Aug 2026· Neurobiology of Aging· Vol 168, pp.
147-158
· 0 citations· 58 references
Medicine
TL;DR
Trans transcranial magnetic stimulation with electromyography is used to investigate mechanisms of motor cortical excitability in biomarker-positive early-AD participants and 72 cognitively unimpaired age-matched adults and shows that early-AD participants have increased motor cortical excitability, related to cognition.
Abstract
Recent studies suggest that cortical hyperexcitability in Alzheimer's disease (AD) may accelerate disease progression. However, the field lacks validated non-invasive methods to assay excitability in humans. In this study we used transcranial magnetic stimulation with electromyography to investigate mechanisms of motor cortical excitability in 63 biomarker-positive early-AD (ranging from mild cognitive impairment to mild dementia) participants and 72 cognitively unimpaired age-matched adults (CU). Single-pulse stimulation was applied to motor cortex to record resting motor thresholds (rMT) and motor-evoked potentials. An Input-Output curve was generated by delivering 10 pulses each at eight different intensities of maximum stimulator output (%MSO). Linear models or equivalent non-parametric tests 1) compared excitability metrics between groups, 2) tested correlations with cognition (mini-mental state exam, MMSE; Alzheimer's disease assessment scale-cognitive, ADAS-Cog), and 3) tested the impact of APOE4. Results show that early-AD participants have increased motor cortical excitability than CU, with lower rMT (p < 0.001), lower Input-Output curve Inflection Point (p = 0.007), and higher Dynamic Range (p = 0.035). An analysis of the Input-Output curve adjusting for rMT showed larger responses in AD specifically in the 135-150% rMT range (p = 0.023). In AD, higher excitability was related to worse cognition (rMT: MMSE p = 0.008, Inflection Point: MMSE p = 0.030 and ADAS-Cog p = 0.041). There was no relationship between APOE4 and excitability. In conclusion, AD participants have increased motor cortical excitability, related to cognition. This is evident both at lower and higher stimulation intensities. TMS may provide a useful measure of target engagement for therapies aimed at preserving cognition or slowing decline in early-AD.
Parkinson’s disease is a neurodegenerative disorder with characteristic motor deficits of bradykinesia and impaired coordination, and non-motor deficits affecting cognitive abilities such as attention and executive functions. Recent evidence suggests that some canonical motor deficits in Parkinson’s disease (e.g., freezing of gait) are associated with abnormalities in frontal cortical processing typically thought to underlie executive functions such as cognitive control. The evidence from human research linking frontal cognitive disruption and motor deficits in people with Parkinson’s disease is correlational. Individuals with cognitive impairments often also display gait and balance deficits, but causal evidence remains lacking. We combined non-invasive brain stimulation with functional MRI (fMRI) to ascertain whether dorsolateral prefrontal cortex (DLPFC) exerts a causal influence modulating motor function and to test the hypothesis that an excitatory stimulation protocol applied to a cognitive control network can improve motor performance in Parkinson disease. Participants with Parkinson’s disease performed a precision force-tracking task shown to track with gait impairment while undergoing functional neuroimaging scans. On half of trials, participants were required to simultaneously perform a cognitively demanding 2-back working memory task to tax attentional systems. Following the initial baseline scan, participants returned for three separate counterbalanced sessions that combined transcranial magnetic stimulation (TMS) in the form of theta burst stimulation (TBS) with fMRI. Just prior to task performance, participants received either excitatory (intermittent TBS) or inhibitory (continuous TBS) stimulation protocols over right DLPFC. In the third session, participants received stimulation to a control site outside the cognitive and motor areas implicated in our task. Our within-subjects experimental design allowed us to examine the effects of stimulation on motor behavior, the influence of cognitive load on motor behavior, and the neural systems supporting cognitive control and motor execution. Consistent with our hypothesis, excitatory stimulation of DLPFC improved motor performance in a precision force-tracking task as indexed by reduced tracking error and smoother movement execution. These effects emerged preferentially under dual-task conditions when cognitive demands were high. Our results show that this improved motor performance coincides with reductions in functional connectivity not only between the stimulation site and primary motor cortex, but also within the recently described somato-cognitive action network (SCAN) thought to support action planning and whole-body movement coordination. We conclude that frontal cognitive control systems play a causal role in modulating movement in Parkinson’s disease and suggest that targeting these systems with non-invasive interventions may enhance motor function.
Rupsha Panda, James A. Brissenden, Teresa Scerbak et al.· bioRxiv· 0 citations
Progressive, age-dependent remodeling of motor cortex somatotopic remodeling is demonstrated in 5XFAD mice, characterized by early expansion of specific simple movement cortical sites followed by deterioration of both complex and simple motor cortical maps as disease advances.
SE Moss, Cassandra C. Wolsh, Rmii Brown et al.· bioRxiv· 0 citations
BACKGROUND
Stroke is a leading cause of death and disability worldwide, with 35-80% of survivors developing cognitive impairment that affects quality of life. Current diagnostic tools are limited, highlighting the need for objective, cost-effective biomarkers for post-stroke cognitive impairment (PSCI).
