Neural oscillations subserve many human perceptual and cognitive operations. Accordingly, brain functional connectivity is not static in time, but fluctuates dynamically following the synchronization and desynchronization of neural populations. This dynamic functional connectivity has recently been demonstrated in spontaneous fluctuations of the Blood Oxygen Level-Dependent (BOLD) signal, measured with functional Magnetic Resonance Imaging (fMRI). We analyzed temporal fluctuations in BOLD connectivity and their electrophysiological correlates, by means of long (≈50 min) joint electroencephalographic (EEG) and fMRI recordings obtained from two populations: 15 awake subjects and 13 subjects undergoing vigilance transitions. We identified positive and negative correlations between EEG spectral power (extracted from electrodes covering different scalp regions) and fMRI BOLD connectivity in a network of 90 cortical and subcortical regions (with millimeter spatial resolution). In particular, increased alpha (8–12 Hz) and beta (15–30 Hz) power were related to decreased functional connectivity, whereas gamma (30–60 Hz) power correlated positively with BOLD connectivity between specific brain regions. These patterns were altered for subjects undergoing vigilance changes, with slower oscillations being correlated with functional connectivity increases. Dynamic BOLD functional connectivity was reflected in the fluctuations of graph theoretical indices of network structure, with changes in frontal and central alpha power correlating with average path length. Our results strongly suggest that fluctuations of BOLD functional connectivity have a neurophysiological origin. Positive correlations with gamma can be interpreted as facilitating increased BOLD connectivity needed to integrate brain regions for cognitive performance. Negative correlations with alpha suggest a temporary functional weakening of local and long-range connectivity, associated with an idling state.

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Abstract-In ventricular cardiac myocytes, T-tubule density is an important determinant of the synchrony of sarcoplasmic reticulum (SR) Ca 2ϩ release and could be involved in the reduced SR Ca 2ϩ release in ischemic cardiomyopathy. We therefore investigated T-tubule density and properties of SR Ca 2ϩ release in pigs, 6 weeks after inducing severe stenosis of the circumflex coronary artery (91Ϯ3%, Nϭ13) with myocardial infarction (8.8Ϯ2.0% of total left ventricular mass). Severe dysfunction in the infarct and adjacent myocardium was documented by magnetic resonance and Doppler myocardial velocity imaging. Myocytes isolated from the adjacent myocardium were compared with myocytes from the same region in weight-matched control pigs. T-tubule density quantified from the di-8-ANEPPS (di-8-butyl-aminonaphthyl-ethylene-pyridinium-propyl-sulfonate) sarcolemmal staining was decreased by 27Ϯ7% (PϽ0.05). Synchrony of SR Ca 2ϩ release (confocal line scan images during whole-cell voltage clamp) was reduced in myocardium myocytes. Delayed release (ie, ] i occurring later than 20 ms) occurred at 35.5Ϯ6.4% of the scan line in myocardial infarction versus 22.7Ϯ2.5% in control pigs (PϽ0.05), prolonging the time to peak of the line-averaged [Ca 2ϩ ] i transient (121Ϯ9 versus 102Ϯ5 ms in control pigs, PϽ0.05). Delayed release colocalized with regions of T-tubule rarefaction and could not be suppressed by activation of protein kinase A. The whole-cell averaged [Ca 2ϩ ] i transient amplitude was reduced, whereas L-type Ca 2ϩ current density was unchanged and SR content was increased, indicating a reduction in the gain of Ca 2ϩ -induced Ca 2ϩ release. In conclusion, reduced T-tubule density during ischemic remodeling is associated with reduced synchrony of Ca 2ϩ release and reduced efficiency of coupling Ca 2ϩ influx to Ca Key Words: myocardial infarction Ⅲ contractility Ⅲ myocytes Ⅲ calcium A lthough new therapeutic approaches have decreased the mortality associated with myocardial infarction (MI) over the past decades, 1 many patients nevertheless sustain a regional loss of myocardial contractile tissue following an ischemic event. The resulting increased hemodynamic burden on the left ventricle leads to structural and functional changes in the remaining viable myocardium, which further reduces ventricular performance, a process referred to as myocardial remodeling. 2 Sustained regional chronic and/or intermittent ischemia further contributes to this process, and the resulting ischemic cardiomyopathy is currently among the major causes of heart failure. 3 Contractile dysfunction of the ventricle is partly related to the abnormal loading in vivo 4 and partly to the intrinsic properties of the cardiomyocytes. Myocytes isolated from patients with ischemic cardiomyopathy at the time of heart transplantation have a reduced contractile function resulting from abnormal Ca 2ϩ handling. [5][6][7] Animal models have examined the mechanisms of cellular dysfunction in ischemic cardiomyopathy in more detail. Myocytes from the infarct border...

