Spencer K.M.,Research Service |
Spencer K.M.,Harvard University
Frontiers in Human Neuroscience | Year: 2012
Several studies have reported deficits in γ oscillatory activity elicited by sensory stimulation or cognitive processes in schizophrenia patients (SZ) compared to healthy control subjects (HC). However, the evidence for cortical hyperexcitability and reduced function of N -methyl-D-aspartate receptors (NMDARs) on parvalbumin-expressing inhibitory interneurons in schizophrenia leads to the prediction that γ activity should rather be increased in SZ, but data supporting this hypothesis have been lacking. One possibility is that baseline induced γ power is increased, an effect that might have gone unnoticed in studies of stimulus-locked oscillations. Here we addressed this question by re-analyzing the data from a previously published study on the 40 Hz auditory steady-state response (ASSR) in schizophrenia in which dipole source localization was used to examine γ responses in the left and right auditory cortices. Subjects were 16 HC and 18 chronic SZ, who listened to trains of clicks presented at 40 Hz during electroencephalogram recording. Independent component analysis was used to remove ocular artifacts. Power spectra were computed for the pre-stimulus baseline period. We found that baseline power was higher in SZ than HC at 40 Hz in the left auditory cortex. Baseline 40 Hz power in the left auditory cortex was also correlated with ASSR evoked power in SZ. Thus, γ oscillation abnormalities in schizophrenia may include abnormal increases in baseline power as well as deficits in evoked oscillations. These baseline increases could be the sign of NMDAR hypofunction on parvalbumin-expressing inhibitory interneurons, which would be consistent with acute NMDAR antagonism and genetic ablation models of schizophrenia. © 2012 Spencer.
Tregellas J.R.,Research Service |
Tregellas J.R.,Aurora University
Biological Psychiatry | Year: 2014
Given the relative inability of currently available antipsychotic treatments to adequately provide sustained recovery and improve quality of life for patients with schizophrenia, new treatment strategies are urgently needed. One way to improve the therapeutic development process may be an increased use of biomarkers in early clinical trials. Reliable biomarkers that reflect aspects of disease pathophysiology can be used to determine if potential treatment strategies are engaging their desired biological targets. This review evaluates three potential neuroimaging biomarkers: hippocampal hyperactivity, gamma-band deficits, and default network abnormalities. These deficits have been widely replicated in the illness, correlate with measures of positive symptoms, are consistent with models of disease pathology, and have shown initial promise as biomarkers of biological response in early studies of potential treatment strategies. Two key features of these deficits, and a guiding rationale for the focus of this review, are that the deficits are not dependent upon patients' performance of specific cognitive tasks and they have analogues in animal models of schizophrenia, greatly increasing their appeal for use as biomarkers. Using neuroimaging biomarkers such as those proposed here to establish early in the therapeutic development process if treatment strategies are having their intended biological effect in humans may facilitate development of new treatments for schizophrenia.
Young J.W.,University of California at San Diego |
Geyer M.A.,Research Service
Journal of Psychopharmacology | Year: 2015
Schizophrenia is a life-long debilitating mental disorder affecting tens of millions of people worldwide. The serendipitous discovery of antipsychotics focused pharmaceutical research on developing a better antipsychotic. Our understanding of the disorder has advanced however, with the knowledge that cognitive enhancers are required for patients in order to improve their everyday lives. While antipsychotics treat psychosis, they do not enhance cognition and hence are not antischizophrenics. Developing pro-cognitive therapeutics has been extremely difficult, however, especially when no approved treatment exists. In lieu of stumbling on an efficacious treatment, developing targeted compounds can be facilitated by understanding the neural mechanisms underlying altered cognitive functioning in patients. Equally importantly, these cognitive domains will need to be measured similarly in animals and humans so that novel targets can be tested prior to conducting expensive clinical trials. To date, the limited similarity of testing across species has resulted in a translational bottleneck. In this review, we emphasize that schizophrenia is a disorder characterized by abnormal cognitive behavior. Quantifying these abnormalities using tasks having cross-species validity would enable the quantification of comparable processes in rodents. This approach would increase the likelihood that the neural substrates underlying relevant behaviors will be conserved across species. Hence, we detail cross-species tasks which can be used to test the effects of manipulations relevant to schizophrenia and putative therapeutics. Such tasks offer the hope of providing a bridge between non-clinical and clinical testing that will eventually lead to treatments developed specifically for patients with deficient cognition. © The Author(s) 2014.
Madden J.A.,Medical College of Wisconsin |
Madden J.A.,Research Service
Neurology | Year: 2012
The underlying cause of stroke lies in the damage to the arterial endothelial cell layer. The most profound damage is due to atherosclerosis, which can either occlude an artery or produce a thromboembolism. Diabetes and inflammation contribute to atherosclerosis and the associated endothelial damage by initiating and promoting the deposition of modified lipids in the subendothelium and by inhibiting endothelial nitric oxide (NO) production. At the same time, both production of endothelin-1 and generation of reactive oxygen species increase. In addition, leukocytes adhere to the endothelium and levels of C-reactive protein increase. The stroke that ensues upon cerebral artery occlusion or plaque rupture continues and exacerbates endothelial damage. Statins have been shown to be helpful in preventing stroke and diminishing its consequences. An international clinical trial to determine if an NO donor is effective (Efficacy of Nitric Oxide in Stroke study) is currently under way. Other interventions such as antioxidants, ρ kinase inhibition, and endothelial progenitor cells offer promising avenues of research and perhaps therapeutic avenues for treatment of stroke. This article discusses the role of the vascular endothelium in ischemic stroke and those interventions that may provide plausible avenues for future therapy. © 2012 American Academy of Neurology.
Choubey D.,University of Cincinnati |
Choubey D.,Research Service
Clinical Immunology | Year: 2012
Upon sensing microbial and self-derived DNA, DNA sensors initiate innate immune responses. These sensors include the interferon (IFN)-inducible Toll-like receptor 9 (TLR9) and PYHIN proteins. Upon sensing DNA, cytosolic (murine Aim2 and human AIM2) and nuclear (IFI16) PYHIN proteins recruit an adaptor protein (ASC) and pro-caspase-1 to form an inflammasome, which activates caspase-1. The activated caspase-1 cleaves pro-IL-1β and pro-IL-18 to generate active forms. However, upon sensing cytosolic DNA, the IFI16 protein recruits STING to induce the expression of type I IFN. Recognition of self DNA by innate immune cells contributes to the production of increased levels of type I IFN. Given that the type I IFNs modulate the expression of inflammasome proteins and that the IFN-inducible proteins inhibit the activity of DNA-responsive inflammasomes, an improved understanding of the molecular mechanisms that regulate the activity of DNA-responsive inflammasomes is likely to identify new therapeutic targets to treat autoimmune diseases. © 2012 Elsevier Inc.