Medicine (RMH Academic Centre) - Research Publications
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ItemReversal of evoked gamma oscillation deficits is predictive of antipsychotic activity with a unique profile for clozapine(NATURE PUBLISHING GROUP, 2016-04-19)Recent heuristic models of schizophrenia propose that abnormalities in the gamma frequency cerebral oscillations may be closely tied to the pathophysiology of the disorder, with hypofunction of N-methyl-d-aspartate receptors (NMDAr) implicated as having a crucial role. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating that is disrupted in schizophrenia. We tested the ability for antipsychotic drugs with diverse pharmacological actions to (1) ameliorate NMDAr antagonist-induced disruptions to gamma oscillations and (2) attenuate NMDAr antagonist-induced disruptions to PPI. We hypothesized that antipsychotic-mediated improvement of PPI deficits would be accompanied by a normalization of gamma oscillatory activity. Wistar rats were implanted with extradural electrodes to facilitate recording of electroencephalogram during PPI behavioural testing. In each session, the rats were administered haloperidol (0.25 mg kg(-1)), clozapine (5 mg kg(-1)), olanzapine (5 mg kg(-1)), LY379268 (3 mg kg(-1)), NFPS (sarcosine, 1 mg kg(-1)), d-serine (1800 mg kg(-1)) or vehicle, followed by the NMDAr antagonists MK-801(0.16 mg kg(-1)), ketamine (5 mg kg(-1)) or vehicle. Outcome measures were auditory-evoked, as well as ongoing, gamma oscillations and PPI. Although treatment with all the clinically validated antipsychotic drugs reduced ongoing gamma oscillations, clozapine was the only compound that prevented the sensory-evoked gamma deficit produced by ketamine and MK-801. In addition, clozapine was also the only antipsychotic that attenuated the disruption to PPI produced by the NMDAr antagonists. We conclude that disruptions to evoked, but not ongoing, gamma oscillations caused by NMDAr antagonists are functionally relevant, and suggest that compounds, which restore sensory-evoked gamma oscillations may improve sensory processing in patients with schizophrenia.
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ItemCommon and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status(PUBLIC LIBRARY SCIENCE, 2016-03)Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.
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ItemThe dopamine D1 receptor gene is associated with negative schizotypy in a non-clinical sample(ELSEVIER IRELAND LTD, 2016-01-30)
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ItemCurrent Treatment Options for Cognitive Impairment in Bipolar Disorder: a Review(Springer Science and Business Media LLC, 2016-12-01)
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ItemFacial Emotion Recognition Impairments in Bipolar Disorder. A Cognitive Problem?(CAMBRIDGE UNIV PRESS, 2016-07)
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ItemDoes cognitive performance map to categorical diagnoses of schizophrenia, schizoaffective disorder and bipolar disorder? A discriminant functions analysis(ELSEVIER, 2016-03-01)OBJECTIVES: Despite known overlaps in the pattern of cognitive impairments in individuals with bipolar disorder (BD), schizophrenia (SZ) and schizoaffective disorder (SZA), few studies have examined the extent to which cognitive performance validates traditional diagnostic boundaries in these groups. METHOD: Individuals with SZ (n=49), schizoaffective disorder (n=33) and BD (n=35) completed a battery of cognitive tests measuring the domains of processing speed, immediate memory, semantic memory, learning, working memory, executive function and sustained attention. RESULTS: A discriminant functions analysis revealed a significant function comprising semantic memory, immediate memory and processing speed that maximally separated patients with SZ from those with BD. Initial classification scores on the basis of this function showed modest diagnostic accuracy, owing in part to the misclassification of SZA patients as having SZ. When SZA patients were removed from the model, a second cross-validated classifier yielded slightly improved diagnostic accuracy and a single function solution, of which semantic memory loaded most heavily. CONCLUSIONS: A cluster of non-executive cognitive processes appears to have some validity in mapping onto traditional nosological boundaries. However, since semantic memory performance was the primary driver of the discrimination between BD and SZ, it is possible that performance differences between the disorders in this cognitive domain in particular, index separate underlying aetiologies.
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ItemTaking It at "Face Value": The Use of Face Processing Strategies in Bipolar Disorder and Schizophrenia(CAMBRIDGE UNIV PRESS, 2016-07)OBJECTIVES: Use of appropriate face processing strategies is important for facial emotion recognition, which is known to be impaired in schizophrenia (SZ) and bipolar disorder (BD). There is preliminary evidence of abnormalities in the use of face processing strategies in the former, but there has been no explicit attempt to assess face processing in patients with BD. METHODS: Twenty-eight BD I, 28 SZ, and 28 healthy control participants completed tasks assessing featural and configural face processing. The facial inversion effect was used as a proxy of second order configural face processing and compared to featural face processing performance (which is known to be relatively less affected by facial inversion). RESULTS: Controls demonstrated the usual second-order inversion pattern. In the BD group, the absence of a second-order configural inversion effect in the presence of a disproportionate bias toward a featural inversion effect was evident. Despite reduced accuracy performance in the SZ group compared to controls, this group unexpectedly showed a normal second-order configural accuracy inversion pattern. This was in the context of a reverse inversion effect for response latency, suggesting a speed-versus-accuracy trade-off. CONCLUSIONS: To our knowledge, this is the first study to explicitly examine and contrast face processing in BD and SZ. Our findings indicate a generalized impairment on face processing tasks in SZ, and the presence of a second-order configural face processing impairment in BD. It is possible that these face processing impairments represent a catalyst for the facial emotion recognition deficits that are commonly reported in the literature. (JINS, 2016, 22, 652-661).