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BACKGROUNDWe aimed to characterize factors associated with the under-studied complication of cognitive decline in aging people with long-duration type 1 diabetes (T1D).METHODSJoslin \"Medalists\" (n = 222; T1D ≥ 50 years) underwent cognitive testing. Medalists (n = 52) and age-matched nondiabetic controls (n = 20) underwent neuro- and retinal imaging. Brain pathology (n = 26) was examined. Relationships among clinical, cognitive, and neuroimaging parameters were evaluated.RESULTSCompared with controls, Medalists had worse psychomotor function and recall, which associated with female sex, lower visual acuity, reduced physical activity, longer diabetes duration, and higher inflammatory cytokines. On neuroimaging, compared with controls, Medalists had significantly lower total and regional brain volumes, equivalent to 9 years of accelerated aging, but small vessel disease markers did not differ. Reduced brain volumes associated with female sex, reduced psychomotor function, worse visual acuity, longer diabetes duration, and higher inflammation, but not with glycemic control. Worse cognitive function, lower brain volumes, and diabetic retinopathy correlated with thinning of the outer retinal nuclear layer. Worse baseline visual acuity associated with declining psychomotor function in longitudinal analysis. Brain volume mediated the association between visual acuity and psychomotor function by 57%. Brain pathologies showed decreased volumes, but predominantly mild vascular or Alzheimer's-related pathology.CONCLUSION To our knowledge, this is the first comprehensive study of cognitive function, neuroimaging, and pathology in aging T1D individuals demonstrated that cognitive decline was related to parenchymal rather than neurovascular abnormalities, unlike type 2 diabetes, suggestive of accelerated aging in T1D. Improving visual acuity could perhaps be an important preventive measure against cognitive decline in people with T1D.FUNDINGThe Beatson Foundation, NIH/NIDDK grants 3P30DK036836-34S1 and P30DK036836-37, and Mary Iacocca fellowships.

Introduction Functional MRI is widely used to study task‐related changes in neuronal activity as well as resting‐state functional connectivity. In this study, we explore task‐related changes in functional connectivity networks using fMRI. Dynamic connectivity may represent a new measure of neural network robustness that would impact both clinical and research efforts. However, prior studies of task‐related changes in functional connectivity have shown apparently conflicting results, leading to several competing hypotheses regarding the relationship between task‐related and resting‐state brain networks. Methods We used a graph theory‐based network approach to compare functional connectivity in healthy subjects between the resting state and when performing a clinically used semantic decision task. We analyzed fMRI data from 21 healthy, right‐handed subjects. Results While three nonoverlapping, highly intraconnected functional modules were observed in the resting state, an additional language‐related module emerged during the semantic decision task. Both overall and within‐module connectivity were greater in default mode network (DMN) and classical language areas during semantic decision making compared to rest, while between‐module connectivity was diffusely greater at rest, revealing a more widely distributed pattern of functional connectivity at rest. Conclusions The results of this study suggest that there are differences in network topology between resting and task states. Specifically, semantic decision making is associated with a reduction in distributed connectivity through hub areas of the DMN as well as an increase in connectivity within both default and language networks. Functional connectivity networks are more widely distributed at rest compared to during visual semantic decision making. During a semantic decision task, classical language areas as well as default mode areas form distinct highly intraconnected functional networks which may be related to language and verbal memory function.

Generalized tonic–clonic seizures cause widespread physiological changes throughout the cerebral cortex and subcortical structures in the brain. Using combined blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at 9.4 T and electroencephalography (EEG), these changes can be characterized with high spatiotemporal resolution. We studied BOLD changes in anesthetized Wistar rats during bicuculline-induced tonic–clonic seizures. Bicuculline, a GABAA receptor antagonist, was injected systemically and seizure activity was observed on EEG as high-amplitude, high-frequency polyspike discharges followed by clonic paroxysmal activity of lower frequency, with mean electrographic seizure duration of 349 s. Our aim was to characterize the spatial localization, direction, and timing of BOLD signal changes during the pre-ictal, ictal and post-ictal periods. Group analysis was performed across seizures using paired t-maps of BOLD signal superimposed on high-resolution anatomical images. Regional analysis was then performed using volumes of interest to quantify BOLD timecourses. In the pre-ictal period we found focal BOLD increases in specific areas of somatosensory cortex (S1, S2) and thalamus several seconds before seizure onset. During seizures we observed BOLD increases in cortex, brainstem and thalamus and BOLD decreases in the hippocampus. The largest ictal BOLD increases remained in the focal regions of somatosensory cortex showing pre-ictal increases. During the post-ictal period we observed widespread BOLD decreases. These findings support a model in which “generalized” tonic–clonic seizures begin with focal changes before electrographic seizure onset, which progress to non-uniform changes during seizures, possibly shedding light on the etiology and pathophysiology of similar seizures in humans.

Objective Brain connectivity at rest is altered in temporal lobe epilepsy (TLE), particularly in “hub” areas such as the posterior default mode network (DMN). Although both functional and anatomical connectivity are disturbed in TLE, the relationships between measures as well as to seizure frequency remain unclear. We aim to clarify these associations using connectivity measures specifically sensitive to hubs. Methods Connectivity between 1000 cortical surface parcels was determined in 49 TLE patients and 23 controls with diffusion and resting‐state functional magnetic resonance imaging. Two types of hub connectivity were investigated across multiple brain modules (the DMN, motor system, etcetera): (1) within‐module connectivity (a measure of local importance that assesses a parcel's communication level within its own subnetwork) and (2) between‐module connectivity (a measure that assesses connections across multiple modules). Results In TLE patients, there was lower overall functional integrity of the DMN as well as an increase in posterior hub connections with other modules. Anatomical between‐module connectivity was globally decreased. Higher DMN disintegration (DD) coincided with higher anatomical between‐module connectivity, whereas both were associated with increased seizure frequency. DD related to seizure frequency through mediating effects of anatomical connectivity, but seizure frequency also correlated with anatomical connectivity through DD, indicating a complex interaction between multimodal networks and symptoms. Interpretation We provide evidence for dissociated anatomical and functional hub connectivity in TLE. Moreover, shifts in functional hub connections from within to outside the DMN, an overall loss of integrative anatomical communication, and the interaction between the two increase seizure frequency.

Optimal brain function depends upon efficient control over the brain entry of blood components; this is provided by the blood-brain barrier (BBB). Curiously, some brain-impermeable drugs can still cause behavioral side effects. To investigate this phenomenon, we asked whether the promiscuous drug efflux transporter Mdr1 has dual functions in transporting drugs and endogenous molecules. If this is true, brain-impermeable drugs may cause behavioral side effects by affecting brain levels of endogenous molecules. Using computational, genetic and pharmacologic approaches across diverse organisms we demonstrate that BBB-localized efflux transporters are critical for regulating brain levels of endogenous steroids, and steroid-regulated behaviors (sleep in Drosophila and anxiety in mice). Furthermore, we show that Mdr1-interacting drugs are associated with anxiety-related behaviors in humans. We propose a general mechanism for common behavioral side effects of prescription drugs: pharmacologically challenging BBB efflux transporters disrupts brain levels of endogenous substrates, and implicates the BBB in behavioral regulation.