A longitudinal proton magnetic resonance spectroscopy study investigating oxidative stress as a result of alcohol and tobacco use in youth with bipolar disorder

Alcohol and tobacco have been suggested to be "aggravating factors" for neuroprogression in bipolar disorder (BD), however the impact of these substances on the underlying neurobiology is limited. Oxidative stress is a key target for research into neuroprogression in BD and in accordance with this model, our previous cross-sectional studies have found that risky alcohol and tobacco use in BD is associated with increased oxidative stress, investigated via in vivo glutathione (GSH) measured by proton magnetic resonance spectroscopy ((1)H-MRS) in the anterior cingulate cortex (ACC). What remains unknown is whether the negative impact on GSH levels can be modified as a result of limiting alcohol and tobacco use. Thirty BD patients were included in the study. (1)H-MRS and tobacco and alcohol measures were conducted at baseline and follow-up assessments (15.5±4.6 months apart). Pearson׳s correlations were performed between percentage change in GSH concentration and changes in alcohol/tobacco use. Regression analyses were then conducted to further explore the significant correlations. An increase in GSH was associated with a decrease in alcohol consumption (r=-0.381, p<0.05) and frequency of tobacco use (-0.367, p=0.05). Change in alcohol consumption, tobacco use and age were significant predictors of change in GSH concentration (F (3, 26)=3.69, p<0.05). Due to the high comorbidity of alcohol and tobacco use in the sample, the individual effects of these substances on GSH levels could not be determined. This study offers longitudinal evidence that changing risky drinking patterns and tobacco use early in the course of BD is associated with improvements in antioxidant capacity, and therefore may be specific targets for early intervention and prevention of neuroprogression in BD.NHMRC Australia Fellowship 46491

Hippocampal glutamatergic/NMDA receptor functioning in bipolar disorder: a combined MMN and 1H-MRS study

Disturbances in the hippocampal glutamate (Glu)/N-methyl-d-aspartate (NMDA) system have been implicated in the pathophysiology of bipolar disorder (BD). Here we aim to provide a targeted integration of two measures of glutamatergic functioning in BD; the association between mismatch negativity (MMN) and in vivo hippocampal-Glu measured via proton magnetic resonance spectroscopy ((1)H MRS). Participants comprised of 33 patients with BD and 23 matched controls who underwent a two-tone passive, duration deviant MMN paradigm and (1)H MRS. Levels of Glu/creatine (Cr) in the hippocampus were determined. Pearson's correlations were used to determine associations between MMN and Glu/Cr. In controls, MMN amplitude was positively associated with Glu/Cr at the left temporal site. We did not find any significant associations with Glu/Cr and frontocentral MMN nor did we find any significant associations in BD patients. The results provide further insight into the neurophysiology of MMN, with evidence supporting the role of hippocampal-Glu signalling through the NMDA receptor in temporal MMN. Our data also demonstrate that Glu/Cr regulation of MMN is dampened in BD, which may indicate a lack of tightly regulated hippocampal NMDA functioning. These findings provide insight into the underlying basis of glutamatergic transmission disturbances implicated in the disorder.NHMRC Australia Fellowship 46491

Brain Volumetrics, Regional Cortical Thickness and Radiographic Findings in Adults with Cyanotic Congenital Heart Disease

