Kate M. Chitty

A systematic review and meta-analysis of magnetic resonance imaging measurement of structural volumes in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a debilitating condition associated with mild to moderate cognitive impairment and with a prevalence rate of up to 22% in veterans. This systematic review and quantitative meta-analysis explore volumetric differences of three key structural brain regions (hippocampus, amygdala and anterior cingulate cortex (ACC)), all of which have been implicated in dysfunction of both salience network (SN) and default mode network (DMN) in PTSD sufferers. A literature search was conducted in Embase, Medline, PubMed and PsycINFO in May 2013. Fifty-nine volumetric analyses from 44 articles were examined and included (36 hippocampus, 14 amygdala and nine ACC) with n=846 PTSD participants, n=520 healthy controls (HCs) and n=624 traumatised controls (TCs). Nine statistical tests were performed for each of the three regions of interest (ROIs), measuring volume differences in PTSD subjects, healthy and traumatised controls. Hippocampal volume was reduced in subjects with PTSD, with a greater reduction in the left hippocampus. A medium effect size reduction was found in bilateral amygdala volume when compared with findings in healthy controls; however, no significant differences in amygdala volume between PTSD subjects and trauma-exposed controls were found. Significant volume reductions were found bilaterally in the ACC. While often well matched with their respective control groups, the samples of PTSD subjects composed from the source studies used in the meta-analyses are limited in their homogeneity. The current findings of reduced hippocampal volume in subjects with PTSD are consistent with the existing literature. Amygdala volumes did not show significant reductions in PTSD subjects when compared with volumes in trauma-exposed controls-congruous with reported symptoms of hypervigilance and increased propensity in acquisition of conditioned fear memories-but a significant reduction was found in the combined left and right hemisphere volume analysis when compared with healthy controls. Bilateral volume reductions in the ACC may underpin the attentional deficits and inabilities to modulate emotions that are characteristically associated with PTSD patients.

A systematic review and meta-analysis of eye-tracking studies in children with autism spectrum disorders

Aberrant eye gaze mechanisms have been implicated in autism spectrum disorders (ASD). Studies of eye movements in children with ASD reveal diminished eye gaze duration and lack of specific eye gaze fixation to the eyes and/or mouth compared with controls. However, findings to date have been contradictory. We examined eye-tracking studies on face processing in children with ASD and conducted meta-analyses to examine whether these children demonstrate atypical fixation on primary facial regions. Twenty eye-tracking studies in children with ASD were reviewed, of which the results from 14 studies were incorporated in the meta-analyses that evaluated fixation duration on (i) eyes (eight studies) and (ii) mouth (six studies). The results reveal that children with ASD have significantly reduced gaze fixation to the eye region of faces. The results of the meta-analyses indicate that ASD patients have significant impairments in gaze fixation to the eyes. On the other hand, no significant difference was uncovered in terms of fixation to the mouth region; however, this finding needs to be interpreted with caution because of the significant heterogeneity in the mouth fixation studies. The findings of this meta-analysis add further clarity to an expanding literature and suggest that specific eye gaze fixation to the eye region may represent a robust biomarker for the condition. The heterogeneity associated with the mouth fixation data precludes any definitive statement as to the robustness of these findings.

Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics

BACKGROUND Reports of neuroleptic malignant syndrome (NMS) induced by second-generation antipsychotic drugs highlight a propensity for atypical clinical presentations. AIMS To systematically compare the clinical profile of NMS induced by first- (1G-NMS) and second-generation antipsychotic drugs (2G-NMS). METHOD The Australian Adverse Drug Reaction Advisory Committee (ADRAC) database was searched to identify individuals with NMS reported between April 1994 and September 2010. The clinical characteristics of 208 people with NMS induced by monotherapy with first- or second-generation antipsychotic drugs, as well as presenting features of NMS, were compared. RESULTS The individuals with 2G-NMS were younger and more likely to have a psychotic disorder diagnosis. The features of NMS in the two groups were very similar, except that people with 2G-NMS were less likely to present with rigidity or extrapyramidal signs compared with those with 1G-NMS. This difference was due to the lower rates of rigidity in those with clozapine-induced NMS. Mortality was considerably lower for those with 2G-NMS (3.0%) compared with 1G-NMS (16.3%), and the former were more likely to have received supportive treatment. CONCLUSIONS The clinical profile of 2G-NMS is largely similar to 1G-NMS, with clozapine-induced NMS being differentiated by the relative lack of rigidity as a feature. Mortality is lower for 2G-NMS.

