Anterior cingulate cortex (ACC) is known to be involved in functions such as emotion, pain, and cognitive control. While studies in humans and nonhuman mammals have advanced our understanding of ACC ...function, the subjective correlates of ACC activity have remained largely unexplored. In the current study, we show that electrical charge delivery in the anterior midcingulate cortex (aMCC) elicits autonomic changes and the expectation of an imminent challenge coupled with a determined attitude to overcome it. Seed-based, resting-state connectivity analysis revealed that the site of stimulation in both patients was at the core of a large-scale distributed network linking aMCC to the frontoinsular and frontopolar as well as some subcortical regions. This report provides compelling, first-person accounts of electrical stimulation of this brain network and suggests its possible involvement in psychopathological conditions that are characterized by a reduced capacity to endure psychological or physical distress.
•Electrical stimulation of the anterior cingulate region performed in two subjects•A stereotyped set of cognitive and autonomic changes was elicited in both subjects•This included feeling of anticipated challenge and strong motivation to overcome it•Site of stimulation in both subjects was a core node of the brain’s salience network
Parvizi et al. combine functional neuroimaging with electrical stimulation of the human brain in two participants implanted with electrodes inside their brain. They highlight the importance of a key brain network for producing the “the will to persevere.”
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Alzheimer’s disease (AD) is considered a polygenic disorder. This view is clouded, however, by lingering uncertainty over how to treat the quasi “monogenic” role of apolipoprotein E (APOE). The APOE4 ...allele is not only the strongest genetic risk factor for AD, it also affects risk for cardiovascular disease, stroke, and other neurodegenerative disorders. This review, based mostly on data from human studies, ranges across a variety of APOE-related pathologies, touching on evolutionary genetics and risk mitigation by ethnicity and sex. The authors also address one of the most fundamental question pertaining to APOE4 and AD: does APOE4 increase AD risk via a loss or gain of function? The answer will be of the utmost importance in guiding future research in AD.
Does APOE4 increase risk for Alzheimer’s disease via a gain or loss of function? Belloy et al., focusing on human data, examine critical issues like pleiotropy, sex, and ancestral background, to address this fundamental question.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from ...aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. Our analysis supports the conduct of a third, phase III trial with high‐dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Functional brain networks detected in task-free ("resting-state") functional magnetic resonance imaging (fMRI) have a small-world 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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case–control studies suggest the APOE4 link to AD is stronger in women. We examined the ...APOE4‐by‐sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels.
Methods
Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE‐by‐sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative.
Results
Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4‐by‐sex interaction on biomarker levels was significant for MCI patients for total tau and the tau‐to‐Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD‐like in women).
Interpretation
APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE‐related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis. Ann Neurol 2014;75:563–573
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Resting-state functional connectivity magnetic resonance imaging (fcMRI) studies constitute a growing proportion of functional brain imaging publications. This approach detects temporal correlations ...in spontaneous blood oxygen level–dependent (BOLD) signal oscillations while subjects rest quietly in the scanner. Although distinct resting-state networks related to vision, language, executive processing, and other sensory and cognitive domains have been identified, considerable skepticism remains as to whether resting-state functional connectivity maps reflect neural connectivity or simply track BOLD signal correlations driven by nonneural artifact. Here we combine diffusion tensor imaging (DTI) tractography with resting-state fcMRI to test the hypothesis that resting-state functional connectivity reflects structural connectivity. These 2 modalities were used to investigate connectivity within the default mode network, a set of brain regions—including medial prefrontal cortex (MPFC), medial temporal lobes (MTLs), and posterior cingulate cortex (PCC)/retropslenial cortex (RSC)—implicated in episodic memory processing. Using seed regions from the functional connectivity maps, the DTI analysis revealed robust structural connections between the MTLs and the retrosplenial cortex whereas tracts from the MPFC contacted the PCC (just rostral to the RSC). The results demonstrate that resting-state functional connectivity reflects structural connectivity and that combining modalities can enrich our understanding of these canonical brain networks.
