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Network-Targeted TMS-EEG Markers in Mild Cognitive Impairment and Alzheimer's Disease Dementia

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Title: Network-Targeted TMS-EEG Markers in Mild Cognitive Impairment and Alzheimer's Disease Dementia
Authors: Bertazzoli, Giacomo, Canu, Elisa, Bagattini, Chiara, Freri, Fabiola, Bonfiglio, Natale Salvatore, Brignani, Debora, Bulgari, Martina, Castelnovo, Veronica, Delai, Mara, Ferrari, Elisabetta, Fracassi, Claudia, Fried, Peter J, Lucarelli, Delia, Marcantoni, Eleonora, Marizzoni, Moira, Cattaneo, Annamaria, Nicolosi, Valentina, Quattrini, Giulia, Saglia, Silvia, Pievani, Michela, Romei, Vincenzo, Stango, Antonietta, Filippi, Massimo, Agosta, Federica, Bortoletto, Marta
Publisher Information: Zenodo, 2025.
Publication Year: 2025
Subject Terms: Alzheimer Disease/physiopathology, Electroencephalography, Transcranial Magnetic Stimulation
Description: Alzheimer’s disease is marked by progressive network disconnection, beginning decades before clinical symptoms emerge. Detecting early functional disruptions remains a key challenge. Transcranial magnetic stimulation combined with electroencephalography (TMS–EEG) offers a direct, non-invasive probe of cortical network dynamics and may provide novel biomarkers of disease-related dysfunction. Here, we investigated whether the amplitude of early TMS-evoked potential (TEP) peaks can differentiate between healthy controls (HC), individuals with mild cognitive impairment (MCI), and patients with Alzheimer’s disease dementia (ADD), and whether these measures relate to structural and cognitive markers both cross-sectionally and longitudinally. Eighty-six participants were tested: 28 HC (mean age 69.7±6.0, 15 female), 27 MCI (73.1±5.2, 16 female), and 31 ADD (75.8±4.9, 17 female). TMS-EEG was delivered to individualized targets within the default mode network (DMN, parietal sites) and executive control network (ECN, frontal sites), identified via resting-state fMRI. Using a data-driven peak identification strategy, we extracted four early TEP components from DMN stimulation—two frontal (N20F, P20F), one parietal (P20P), and one under the coil (N20C)—and three from ECN stimulation—two frontal (N20F, N20C) and one parietal (P20P)—all occurring within the first 50 ms. We assessed diagnostic group differences in TEP amplitudes, their relationship with hippocampal volume and white matter microstructure, their association with cognition, and their ability to predict cognitive decline over about 1.5 years. TEP amplitude differed significantly across diagnostic groups. After left DMN single-pulse stimulation, the N20F peak was increased in both MCI and ADD relative to HC (P = 0.011 and 0.001). In the ECN, N20C amplitude was reduced in MCI after left hemisphere stimulation (P = 0.036) but increased after right hemisphere stimulation in both MCI and ADD (P = 0.028 and 0.048). TEPs showed hemisphere-specific associations with white matter integrity and cognition. For white matter integrity, left DMN N20C amplitude showed a significant positive relationship with the integrity of the left superior longitudinal fasciculus (P = 0.009). For cognition, in ADD patients, higher left DMN P20P amplitude correlated with worse executive performance (P = 0.001). Under ECN stimulation, hemisphere-dependent effects emerged: smaller left N20F amplitudes (P < 0.001) and larger right N20F amplitudes (P < 0.001) both predicted better executive performance. Longitudinally, lower left DMN N20C amplitude predicted steeper global cognitive decline (P = 0.01), and right ECN N20C amplitude predicted executive decline in MCI (P = 0.0037). These findings demonstrate that early TEP peaks evoked from network-targeted stimulation capture functional alterations linked to Alzheimer’s disease progression. Network-specific, hemisphere-sensitive TEPs may serve as valuable biomarkers for diagnosis, tracking, and prognosis of cognitive decline in Alzheimer’s disease.
Document Type: Article
Language: English
DOI: 10.5281/zenodo.17162745
DOI: 10.5281/zenodo.17162524
DOI: 10.5281/zenodo.17162525
Accession Number: edsair.doi.dedup.....553697c1428194dbd1a61e98b1c41110
Database: OpenAIRE
Description
Abstract:Alzheimer’s disease is marked by progressive network disconnection, beginning decades before clinical symptoms emerge. Detecting early functional disruptions remains a key challenge. Transcranial magnetic stimulation combined with electroencephalography (TMS–EEG) offers a direct, non-invasive probe of cortical network dynamics and may provide novel biomarkers of disease-related dysfunction. Here, we investigated whether the amplitude of early TMS-evoked potential (TEP) peaks can differentiate between healthy controls (HC), individuals with mild cognitive impairment (MCI), and patients with Alzheimer’s disease dementia (ADD), and whether these measures relate to structural and cognitive markers both cross-sectionally and longitudinally. Eighty-six participants were tested: 28 HC (mean age 69.7±6.0, 15 female), 27 MCI (73.1±5.2, 16 female), and 31 ADD (75.8±4.9, 17 female). TMS-EEG was delivered to individualized targets within the default mode network (DMN, parietal sites) and executive control network (ECN, frontal sites), identified via resting-state fMRI. Using a data-driven peak identification strategy, we extracted four early TEP components from DMN stimulation—two frontal (N20F, P20F), one parietal (P20P), and one under the coil (N20C)—and three from ECN stimulation—two frontal (N20F, N20C) and one parietal (P20P)—all occurring within the first 50 ms. We assessed diagnostic group differences in TEP amplitudes, their relationship with hippocampal volume and white matter microstructure, their association with cognition, and their ability to predict cognitive decline over about 1.5 years. TEP amplitude differed significantly across diagnostic groups. After left DMN single-pulse stimulation, the N20F peak was increased in both MCI and ADD relative to HC (P = 0.011 and 0.001). In the ECN, N20C amplitude was reduced in MCI after left hemisphere stimulation (P = 0.036) but increased after right hemisphere stimulation in both MCI and ADD (P = 0.028 and 0.048). TEPs showed hemisphere-specific associations with white matter integrity and cognition. For white matter integrity, left DMN N20C amplitude showed a significant positive relationship with the integrity of the left superior longitudinal fasciculus (P = 0.009). For cognition, in ADD patients, higher left DMN P20P amplitude correlated with worse executive performance (P = 0.001). Under ECN stimulation, hemisphere-dependent effects emerged: smaller left N20F amplitudes (P < 0.001) and larger right N20F amplitudes (P < 0.001) both predicted better executive performance. Longitudinally, lower left DMN N20C amplitude predicted steeper global cognitive decline (P = 0.01), and right ECN N20C amplitude predicted executive decline in MCI (P = 0.0037). These findings demonstrate that early TEP peaks evoked from network-targeted stimulation capture functional alterations linked to Alzheimer’s disease progression. Network-specific, hemisphere-sensitive TEPs may serve as valuable biomarkers for diagnosis, tracking, and prognosis of cognitive decline in Alzheimer’s disease.
DOI:10.5281/zenodo.17162745