Decreased Frontal Gamma Activity in Alzheimer Disease Patients

Abstract

Objective In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high‐frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS‐EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild‐to‐moderate AD patients. Methods Sixty mild‐to‐moderate AD patients and 21 age‐matched healthy volunteers (HVs) underwent 3 TMS‐EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS‐based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution. Results AD patients showed a significant reduction of frontal gamma activity as compared to age‐matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long‐term potentiation–like plasticity and a more pronounced cognitive decline at subsequent follow‐up evaluation at 24 weeks. Interpretation Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS‐EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 2022;92:464–475

The Effect of Coil Orientation on the Stimulation of the Pre–Supplementary Motor Area: A Combined TMS and EEG Study

“…Table 1 and Figure 3 report the E–fields computed for the 12 conditions explored. Our results showed that, even with the lowest intensity of stimulation (100% RMT), the estimated E–fields were well above the threshold of 40 V/m to evoke a reliable TMS–evoked EEG response [ 22 , 26 ]. To note that the E–fields obtained at 0° and 90° CO were higher than those at 180° and 270°; this might, to an extent, have contributed to our results (see below).…”

“…To ensure that the chosen stimulation intensities could generate an electric field (E–field) in the cortex sufficient for a reliable TEP, i.e., at least 40 V/m [ 22 , 26 ], we computed the induced E–field over the TMS target with SimNIBS v3.2, an open–source simulation package that integrates segmentation of MRI scans, mesh generation and FEM E–field estimate [ 27 ]. The E–field was computed for the twelve stimulation conditions resulting from the combination of four COs (0°, 90°, 180°, 360°) and three SIs (100%, 120%, 140% RMT).…”

“…It is possible that, as for M1, different neuronal populations can be activated in the pre–SMA by varying CO and SI; however, investigating this outside M1 is difficult due to the absence of a direct readout such as MEP. This problem can be solved with the use of combined TMS and electroencephalography (TMS–EEG), which allows to record postsynaptic potentials generated by the magnetic pulse in the form of transcranial evoked potentials (TEPs) [ 7 , 18 , 19 , 20 ] or oscillations [ 21 , 22 ], and, thus, to have a readout from cortical areas outside M1.…”

“…To assess cortical excitability, we analysed TEPs in terms of discrete peaks and local mean field potential (LMFP), a reference–free measure commonly used to measure local excitability of a specific area, from a cluster of nearby electrodes [ 6 , 23 , 24 ]. To assess cortical oscillations, we computed TMS–related spectral perturbation (TRSP), a measure reflecting the power of TMS–evoked response in the frequency domain [ 21 , 22 , 24 ]. These variables were computed locally to the SMA since we were interested in the response of this area obtained with three different SIs (100%, 120% and 140%) of resting motor threshold (RMT) and four different COs (0°, 90°, 180° and 270°, starting with the coil handle pointing posteriorly on the transverse plane and proceeding counterclockwise).…”

Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders

“…Moreover, in AD animal models, the synaptic dysfunction has been linked to a disorder of high-frequency neuronal oscillatory activity, in particular in the gamma range (40 Hz) [ 19 , 20 ]. Accordingly, in a recent work, TMS combined with EEG (TMS-EEG) recordings have shown that AD patients had more prominent decrease in gamma activity in the prefrontal cortex with a stronger impairment of LTP-like plasticity mechanisms and more prominent cognitive decline [ 21 ]. Interestingly, the optogenetic entrainment of fast-spiking parvalbumin-positive interneurons of AD animal model at gamma frequencies was able to reduce the total amyloid levels, probably acting on both neurons and microglia [ 22 ].…”