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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potential of dopamine D(1) receptor agonists to have beneficial effects on cognitive function has been suggested by a body of preclinical evidence. We now report the use of dihydrexidine (DAR-0100), the first full D(1) agonist, in a pilot study assessing single low dose safety and tolerability in patients with schizophrenia. A within-subject cross-over design was used in 20 adults (18-65 years) with SCID-IV diagnosed schizophrenia. Subjects were outpatients with a moderate level of residual negative symptoms, and were on stable dosing of non-D(1)-blocking antipsychotic drugs. Following screening, subjects were hospitalized for 48 h, and at 0800 h each morning scanned on a 3 T MRI scanner for resting brain perfusion, followed by a Blood Oxygen Level Dependent (BOLD) fMRI scan during an N-Back working memory task. They then received 20 mg subcutaneously (SC) of dihydrexidine or placebo over 15 min, followed by 45 min of intermittent MRI scans of perfusion and BOLD activity during the working memory task. Blood was drawn for serum drug levels and subjects were evaluated for clinical and cognitive changes. The procedure was repeated using the opposite challenge 2 days later. Dihydrexidine was well tolerated with no serious adverse events although three subjects had mild dizziness and five subjects experienced nausea. There was no significant effect of drug on clinical interview ratings or delayed (afternoon) neuropsychological performance. No medication interactions were seen. Thus, a single subcutaneous dose of dihydrexidine is tolerated and safe in patients with schizophrenia and does not produce delayed clinical or neuropsychological improvements.
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PMID:A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia. 1746 56

It is hypothesized that due to an abnormal functioning of the reward system patients with schizophrenia form context-inappropriate associations. It has been shown that the dopamine target regions, especially the ventral striatum, are critical in the formation of reward associations. We wanted to examine how the ventral striatum responds as patients learn reward-related associations and how this neural response is linked to objective and subjective behavioral measures. Functional magnetic resonance imaging (fMRI) Blood oxygen level dependent (BOLD) responses were examined using aversive Pavlovian learning in 13 medicated patients with schizophrenia and 13 matched healthy controls. Colored circles served as conditioned stimulus (CS+) while a loud, individually adjusted, noise served as the unconditioned stimulus. Circles of another color served as neutral comparators (CS-). Subjective indices were assessed by a post-scan self-report, and galvanic skin responses (GSR) were used as objective measures of associative learning. fMRI data were analyzed using a random effects model in SPM2. Patients showed inappropriately strong activations in the ventral striatum in response to the neutral stimulus (CS-) as compared to the healthy controls. Consistent with this neural evidence of aberrant learning, patients also showed evidence of abnormal learning by self-report and as indexed by GSR. The main finding here is that patients with schizophrenia, when exposed to neutral stimuli in a threatening situation, show an abnormal pattern of learning. The aberrant activations and response are consistent with the idea that patients aberrantly assign motivational salience to neutral stimuli, and this process may be one of the aberrations that predisposes them to psychosis.
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PMID:The formation of abnormal associations in schizophrenia: neural and behavioral evidence. 1747 38

Most models of schizophrenia are based on basal ganglia-thalamocortical (BGTC) neuronal circuits or brain structures that project to them. Two new neuronal networks have been described which include many of the brain regions associated with BGTC neuronal circuits. These networks have been characterized with a new brain-imaging technique based on low-frequency fluctuations of the blood oxygen level-dependent (BOLD) signal. The new network associated with attention-demanding tasks is referred to as the task-related network and the network associated with stimulus-independent thought during the resting state is referred to as the default network. The 2 networks have been proposed to be negatively correlated or anticorrelated. This article critically reviews the rationale for these anticorrelated networks, the technique with which they are characterized, and preliminary findings in schizophrenia and other neuropsychiatric disorders. Regions associated with the default network overlap with regions important in motivation and are activated by memory retrieval, auditory hallucinations, and ketamine. Task-related networks are necessary for performance of neurocognitive tasks on which schizophrenic patients often perform poorly. It is concluded that anticorrelated networks can be viewed as complementary ways of understanding self-monitoring and task performance which extend present models of schizophrenia based on BGTC circuits. However, there are some limitations with regard the present understanding of brain structures involved in self-monitoring and the lack of asymmetry in the network which may mediate stimulus-independent thought. Further investigations of the default network assessed by low-frequency fluctuations in the BOLD signal seem warranted.
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PMID:Are anticorrelated networks in the brain relevant to schizophrenia? 1749 57