AIM
To investigate the relationship between PSCI severity and sensorimotor evoked potentials, compare interhemispheric sensorimotor cortex excitability, and assess the utility of these potentials for PSCI screening.
SUBJECTS AND METHODS
Twenty-two stroke patients underwent neuropsychological and clinical evaluations at 3-6 months post-stroke, with testing performed within 7±3 days of the scheduled date. Patients were divided into mild cognitive impairment (MCI) and dementia groups. Motor evoked potentials (MEP) elicited by single-pulse transcranial magnetic stimulation assessed primary motor cortex excitability, while somatosensory evoked potentials (SEP) from median nerve stimulation evaluated primary somatosensory cortex excitability.
RESULTS
MEP absence showed a dose-dependent relationship with cognitive severity (Kendall's tau-b = -0.467, p = 0.029); 80% of MEP-absent patients had dementia versus 20% of MEP-present cases. In hemispheric analysis, affected hemispheres displayed elevated the resting motor threshold (RMT) (p < 0.001) and prolonged SEP N20 latency (p < 0.05), while unaffected hemispheres showed increased RMT in the MCI-with-MEP and dementia-without-MEP groups (p < 0.05), with reduced amplitude in dementia-with-MEP patients (p < 0.01). No linear SEP-cognition relationship emerged.
CONCLUSIONS
PSCI severity correlates with MEP presence/absence, not SEP measures. Notably, the excitability of the unaffected motor cortex progressively declines with worsening cognition. Although MEP shows promise as a biomarker for cognitive impairment assessment, longitudinal validation is needed to confirm its predictive utility.
Zhipeng Yan, Hao Luo, Bilian Guo· Annals of Human Biology· 0 citations
Early identification of mild cognitive impairment in Parkinson’s disease (PD-MCI) is crucial for delaying dementia progression, yet the mechanisms underlying cortical excitability and time-varying network dysconnectivity remain elusive. This study utilized transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to characterize time-varying directed brain network alterations targeting the right posterior parietal cortex (PPC) in PD-MCI. 20 PD patients were categorized into PD-MCI and cognitively normal (PD-NC) groups using the Montreal Cognitive Assessment (MoCA). Adaptive directed transfer function (ADTF) was applied to assess whole-brain directed time-varying functional connectivity following right PPC stimulation. Machine learning models were then employed to classify PD-MCI using spatiotemporal network features. Compared to PD-NC, the PD-MCI group exhibited significantly reduced cross-regional directed connectivity across the full 1–45 Hz frequency band. Notably, this decoupling was most pronounced in the γ band, with widespread disruptions across multiple time windows. Abnormal connectivity strengths were significantly positively correlated with MoCA cognitive scores. A KNN classification model was constructed based on 5 key spatiotemporal features, and using 5 repetitions of 5-fold cross-validation, ultimately achieving an optimal classification accuracy of 93.33%. These findings reveal that PPC-targeted, full-frequency time-varying network decoupling is a core neuropathological mechanism in PD-MCI. The identified spatiotemporal features hold promise as objective biomarkers for the early identification of PD-MCI, providing a foundation for early diagnosis and targeted neuromodulation.
Qi Zhu, Guangying Pei, Meng-Xuan Hu et al.· Journal of Physics, Conferen...· 0 citations
Different diagnostic group-specific patterns in the olfaction-brain structure relationship are highlighted, with implications for understanding early pathological aging and neurodegeneration.
P. P. Giriprakash, J. Caldwell, R. L. Doty et al.· Journal of Neurological Scie...· 0 citations
INTRODUCTION
Cortical inhibitory-excitatory imbalance may contribute to motor dysfunction in Parkinson's disease (PD), but in vivo primary motor cortex (M1) neurochemistry remains incompletely characterized.
METHODS
We used 7T proton MR spectroscopy to quantify γ-aminobutyric acid (GABA) and glutamate (Glu) in M1 in patients with mild-to-moderate PD and healthy controls. The inhibitory/excitatory ratio (I/E ratio, GABA/Glu) was derived as an exploratory measure. After quality control, baseline analyses included 32 patients and 28 controls. A self-paced bilateral handgrip task was conducted in a subgroup with15 patients and 14 controls.
RESULTS
At rest, patients with PD showed higher GABA concentrations than controls, but this did not survive FDR correction across the two primary metabolites (pFDR = 0.06). There was no difference in Glu between the two groups. The I/E ratio was also higher in PD. Higher GABA showed nominal associations with greater MDS-UPDRS III scores, but these did not survive correction. During the motor task, Glu increased across groups, with no significant group × condition interaction for GABA, Glu. Task findings were preliminary given limited power.
CONCLUSIONS
Ultra-high-field MRS preliminary evidence for altered resting M1 GABAergic neurochemistry in mild-to-moderate PD. Task-related findings require validation in larger cohorts. These findings support the utility of 7T MRS for probing motor-cortical neurochemistry in PD.
Ning Wei, Dong-Ning Su, Zhe Zhang et al.· Parkinsonism & Related Disor...· 0 citations
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