Background Transcranial magnetic stimulation (TMS) to the left dorsolateral prefrontal cortex (DLPFC) is used clinically for the treatment of depression. However, the antidepressant mechanism remains ...unknown and its therapeutic efficacy remains limited. Recent data suggest that some left DLPFC targets are more effective than others; however, the reasons for this heterogeneity and how to capitalize on this information remain unclear. Methods Intrinsic (resting state) functional magnetic resonance imaging data from 98 normal subjects were used to compute functional connectivity with various left DLPFC TMS targets employed in the literature. Differences in functional connectivity related to differences in previously reported clinical efficacy were identified. This information was translated into a connectivity-based targeting strategy to identify optimized left DLPFC TMS coordinates. Results in normal subjects were tested for reproducibility in an independent cohort of 13 patients with depression. Results Differences in functional connectivity were related to previously reported differences in clinical efficacy across a distributed set of cortical and limbic regions. Dorsolateral prefrontal cortex TMS sites with better clinical efficacy were more negatively correlated (anticorrelated) with the subgenual cingulate. Optimum connectivity-based stimulation coordinates were identified in Brodmann area 46. Results were reproducible in patients with depression. Conclusions Reported antidepressant efficacy of different left DLPFC TMS sites is related to the anticorrelation of each site with the subgenual cingulate, potentially lending insight into the antidepressant mechanism of TMS and suggesting a role for intrinsically anticorrelated networks in depression. These results can be translated into a connectivity-based targeting strategy for focal brain stimulation that might be used to optimize clinical response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
It is commonly assumed that functional brain connectivity reflects structural brain connectivity. The exact relationship between structure and function, however, might not be straightforward. In this ...review we aim to examine how our understanding of the relationship between structure and function in the ‘resting’ brain has advanced over the last several years. We discuss eight articles that directly compare resting-state functional connectivity with structural connectivity and three clinical case studies of patients with limited white matter connections between the cerebral hemispheres. All studies examined show largely convergent results: the strength of resting-state functional connectivity is positively correlated with structural connectivity strength. However, functional connectivity is also observed between regions where there is little or no structural connectivity, which most likely indicates functional correlations mediated by indirect structural connections (i.e. via a third region). As the methodologies for measuring structural and functional connectivity continue to improve and their complementary strengths are applied in parallel, we can expect important advances in our diagnostic and prognostic capacities in diseases like Alzheimer’s, multiple sclerosis, and stroke.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
During resting conditions the brain remains functionally and metabolically active. One manifestation of this activity that has become an important research tool is spontaneous fluctuations in the ...blood oxygen level-dependent (BOLD) signal of functional magnetic resonance imaging (fMRI). The identification of correlation patterns in these spontaneous fluctuations has been termed resting state functional connectivity (fcMRI) and has the potential to greatly increase the translation of fMRI into clinical care. In this article we review the advantages of the resting state signal for clinical applications including detailed discussion of signal to noise considerations. We include guidelines for performing resting state research on clinical populations, outline the different areas for clinical application, and identify important barriers to be addressed to facilitate the translation of resting state fcMRI into the clinical realm.
Deactivation refers to increased neural activity during low-demand tasks or rest compared with high-demand tasks. Several groups have reported that a particular set of brain regions, including the ...posterior cingulate cortex and the medial prefrontal cortex, among others, is consistently deactivated. Taken together, these typically deactivated brain regions appear to constitute a default-mode network of brain activity that predominates in the absence of a demanding external task. Examining a passive, block-design sensory task with a standard deactivation analysis (rest epochs vs. stimulus epochs), we demonstrate that the default-mode network is undetectable in one run and only partially detectable in a second run. Using independent component analysis, however, we were able to detect the full default-mode network in both runs and to demonstrate that, in the majority of subjects, it persisted across both rest and stimulus epochs, uncoupled from the task waveform, and so mostly undetectable as deactivation. We also replicate an earlier finding that the default-mode network includes the hippocampus suggesting that episodic memory is incorporated in default-mode cognitive processing. Furthermore, we show that the more a subject's default-mode activity was correlated with the rest epochs (and “deactivated” during stimulus epochs), the greater that subject's activation to the visual and auditory stimuli. We conclude that activity in the default-mode network may persist through both experimental and rest epochs if the experiment is not sufficiently challenging. Time-series analysis of default-mode activity provides a measure of the degree to which a task engages a subject and whether it is sufficient to interrupt the processes—presumably cognitive, internally generated, and involving episodic memory—mediated by the default-mode network.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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