Neuropsychological and Functional Outcomes in Recent-Onset Major Depression, Bipolar Disorder and Schizophrenia-Spectrum Disorders: A Longitudinal Cohort Study.

Functional disability is the lead contributor to burden of mental illness. Cognitive deficits frequently limit functional recovery, although whether changes in cognition and disability are longitudinally associated in recent-onset individuals remains unclear. Using a prospective, cohort design, 311 patients were recruited and assessed at baseline. One hundred and sixty-seven patients met eligibility criteria (M=21.5 years old, s.d.=4.8) and returned for follow-up (M=20.6 months later, s.d.=7.8). Two-hundred and thirty participants were included in the final analysis, comprising clinically stable patients with major depression (n=71), bipolar disorder (BD; n=61), schizophrenia-spectrum disorders (n=35) and 63 healthy controls. Neuropsychological functioning and self-rated functional disability were examined using mixed-design, repeated-measures analysis, across diagnoses and cognitive clusters, covarying for relevant confounds. Clinical, neuropsychological and functional changes did not differ between diagnoses (all P>0.05). Three reliable neuropsychological subgroups emerged through cluster analysis, characterized by psychomotor slowing, improved sustained attention, and improved verbal memory. Controlling for diagnosis and changes in residual symptoms, clusters with improved neuropsychological functioning observed greater reductions in functional disability than the psychomotor slowing cluster, which instead demonstrated a worsening in disability (P<0.01). Improved sustained attention was independently associated with greater likelihood of follow-up employment (P<0.01). Diagnosis of BD uniquely predicted both follow-up employment and independent living. Neuropsychological course appears to be independently predictive of subjective and objective functional outcomes. Importantly, cognitive phenotypes may reflect distinct pathophysiologies shared across major psychiatric conditions, and be ideal targets for personalized early intervention.

Risky alcohol use in young persons with emerging bipolar disorder is associated with increased oxidative stress

BACKGROUND Alcohol misuse is highly prevalent in bipolar disorder (BD) and has been associated with increased formation of reactive oxygen species in the CNS. Proton magnetic resonance spectroscopy ((1)H-MRS) is an in vivo tissue-based imaging modality that allows the investigation of changes in the brains primary antioxidant, glutathione (GSH), as a result of alcohol use in this population. METHODS Thirty-three patients with BD and 17 controls aged 18-30 years were recruited. Participants completed the Alcohol Use Disorders Identification Test (AUDIT) and underwent (1)H-MRS. Levels of GSH in the anterior cingulate cortex (ACC) were determined. ANOVA was conducted to determine differences between high and low risk drinking bipolar participants and controls. RESULTS ANOVA with all groups revealed a significant difference in GSH between bipolar high and low risk drinkers, with those in the high-risk group displaying reduced GSH levels. A significant negative correlation was found between total AUDIT score and GSH in bipolar (R=-0.478, p=0.005) which remained significant when controlling for age and medication status. LIMITATIONS Our participant sample consisted of a heterogeneous group of patients, most of whom were medicated at time of testing. CONCLUSIONS Young people with emerging BD who drink at risky levels display reduced levels of ACC-GSH. Increased oxidative stress and its resulting neurotoxic effects may be especially detrimental in an emerging bipolar sample where the illness trajectory is unclear and the brain is still undergoing significant development.