Odorants represent powerful stimuli capable of eliciting various emotional responses. In schizophrenia patients and their non-affected relatives, olfactory and emotional functions are impaired, revealing a familial influence on these deficits. We aimed at determining the neural basis of emotional olfactory dysfunctions using odors of different emotional valence for mood induction and functional magnetic resonance imaging (fMRI) by comparing 13 schizophrenia patients, their non-affected brothers and 26 matched healthy controls. Blood-oxygen-level-dependent (BOLD) effects and subjective mood changes were assessed during negative (rotten yeast), positive (vanilla) and neutral (ambient air) olfactory stimulation. Group comparisons of brain activation were performed in regions of interest. Subjective ratings were comparable between groups and indicated successful mood induction. However, during stimulation with the negative odor, hypofunctional activity emerged in regions of the right frontal and temporal cortex in the patients. A familial influence in the neural substrates of negative olfactory dysfunction was indicated by a similar reduced frontal brain activity in relatives. Dysfunctions therefore appeared to be located in regions involved in higher cognitive processes associated with olfaction. No familial influences were indicated for cerebral dysfunctions during positive olfactory stimulation. Results point to a differentiation between trait and state components in cerebral dysfunctions during emotional olfactory processing in schizophrenia.
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PMID:Neural substrates of olfactory processing in schizophrenia patients and their healthy relatives. 1753 93

Spontaneous low-frequency fluctuations in the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (MRI) signal have been shown to reflect neural synchrony between brain regions. A "default network" of spontaneous low-frequency fluctuations has been described in healthy volunteers during stimulus-independent thought. Negatively correlated with this network are regions activated during attention-demanding tasks. Both these networks involve brain regions and functions that have been linked with schizophrenia in previous research. The present study examined spontaneous slow fluctuations in the BOLD signal at rest, as measured by correlation with low-frequency oscillations in the posterior cingulate, in 17 schizophrenic patients, and 17 comparable healthy volunteers. Healthy volunteers demonstrated correlation between spontaneous low-frequency fluctuations of the BOLD signal in the posterior cingulate and fluctuations in the lateral parietal, medial prefrontal, and cerebellar regions, similar to previous reports. Schizophrenic patients had significantly less correlation between spontaneous slow activity in the posterior cingulate and that in the lateral parietal, medial prefrontal, and cerebellar regions. Connectivity of the posterior cingulate was found to vary with both positive and negative symptoms in schizophrenic patients. Because these data suggest significant abnormalities in resting-state neural networks in schizophrenia, further investigations of spontaneous slow fluctuations of the BOLD signal seem warranted in this population.
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PMID:Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. 1755 52

Neuregulin-1 (NRG-1), a replicated gene in schizophrenia-association studies, exhibits six mRNA-types and two types of the EGF-like domain, alpha and beta. The beta-isoform was extensively studied, less is known about the extent and specific localization of adult brain NRG-1alpha. NRG-1alpha protein levels were reported reduced in postmortem prefrontal-cortex of schizophrenia patients. NRG-1 type I mRNA levels were found higher in postmortem brain in schizophrenia. In an attempt to decipher between a genetic or environmental involvement in the differences in NRG-1 levels in postmortem brain in schizophrenia, and since obstetric complications were suggested non-genetic risk-factors of schizophrenia, we studied the effect of perinatal hypoxia in rats on brain NRG-1alpha protein levels. Seven-day-old rats were exposed to hypoxia versus air. Frontal-cortex levels of NRG-1alpha isoform were quantified at adulthood by Western blotting. Frontal-cortex NRG-1alpha was 32% elevated in hypoxia-exposed rats. The data support the role of non-genetic factors, e.g. oxygen restriction, in the expression of genes associated with schizophrenia.
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PMID:Oxygen restriction of neonate rats elevates neuregulin-1alpha isoform levels: possible relationship to schizophrenia. 1763 47

