Hearing loss often triggers an inescapable buzz (tinnitus) and causes everyday sounds to become intolerably loud (hyperacusis), but exactly where and how this occurs in the brain is unknown. To identify the neural substrate for these debilitating disorders, we induced both tinnitus and hyperacusis with an ototoxic drug (salicylate) and used behavioral, electrophysiological, and functional magnetic resonance imaging (fMRI) techniques to identify the tinnitus–hyperacusis network. Salicylate depressed the neural output of the cochlea, but vigorously amplified sound-evoked neural responses in the amygdala, medial geniculate, and auditory cortex. Resting-state fMRI revealed hyperactivity in an auditory network composed of inferior colliculus, medial geniculate, and auditory cortex with side branches to cerebellum, amygdala, and reticular formation. Functional connectivity revealed enhanced coupling within the auditory network and segments of the auditory network and cerebellum, reticular formation, amygdala, and hippocampus. A testable model accounting for distress, arousal, and gating of tinnitus and hyperacusis is proposed.DOI: http://dx.doi.org/10.7554/eLife.06576.001

Objective. Subjective tinnitus is hypothesized to arise from aberrant neural activity; however, its neural bases are poorly understood. To identify aberrant neural networks involved in chronic tinnitus, we compared the resting-state functional magnetic resonance imaging (fMRI) patterns of tinnitus patients and healthy controls. Materials and Methods. Resting-state fMRI measurements were obtained from a group of chronic tinnitus patients (n = 29) with normal hearing and well-matched healthy controls (n = 30). Regional homogeneity (ReHo) analysis and functional connectivity analysis were used to identify abnormal brain activity; these abnormalities were compared to tinnitus distress. Results. Relative to healthy controls, tinnitus patients had significant greater ReHo values in several brain regions including the bilateral anterior insula (AI), left inferior frontal gyrus, and right supramarginal gyrus. Furthermore, the left AI showed enhanced functional connectivity with the left middle frontal gyrus (MFG), while the right AI had enhanced functional connectivity with the right MFG; these measures were positively correlated with Tinnitus Handicap Questionnaires (r = 0.459, P = 0.012 and r = 0.479, P = 0.009, resp.). Conclusions. Chronic tinnitus patients showed abnormal intra- and interregional synchronization in several resting-state cerebral networks; these abnormalities were correlated with clinical tinnitus distress. These results suggest that tinnitus distress is exacerbated by attention networks that focus on internally generated phantom sounds.

Thrombolysis has been a standard treatment for ischemic stroke. However, only 2-7% patients benefit from it because the thrombolytic agent has to be injected within 4.5 h after the onset of symptoms to avoid the increasing risk of intracerebral hemorrhage. As the only clinically approved neuroprotective drug, edaravone (EDV) rescues ischemic brain tissues by eradicating over-produced reactive oxygen species (ROS) without the limitation of therapeutic time-window. However, EDV's short circulation half-life and inadequate cerebral uptake attenuate its therapeutic efficacy. Here we developed an EDV-encapsulated agonistic micelle (EDV-AM) to specifically deliver EDV into brain ischemia by actively tuning blood-brain barrier (BBB) permeability. The EDV-AM actively up-regulated endothelial monolayer permeability in vitro. HPLC studies showed that EDV-AM delivered more EDV into brain ischemia than free EDV after intravenous injection. Magnetic resonance imaging also demonstrated that EDV-AM more rapidly salvaged ischemic tissue than free EDV. Diffusion tensor imaging indicated the highest efficiency of EDV-AM in accelerating axonal remodeling in the ipsilesional white matter and improving functional behaviors of ischemic stroke models. The agonistic micelle holds promise to improve the therapeutic efficiency of ischemic stroke patients who miss the thrombolytic treatment.

Background and Purpose Type 2 diabetes is associated with an increased risk for dementia. This study investigated the global connectivity patterns in the brains of patients with type 2 diabetes using a functional MRI technique. Materials and Methods Forty patients and 43 age-, sex- and education-matched healthy controls underwent resting-state functional imaging in a 3T MR unit. Degree centrality, a commonly employed measurement of global connectivity, was computed for a full-brain exploration of the regions influenced by type 2 diabetes. We then examined the functional connectivity of each region using the seed-based approach. Finally, voxel-wise correlation analyses were performed to explore the relationship between the connectivity changes, cognitive performance and diabetes-related variables. Results Patients exhibited decreased degree centrality in the left lingual gyrus, and increased centrality in the right insula and dorsal anterior cingulate cortex (corrected P <0.05). The occipital network anchored in the lingual gyrus showed extensively reduced connectivity, while the network connectivity of insula and cingulate cortex (mostly included in the salience network) was significantly elevated (corrected P <0.05). Correlational analyses revealed that in the diabetic group, impaired visual memory and executive-function performance were correlated with occipital hypoconnectivity, while higher fasting plasma glucose levels and better executive functioning was related to anterior cingulate cortex hyperconnectivity (all corrected P values <0.05). Similar effects were not detected in the controls. Conclusion This preliminary study shows that network connectivity is altered in patients with type 2 diabetes, which may provide critical insights into the neural substrate of diabetes-related cognitive decline.