The integration of segregated brain functional modules is a prerequisite for conscious awareness during wakeful rest. Here, we test the hypothesis that temporal integration, measured as longterm memory in the history of neural activity, is another important quality underlying conscious awareness. For this aim, we study the temporal memory of blood oxygen level-dependent signals across the human nonrapid eye movement sleep cycle. Results reveal that this property gradually decreases from wakefulness to deep nonrapid eye movement sleep and that such decreases affect areas identified with default mode and attention networks. Although blood oxygen level-dependent spontaneous fluctuations exhibit nontrivial spatial organization, even during deep sleep, they also display a decreased temporal complexity in specific brain regions. Conversely, this result suggests that long-range temporal dependence might be an attribute of the spontaneous conscious mentation performed during wakeful rest.T he human brain displays complex spatiotemporal patterns of energy-consuming activity, even in the absence of an explicit task or stimulation (1). Large efforts have been devoted to the study of spontaneous neural activity encoded in the slow (∼0.1 Hz) fluctuations of the blood oxygen level-dependent (BOLD) signal, which are measured with functional MRI (fMRI). Nontrivial spatial organization of functional brain activity in resting state networks (RSNs) was consistently shown (2-4), comprising brain regions with high BOLD signal coherence and anatomical consistency with systems activated during task performance or stimulation (5).Remarkably, although human nonrapid eye movement (NREM) sleep is characterized by impaired awareness and reduced conscious mentation, organization into RSNs is preserved in light sleep (6) and to a large extent, deeper sleep stages (7, 8) (SI Appendix, Fig. S8.1). In particular, the default mode network (DMN; a set of task-deactivated regions implied with internal conscious cognitive processes) (9, 10) was repeatedly observed during deep sleep, albeit with reduced frontal connectivity (11,12). Although brain modules are preserved, even in the absence of conscious awareness, their functional integration is greatly impaired (8,13,14), which was predicted by an information integration account of consciousness (15). These results suggest that ongoing conscious mentation is not the only origin of RSN activity, whereas the level of consciousness is reflected in the interaction of functional networks.However, brain activity is not completely characterized in the spatial domain only. fMRI BOLD signals display rich temporal organization, including scale-free 1/f power spectra and long-range temporal autocorrelations (16)(17)(18), with activity at any given time being influenced by the previous history of the system up to several minutes into the past. These landmarks of complex information processing and rapid adaptability are shared by many systems found in nature (19,20). Evidence for such properties is also manifest...

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This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.

Progressive force loss in Duchenne muscular dystrophy is characterized by degeneration/regeneration cycles and fibrosis. Disease progression may involve structural remodeling of muscle tissue. An effect on molecular motorprotein function may also be possible. We used second harmonic generation imaging to reveal vastly altered subcellular sarcomere microarchitecture in intact single dystrophic mdx muscle cells (approximately 1 year old). Myofibril tilting, twisting, and local axis deviations explain at least up to 20% of force drop during unsynchronized contractile activation as judged from cosine angle sums of myofibril orientations within mdx fibers. In contrast, in vitro motility assays showed unaltered sliding velocities of single mdx fiber myosin extracts. Closer quantification of the microarchitecture revealed that dystrophic fibers had significantly more Y-shaped sarcomere irregularities ("verniers") than wild-type fibers (approximately 130/1000 microm(3) vs. approximately 36/1000 microm(3)). In transgenic mini-dystrophin-expressing fibers, ultrastructure was restored (approximately 38/1000 microm(3) counts). We suggest that in aged dystrophic toe muscle, progressive force loss is reflected by a vastly deranged micromorphology that prevents a coordinated and aligned contraction. Second harmonic generation imaging may soon be available in routine clinical diagnostics, and in this work we provide valuable imaging tools to track and quantify ultrastructural worsening in Duchenne muscular dystrophy, and to judge the beneficial effects of possible drug or gene therapies.

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