The purpose of this study was to explore whether there are differences in cerebral asymmetry between subgroups of schizophrenic patients with or without auditory verbal hallucinations (AVHs) and normal controls by using event-related functional magnetic resonance imaging (efMRI). A total of 26 Chinese Han male patients with paranoid schizophrenia (diagnosed by DSM IV, including 13 patients with AVHs and 13 patients without) and 13 matched normal controls were recruited for the present study. The participants had been instructed to listen to short sentences from left or right side and to indicate laterality during efMRI scanning. Functional data were acquired using a 1.5T MR, and were analyzed using statistical parametric mapping. A random-effect model was employed to asses the difference in blood oxygen level dependent response between "left-sided" and "right-sided" conditions. The results from the present study have shown (1) within group comparisons: right precuneus and right superior parietal lobule were significantly activated showed significantly greater activation by left-sided voices than right-sided ones in controls. However, no significant difference in activation was found in any brain region between left and right-sided voices in either of the two patient subgroups, (2) between group comparisons: in comparison with AVHs patients, right middle frontal gyrus (MFG) was markedly activated when control subjects were differentiating right-sided voices. In comparison with patients without AVHs, right-side stimuli significantly activated bilateral MFG and left postcentral gyrus in control group. Furthermore, compared to the non-hallucination group, left Wernicke's area, including supramarginal gyrus, angular gyrus and superior temporal gyrus, was significantly activated by both left and right-sided voices in the hallucination group. In summary, auditory-related asymmetry in control subjects is attenuated in schizophrenic patients. The symptoms of AVHs in schizophrenia are possibly correlated with left hemispheric, particularly auditory and language-related areas dysfunction.
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PMID:Relationship of auditory verbal hallucinations with cerebral asymmetry in patients with schizophrenia: an event-related fMRI study. 1767 31

An accumulating body of evidences point to the significance of neuroinflammation and immunogenetics in schizophrenia, characterized by increased serum concentration of several pro-inflammatory cytokines. In the central nervous system (CNS), the microglial cells are the major immunocompetent cells which release pro-inflammatory cytokines, nitric oxide (NO) and reactive oxygen species to mediate the inflammatory process. In the present study, we investigated whether or not atypical antipsychotics, namely perospirone, quetiapine and ziprasidone, would have anti-inflammatory effects on the activated microglia which may potentiate neuroprotection. All three atypical antipsychotics significantly inhibited NO generation from activated microglia while perospirone and quetiapine significantly inhibited the TNF-alpha release from activated microglia. Antipsychotics, especially perospirone and quetiapine may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia.
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PMID:The effect of atypical antipsychotics, perospirone, ziprasidone and quetiapine on microglial activation induced by interferon-gamma. 1865 69

Deleterious effects of dopamine (DA) involving mitochondrial dysfunction have an important role in DA-associated neuronal disorders, including schizophrenia and Parkinson's disease. DA detrimental effects have been attributed to its ability to be auto-oxidized to toxic reactive oxygen species. Since, unlike Parkinson's disease, schizophrenia does not involve neurodegenerative processes, we suggest a novel mechanism by which DA impairs mitochondrial function without affecting cell viability. DA significantly dissipated mitochondrial membrane potential (delta psi m) in SH-SY5Y cells. Bypassing complex I prevented the DA-induced depolarization. Moreover, DA inhibited complex I but not complex II activity in disrupted mitochondria, suggesting complex I participation in DA-induced mitochondrial dysfunction. We further demonstrated that intact mitochondria can accumulate DA in a saturated manner, with an apparent Km=122.1+/-28.6 nM and Vmax=1.41+/-0.15 pmol/mg protein/min, thereby enabling the interaction between DA and complex I. DA accumulation was an energy and Na+-dependent process. The pharmacological profile of mitochondrial DA uptake differed from that of other characterized DA transporters. Finally, relevance to schizophrenia is demonstrated by an abnormal interaction between DA and complex I in schizophrenic patients. These results suggest a non-lethal interaction between DA and mitochondria possibly via complex I, which can better explain DA-related pathological processes observed in non-degenerative disorders, such as schizophrenia.
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PMID:Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: relevance to dopamine pathology in schizophrenia. 1799 21

After having provided a brief reminder of the principle of the blood oxygen level-dependent (BOLD) contrast effect, the physiological bases of brain activity and the concepts of functional integration and effective connectivity, we describe the most recent approaches, which permit to explore brain activity and putative networks of interconnected active areas in order to examine the normal brain physiology and its dysfunctions. We present various methods and studies of brain activity analysis clinically applicable, and we detail the concepts of functional and effective connectivity, which allow to study the cerebral plasticity which occurs at the child's during the maturation (e.g., dyslexia), at the adult during the ageing (e.g., Alzheimer disease), or still in schizophrenia or Parkinson disease. The study of specific circuits in networks has to allow defining in a more realistic way the dynamic of the central nervous system, which underlies various cerebral functions, both in physiological and pathological conditions. This connectivity approach should improve the diagnostic and facilitate the development of new therapeutic strategies.
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PMID:[Clinical interest of fMRI and functional exploration methods of brain activity and interactivity: physical and neurophysiological considerations]. 1820 38


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