BACKGROUND AND PURPOSE: Deep brain stimulation is a well-established treatment for generalized dystonia, but outcomes remain variable. Establishment of an imaging marker to guide device targeting and programming could possibly impact the efficacy of deep brain stimulation in dystonia, particularly in the absence of acute clinical markers to indicate benefit. We hypothesize that the stimulation-based functional and structural connectivity using resting-state fMRI and DTI can predict therapeutic outcomes in patients with generalized dystonia and deep brain stimulation. MATERIALS AND METHODS:We performed a retrospective analysis of 39 patients with inherited or idiopathic-isolated generalized dystonia who underwent bilateral globus pallidus internus deep brain stimulation. After electrode localization, the volumes of tissue activated were modeled and used as seed regions for functional and structural connectivity measures using a normative data base. Resulting connectivity maps were correlated with postoperative improvement in the Unified Dystonia Rating Scale score.RESULTS: Structural connectivity between the volumes of tissue activated and the primary sensorimotor cortex was correlated with Unified Dystonia Rating Scale improvement, while more anterior prefrontal connectivity was inversely correlated with Unified Dystonia Rating Scale improvement. Functional connectivity between the volumes of tissue activated and primary sensorimotor regions, motor thalamus, and cerebellum was most correlated with Unified Dystonia Rating Scale improvement; however, an inverse correlation with Unified Dystonia Rating Scale improvement was seen in the supplemental motor area and premotor cortex.CONCLUSIONS: Functional and structural connectivity with multiple nodes of the motor network is associated with motor improvement in patients with generalized dystonia undergoing deep brain stimulation. Results from this study may serve as a basis for future development of clinical markers to guide deep brain stimulation targeting and programming in dystonia. ABBREVIATIONS: ACPC ¼ anterior/posterior commissure; DBS ¼ deep brain stimulation; GPi ¼ globus pallidus internus; MNI ¼ Montreal Neurological Institute; UDRS ¼ Unified Dystonia Rating Scale; VTA ¼ volume of tissue activated

Matrix metalloproteinases (MMPs) exert a dual effect in ischemic stroke and thus represent an ideal target for detection and therapy. However, to date, all clinical trials of MMP inhibitors have failed, and alternative drug candidates and therapeutic targets are urgently required. Nonetheless, further investigations are limited by the lack of non-invasive imaging techniques. Here, we report a novel, fast and ultrasensitive MMP activatable optical imaging probe for the dynamic visualization of MMP activity in photothrombotic stroke mice. This probe provides a significant signal enhancement in as little as 15 min, with the highest signal intensity occurring at 1 h post-injection, and shows high sensitivity in measuring MMP activity alterations, which makes it specifically suitable for the real-time visualization of MMP activity and drug discovery in preclinical research. Moreover, using this probe, we successfully demonstrate that the regulation of the p38 mitogen-activated protein kinase (MAPK) signal pathway is capable of modulating MMP activity after stroke, revealing a novel regulatory mechanism of postischemic brain damage and overcoming the limitations of traditional therapeutic strategies associated with MMP inhibitors by using a non-invasive molecular imaging method.

• Dixon imaging demonstrated renal fat deposition in early-stage DN; • Renal fractional anisotropy decreased in patients with early-stage DN; • Renal tractography demonstrated reduced track counts and length in early-stage DN.

Type 2 diabetes mellitus (T2DM) is associated with severe axonal/white matter (WM) injury and poor functional outcomes following ischemic stroke. T2DM induces activation of p38 mitogen-activated protein kinases (MAPKs), which may be linked to the axonal/WM damage. In the present study, adult male C57BL/6J mice with streptozotocin (STZ)-induced T2DM mice were subjected to photothrombotic ischemic stroke and treatment with p38 MAPK inhibitors. The novel p38 MAPK inhibitor, VCP979, significantly promoted axonal/WM remodeling, neural progenitor cell migration, and improved functional recovery in T2DM mice. In vivo diffusion tensor imaging (DTI) revealed that the fractional anisotropy (FA) value, fiber number ratio, and fiber length were increased in the VCP979-treated group. Thus, VCP979 improves axonal/WM remodeling and functional outcomes in a diabetic mouse stroke model. DTI may aid in visualizing axonal/WM remodeling and evaluating the therapeutic efficacy of VCP979.