients with AD.

The earliest and most severe pathological changes in AD occur primarily in the memory circuit of Papez and in the posterior default mode network, which includes the medial temporal lobe, inferior parietal lobule, precuneus, and posterior cingulate gyrus (Jagust 2018). Correspondingly, the primary neurological complaints of patients with AD are deficits in episodic memory, attention, executive function, and visuospatial processing. Aβ is preferentially deposited in the cortical hubs, which have a high degree of structural and functional connectivity and play a pivotal role in functional integration (Elman et al. 2016; Grothe and Teipel 2016). The angular gyrus (AG) is one such a hub, having extensive connections with the medial temporal lobe, precuneus, dorsolateral prefrontal cortex, and superior parietal lobe. Its activity is associated with memory retrieval and formation, perceptual attention, decision-making, and manipulation (Wang et al. 2014; Sestieri et al. 2017). Therefore, improving the function of this core node might facilitate information integration within different cognitive domains for effective AD therapy (Fox et al. 2012, 2014).

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technology that generates a time-varying magnetic field capable of inducing electrical currents in the brain. The induced currents can elicit action potentials in neurons of the targeted brain region (Hallett 2000). TMS could create a “virtual lesion” with low-frequency stimulation as well as augment brain activity, that is, excitability, with high frequency stimulation by neuroplasticity mechanisms. In addition to these local effects, TMS can also produce distant effects in brain regions that are connected with the site of stimulation (Hallett et al. 2017). Recently, TMS has been widely used for therapy of brain disorders including depression, anxiety, insomnia, stroke, and even for AD (Burke et al. 2019).

Recent studies have shown that brain function can be modulated by rhythmic TMS pulses because they regulate brain oscillations by resetting the ongoing oscillatory activity (Brignani et al. 2008; Thut et al. 2011). Recently, gamma-rhythmic sensory stimuli (flicker and acoustic stimulation) have been used to improve cognitive function, thus providing an important advancement in the nonpharmacological treatment of cognitive impairment (Iaccarino et al. 2016, Martorell et al. 2019). Although gamma rhythmic TMS that targets local cortical areas can directly modulate local neuronal firing (Hallett, 2000), whether this technique can be used to treat AD remains unknown. Therefore, exploring whether entrainment of cortical brain rhythms via repetitive transcranial magnetic stimulation (rTMS)-evoked gamma oscillations can improve cognitive function will help us understand how dysfunctional neuronal circuits contribute to AD, which could spur the development of more effective nonpharmacological treatment protocols.

Functional magnetic resonance imaging (fMRI) is an effective tool for detecting changes in brain activity and connectivity, which can help us determine mechanisms of neuromodulation. Moreover, TMS combined with electroencephalography (TMS-EEG) is a valuable real-time method for probing changes in brain connectivity dynamics and the efficiency of information transmission at a high temporal resolution (Hallett et al. 2017; Kaarre et al. 2018; Burke et al. 2019). Thus, by combining fMRI with TMS-EEG, we can better understand functional connections and information transmission within the brains of patients with AD.

Here, we propose 2 hypotheses: 1) Can we rewire brain connections by regulating brain oscillations? 2) Does regulating gamma oscillations increase local functional connections in core brain regions and long-range functional connections between distal brain regions by enhancing synaptic plasticity, promoting information transmission, and improving cognitive function? Here, 40-Hz high-frequency rTMS over the bilateral AG was applied to determine whether rTMS can reverse cognitive decline. fMRI and TMS-EEG neuroimaging analyses were performed to determine the neurophysiological processes underlying the effects of the rTMS.

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