Scopolamine effects on functional brain connectivity: a pharmacological model of Alzheimer's disease (original) (raw)
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Graph theoretical analysis of magnetoencephalographic functional connectivity in Alzheimer's disease
Brain, 2008
In this study we examined changes in the large-scale structure of resting-state brain networks in patients with Alzheimer's disease compared with non-demented controls, using concepts from graph theory. Magneto-encephalograms (MEG) were recorded in 18 Alzheimer's disease patients and 18 non-demented control subjects in a no-task, eyes-closed condition. For the main frequency bands, synchronization between all pairs of MEG channels was assessed using a phase lag index (PLI, a synchronization measure insensitive to volume conduction). PLI-weighted connectivity networks were calculated, and characterized by a mean clustering coefficient and path length. Alzheimer's disease patients showed a decrease of mean PLI in the lower alpha and beta band. In the lower alpha band, the clustering coefficient and path length were both decreased in Alzheimer's disease patients. Network changes in the lower alpha band were better explained by a 'Targeted Attack' model than by a 'Random Failure' model. Thus, Alzheimer's disease patients display a loss of resting-state functional connectivity in lower alpha and beta bands even when a measure insensitive to volume conduction effects is used. Moreover, the large-scale structure of lower alpha band functional networks in Alzheimer's disease is more random. The modelling results suggest that highly connected neural network 'hubs' may be especially at risk in Alzheimer's disease. by guest on February 22, 2016 http://brain.oxfordjournals.org/ Downloaded from C. J. Stam et al. by guest on February 22, 2016 http://brain.oxfordjournals.org/ Downloaded from w , are determined. Finally, the ratiosĈ w andL w are computed (E). Random brain networks in Alzheimer's disease Brain 2009: 132; 213-224 | 217 by guest on February 22, 2016 http://brain.oxfordjournals.org/ Downloaded from Fig. 9 In the left panel the correlation of mean PLI in the lower alpha band and MMSE is shown (Spearman's r = 0.570, P = 0.001), in the right panel the correlation of the mean clustering coefficient with MMSE in the beta band (Spearman's r = 0.475, P = 0.008).
Brain connectivity, 2012
In Alzheimer's disease (AD), structural and functional brain network organization is disturbed. However, many of the present network analysis measures require a priori assumptions and methodological choices that influence outcomes and interpretations. Graph spectral analysis (GSA) is a more direct algebraic method that describes network properties, which might lead to more reliable results. In this study, GSA was applied to magnetoencephalography (MEG) data to explore functional network integrity in AD. Sensor-level resting-state MEG was performed in 18 Alzheimer patients (age 67 ± 9, 6 women) and 18 healthy controls (age 66 ± 9, 11 women). Weighted, undirected graphs were constructed based on functional connectivity analysis using the Synchronization likelihood, and GSA was performed with a focus on network connectivity, synchronizability, and node centrality. The main outcomes were a global loss of network connectivity and altered synchronizability in most frequency bands. Eig...
2011
We have investigated functional connectivity of the default mode network (DMN) in normal aging and Alzheimer's disease (AD) using resting state fMRI at 3T. Images from young and elderly controls, and patients with AD were processed using spatial independent component analysis to identify the DMN. Functional connectivity was quantified using integration and indices derived from graph theory. Four DMN sub-systems were identified: Frontal (medial frontal, superior frontal), Parietal (precuneus-posterior cingulate, lateral parietal), Temporal (medial temporal cortices), and Hippocampal (left and right). There was a decrease in antero-posterior interactions (lower global efficiency), but increased interactions within the Frontal and Parietal sub-systems (higher local clustering) in elderly compared to young controls. The decreased antero-posterior integration was more pronounced in AD patients compared to elderly controls, particularly in the precuneus-posterior cingulate region. The approach allows for a complete characterization of connectivity changes and could be applied to other resting state networks and pathologies.
Neuropharmacology, 2014
Synchronization of electroencephalographic (EEG) oscillations represents a core mechanism for cortical and subcortical networks, and disturbance in neural synchrony underlies cognitive processing deficits in neurological and neuropsychiatric disorders. Here, we investigated the effects of cognition enhancers (donepezil, rivastigmine, tacrine, galantamine and memantine), which are approved for symptomatic treatment of dementia, on EEG oscillations and network connectivity in conscious rats chronically instrumented with epidural electrodes in different cortical areas. Next, EEG network indices of cognitive impairments with the muscarinic receptor antagonist scopolamine were modeled. Lastly, we examined the efficacy of cognition enhancers to normalize those aberrant oscillations. Cognition enhancers elicited systematic ("fingerprint") enhancement of cortical slow theta (4.5-6 Hz) and gamma (30.5-50 Hz) oscillations correlated with lower activity levels. Principal component an...