AbstractBackgroundChronic cyanosis in adults with congenital heart disease (CHD) may cause structural brain changes that could contribute to impaired neurological functioning. The extent of these changes has not been adequately characterized.HypothesisWe hypothesized that adults with cyanotic CHD would have widespread changes including abnormal brain volumetric measures, decreased cortical thickness and an increased burden of small and large vessel ischemic changes.MethodsTen adults with chronic cyanosis from CHD (40±4years) and mean oxygen saturations of 82±2% were investigated using quantitative MRI. Hematological and biochemical parameters were also assessed. All subjects were free from major physical or intellectual impairment. Brain volumetric results were compared with randomly selected age- and sex-matched controls from our database of normal subjects.ResultsFive of 10 cyanotic subjects had cortical lacunar infarcts. The white matter (WM) hyperintensity burden was also abnormally high (Scheltens Scale was 8±2). Quantitative MRI revealed evidence of extensive generalized WM and gray matter (GM) volumetric loss; global GM volume was reduced in cyanosed subjects (630±16 vs. 696±14mL in controls, p=0.01) as was global WM volume (471±10 vs. 564±18mL, p=0.003). Ventricular cerebrospinal fluid volume was increased (35±10 vs. 26±5mL, p=0.002). There were widespread regions of local cortical thickness reduction observed across the brain. These changes included bilateral thickness reductions in the frontal lobe including the dorsolateral prefrontal cortex and precentral gyrus, the posterior parietal lobe and the middle temporal gyrus. Sub-cortical volume changes were observed in the caudate, putamen and in the thalamus (p≤0.005 for all regions). Cortical GM volume negatively correlated with brain natriuretic peptide (R=−0.89, p=0.009), high sensitivity C-reactive protein (R=−0.964, p<0.0001) and asymmetric dimethylarginine (R=−0.75, p=0.026) but not with oxygen saturations, packed cell volume or viscosity.ConclusionsWe present the first comprehensive analysis of brain structure in adults with chronic neurocyanosis due to congenital heart disease. We demonstrate clear evidence for marked macro- and microvascular injury. Cyanotic patients show global evidence for reduced brain volume as well as specific foci of cortical thickness reduction. The GM volume loss correlated with hsCRP, BNP and ADMA suggesting that inflammation, neurohormonal activation and endothelial dysfunction may have important roles in its pathogenesis

Alcohol use in bipolar disorder: A neurobiological model to help predict susceptibility, select treatments and attenuate cortical insult.

In a series of neurophysiological and neuroimaging studies we investigated the neurobiology related to alcohol use in young people with bipolar disorder. Impairments were identified across frontal and temporal representations of event-related potential and proton magnetic resonance spectroscopy markers; mismatch negativity and in vivo glutathione, respectively. We propose these findings reflect impairments in the N-methyl-D-aspartate receptor and antioxidant capacity. This review seeks to place these findings within the broader literature in the context of two propositions: 1. Pathophysiological impairments in N-methyl-D-aspartate receptor functioning in bipolar disorder contribute to susceptibility toward developing alcohol problems. 2. Alcohol aggravates bipolar disorder neuroprogression via oxidative stress. A neurobiological model that incorporates these propositions is presented, with a focus on the potential for N-methyl-D-aspartate receptor antagonism and glutathione augmentation as potential adjunctive pharmacotherapies to treat the comorbidity. While this review highlights the importance of alcohol monitoring and reduction strategies in the treatment of bipolar disorder, the clinical impact of the proposed model remains limited by the lack of controlled trials of novel pharmacological interventions.NHMRC Australia Fellowship 46491

Cortical thinning in young psychosis and bipolar patients correlate with common neurocognitive deficits

Background: People in midlife with established psychosis or bipolar disorder exhibit patterns of cortical thinning across several brain regions. It is unclear whether these patterns are indicative of a continuously active pathological process, residual effects of an earlier illness phase or pre-illness onset developmental risk factors. Here, we investigated whether cortical thinning is evident in younger patients in the early phase of psychosis or bipolar disorder and the relationship between cortical thinning and neurocognitive performance in young people. Methods: Magnetic resonance imaging was obtained from a sample of young patients with psychosis (n = 40; mean age 23.5 years), bipolar disorder (n = 73; mean age 21.9 years) or controls (n = 49; mean age 24.2 years). Group differences in cortical thickness were assessed using statistical difference maps, and regions of cortical thinning were correlated with medication dosage and performance on neurocognitive tasks. As initial comparisons using multiple corrections found no differences between the groups, follow-up analysis with a significance threshold of p < 0.001 was performed. Results and discussion: As distinct from reported findings in older subjects, young patients with psychosis have less extensive thinning in parietal-temporal areas and do not demonstrate significant thinning in the insula or dorsal lateral prefrontal cortex. Young patients with bipolar disorder exhibit cortical thinning in regions more consistent with those previously reported in paediatric bipolar patients. Although there were some differences in the regions of cortical thinning between the two groups, the shared regions of cortical thinning were correlated with neurocognitive deficits in visual sustained attention, semantic verbal fluency and verbal learning and memory that are commonly reported in young people with either psychosis or bipolar disorder

Mismatch negativity/P3a complex in young people with psychiatric disorders : a cluster analysis

Background: We have recently shown that the event-related potential biomarkers, mismatch negativity (MMN) and P3a, are similarly impaired in young patients with schizophrenia- and affective-spectrum psychoses as well as those with bipolar disorder. A data driven approach may help to further elucidate novel patterns of MMN/P3a amplitudes that characterise distinct subgroups in patients with emerging psychiatric disorders. Methods: Eighty seven outpatients (16 to 30 years) were assessed: 19 diagnosed with a depressive disorder; 26 with a bipolar disorder; and 42 with a psychotic disorder. The MMN/P3a complex was elicited using a two-tone passive auditory oddball paradigm with duration deviant tones. Hierarchical cluster analysis utilising frontal, central and temporal neurophysiological variables was conducted. Results: Three clusters were determined: the 'globally impaired' cluster (n = 53) displayed reduced frontal and temporal MMN as well as reduced central P3a amplitudes; the 'largest frontal MMN' cluster (n = 17) were distinguished by increased frontal MMN amplitudes and the 'largest temporal MMN' cluster (n = 17) was characterised by increases in temporal MMN only. Notably, 55% of those in the globally impaired cluster were diagnosed with schizophrenia-spectrum disorder, whereas the three patient subgroups were equally represented in the remaining two clusters. The three cluster-groups did not differ in their current symptomatology; however, the globally impaired cluster was the most neuropsychologically impaired, compared with controls. Conclusions: These findings suggest that in emerging psychiatric disorders there are distinct MMN/P3a profiles of patient subgroups independent of current symptomatology. Schizophrenia-spectrum patients tended to show the most global impairments in this neurophysiological complex. Two other subgroups of patients were found to have neurophysiological profiles suggestive of quite different neurobiological (and hence, treatment) implications

clusterBMA: Bayesian model averaging for clustering

Various methods have been developed to combine inference across multiple sets of results for unsupervised clustering, within the ensemble clustering literature. The approach of reporting results from one `best' model out of several candidate clustering models generally ignores the uncertainty that arises from model selection, and results in inferences that are sensitive to the particular model and parameters chosen. Bayesian model averaging (BMA) is a popular approach for combining results across multiple models that offers some attractive benefits in this setting, including probabilistic interpretation of the combined cluster structure and quantification of model-based uncertainty. In this work we introduce clusterBMA, a method that enables weighted model averaging across results from multiple unsupervised clustering algorithms. We use clustering internal validation criteria to develop an approximation of the posterior model probability, used for weighting the results from each model. From a consensus matrix representing a weighted average of the clustering solutions across models, we apply symmetric simplex matrix factorisation to calculate final probabilistic cluster allocations. In addition to outperforming other ensemble clustering methods on simulated data, clusterBMA offers unique features including probabilistic allocation to averaged clusters, combining allocation probabilities from 'hard' and 'soft' clustering algorithms, and measuring model-based uncertainty in averaged cluster allocation. This method is implemented in an accompanying R package of the same name

Frontal lobe changes occur early in the course of affective disorders in young people

<p>Abstract</p> <p>Background</p> <p>More severe and persistent forms of affective disorders are accompanied by grey matter loss in key frontal and temporal structures. It is unclear whether such changes precede the onset of illness, occur early in the course or develop gradually with persistence or recurrence of illness. A total of 47 young people presenting with admixtures of depressive and psychotic symptoms were recruited from specialist early intervention services along with 33 age matched healthy control subjects. All participants underwent magnetic resonance imaging and patients were rated clinically as to current stage of illness. Twenty-three patients were identified as being at an early 'attenuated syndrome' stage, while the remaining were rated as having already reached the 'discrete disorder' or 'persistent or recurrent illness' stage. Contrasts were carried out between controls subjects and patients cohorts with attenuated syndromes and discrete disorders, separately.</p> <p>Results</p> <p>The patients that were identified as having a discrete or persisting disorder demonstrated decreased grey matter volumes within distributed frontal brain regions when contrasted to both the control subjects as well as those patients in the attenuated syndrome stage. Overall, patients who were diagnosed as more advanced in terms of the clinical stage of their illness, exhibited the greatest grey matter volume loss of all groups.</p> <p>Conclusions</p> <p>This study suggests that, in terms of frontal grey matter changes, a major transition point may occur in the course of affective illness between early attenuated syndromes and later discrete illness stages.</p