European Neuropsychopharmacology, 2016
Acetylcholinesterase inhibitors (AChEIs) are efficacious for the treatment of mild to moderate forms of Alzheimer's dementia (AD). Default-mode network (DMN) connectivity is considered to be early impaired in AD. Long-term effects of AChEIs on the DMN in AD have not yet been investigated. Twenty-eight AD patients and 11 age-matched healthy volunteers (HC) participated in the prospective study. AD patients were randomly assigned to either a pharmacotherapy arm (Galantamine, AD G) or to a placebo arm (AD P +G) for the period of 6 months followed by openlabel Galantamine therapy from month 7-12. All subjects underwent neuropsychological testing, resting-state functional and structural MRI at baseline and after 12 months, AD patients additionally in between after 6 months. Thirteen AD patients completed the treatment trial and underwent all functional MRI follow-up sequences of good quality. Functional connectivity significantly increased within the AD G group in the posterior cingulate cortex and in the Precuneus between baseline and 12 months followup (p corr o0.05). Between-group analyses demonstrated that functional connectivity in the AD G group significantly increased in the posterior cingulate cortex as well as in the Precuneus compared to the HC group and in the anteromedial aspect of the temporal lobes compared to
Effects of scopolamine on MEG spectral power and coherence in elderly subjects
Clinical Neurophysiology, 2003
Objective: Scopolamine, a muscarinic receptor antagonist, can produce temporary cognitive impairments as well as electroencephalographic changes that partially resemble those observed in Alzheimer's disease. In order to test the sensitivity of spectral power and hemispheric coherence to changes in cholinergic transmission, we evaluated quantitative magnetoencephalogram (MEG) after intravenous injection of scopolamine.
Magnetoencephalographic evaluation of resting-state functional connectivity in Alzheimer's disease
NeuroImage, 2006
Statistical interdependencies between magnetoencephalographic signals recorded over different brain regions may reflect the functional connectivity of the resting-state networks. We investigated topographic characteristics of disturbed resting-state networks in Alzheimer's disease patients in different frequency bands. Whole-head 151channel MEG was recorded in 18 Alzheimer patients (mean age 72.1 years, SD 5.6; 11 males) and 18 healthy controls (mean age 69.1 years, SD 6.8; 7 males) during a no-task eyes-closed resting state. Pair-wise interdependencies of MEG signals were computed in six frequency bands (delta, theta, alpha1, alpha2, beta and gamma) with the synchronization likelihood (a nonlinear measure) and coherence and grouped into long distance (intra-and interhemispheric) and short distance interactions. In the alpha1 and beta band, Alzheimer patients showed a loss of long distance intrahemispheric interactions, with a focus on left fronto-temporal/parietal connections. Functional connectivity was increased in Alzheimer patients locally in the theta band (centro-parietal regions) and the beta and gamma band (occipito-parietal regions). In the Alzheimer group, positive correlations were found between alpha1, alpha2 and beta band synchronization likelihood and MMSE score. Resting-state functional connectivity in Alzheimer's disease is characterized by specific changes of long and short distance interactions in the theta, alpha1, beta and gamma bands. These changes may reflect loss of anatomical connections and/or reduced central cholinergic activity and could underlie part of the cognitive impairment. D
Network Analysis of Intrinsic Functional Brain Connectivity in Alzheimer's Disease
PLoS Computational Biology, 2008
Functional brain networks detected in task-free (''resting-state'') functional magnetic resonance imaging (fMRI) have a smallworld architecture that reflects a robust functional organization of the brain. Here, we examined whether this functional organization is disrupted in Alzheimer's disease (AD). Task-free fMRI data from 21 AD subjects and 18 age-matched controls were obtained. Wavelet analysis was applied to the fMRI data to compute frequency-dependent correlation matrices. Correlation matrices were thresholded to create 90-node undirected-graphs of functional brain networks. Small-world metrics (characteristic path length and clustering coefficient) were computed using graph analytical methods. In the low frequency interval 0.01 to 0.05 Hz, functional brain networks in controls showed small-world organization of brain activity, characterized by a high clustering coefficient and a low characteristic path length. In contrast, functional brain networks in AD showed loss of small-world properties, characterized by a significantly lower clustering coefficient (p,0.01), indicative of disrupted local connectivity. Clustering coefficients for the left and right hippocampus were significantly lower (p,0.01) in the AD group compared to the control group. Furthermore, the clustering coefficient distinguished AD participants from the controls with a sensitivity of 72% and specificity of 78%. Our study provides new evidence that there is disrupted organization of functional brain networks in AD. Small-world metrics can characterize the functional organization of the brain in AD, and our findings further suggest that these network measures may be useful as an imaging-based biomarker to distinguish AD from healthy aging.