Hippocampal glutamate is increased and associated with risky drinking in young adults with major depression

BACKGROUND Risky drinking in young people is harmful, highly prevalent and often complicated by comorbid mental health problems that compound alcohol-induced impairment. The hippocampus and the glutamate system have been implicated in the pathophysiology of alcoholism and depression. This study aimed to determine whether risky drinking is associated with glutamate levels recorded within the hippocampus of young adults with major depression. METHODS Sixty-three young persons with major depression (22.1±3.1 years; 65% female) and 38 healthy controls were recruited. Participants completed the alcohol use disorder identification test and underwent proton magnetic resonance spectroscopy to measure in vivo glutamate levels within the hippocampus following a period of at least 48h of abstinence. RESULTS Young adults with depression had significantly increased hippocampal glutamate levels and a positive association between the level of alcohol use and glutamate. Regression analysis revealed that higher levels of hippocampal glutamate were predicted by having increased levels of risky drinking and depression. LIMITATIONS Small sample sizes for testing diagnosis by risky drinking interaction and use of creatine ratios rather than the absolute concentrations of glutamate. DISCUSSION The hippocampus is a critical region; given its role in learning and memory as well as mood regulation, and the neurochemical changes observed in this study may precede structural changes, which are commonly observed in both depression and alcohol misuse. These findings suggest that young adults with major depression who engage in risky drinking may be at increased risk of glutamate excitotoxicity.

Cluster analysis reveals abnormal hippocampal neurometabolic profiles in young people with mood disorders

While numerous studies have employed magnetic resonance spectroscopy (MRS) to determine in vivo neurometabolite levels associated with mood disorders the findings in both unipolar depression and bipolar disorder have been mixed. Data-driven studies may shed new light on this literature by identifying distinct subgroups of patients who may benefit from different treatment strategies. The objective of the present study was to utilize hierarchical cluster analysis in order to generate new hypotheses with respect to neurometabolic profiling of mood disorder. Participants were 165 young persons (18-30 yrs) with a mood disorder and 40 healthy controls. Neurometabolite levels were recorded via proton-MRS ((1)H MRS). The ratios (relative to creatine) of glutamate (GLU), N-acetyl aspartate (NAA) and myo-inositol (MI) measured within the hippocampus. Self-reported and clinician rated symptoms as well as cognition were also measured. The unipolar depression (N=90) and bipolar disorder (N=75) groups did not significantly differ (from each other or controls) in their levels of GLU, NAA or MI. Cluster analyses derived four subgroups of patients who were distinguished by all three metabolites. There was a pattern of positive association between NAA and GLU, whereby clusters were abnormally increased (clusters 1, 2) or normal (cluster 4) or abnormally decreased (cluster 3) in these neurometabolites. These findings suggest that there are neurometabolic abnormalities in subgroups of young people with mood disorder, which may occur despite diagnostic similarities. Such evidence highlights that the underlying neurobiology of mood disorder is complex and MRS may have unique utility in delineating underlying neurobiology and targeting treatment strategies.

Hippocampal glutamatergic/NMDA receptor functioning in bipolar disorder: A study combining mismatch negativity and proton magnetic resonance spectroscopy

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. Pearsons 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.

The N-methyl-D-aspartate receptor as a neurobiological intersection between bipolar disorder and alcohol use: a longitudinal mismatch negativity study.

Background: Comorbid risky alcohol use in bipolar disorder (BD) is recognized for its high prevalence and clinical relevance, though understanding of its neurobiological underpinning is limited. The N-methyl-D-aspartate (NMDA) receptor has recognized alterations in BD and is a major site of ethanol’s effects in the brain. The present study aimed to examine the NMDA receptor system in adolescents and young adults with BD by evaluating the longitudinal changes in a robust marker of NMDA function, mismatch negativity (MMN), in relation to changes in alcohol use patterns. Methods: Forty-six BD patients (aged 16–30) were recruited at baseline and 59% (n = 27) returned for follow-up 17.9 +/- 7.3 months later. At both time-points a two-tone, passive, duration-deviant MMN paradigm was conducted and alcohol measures were collected. Pearson’s correlations were performed between changes in MMN amplitudes and changes in alcohol use. Multiple regression was used to assess whether MMN amplitudes at baseline could predict alcohol use at follow-up. Results: Reduction in risky drinking patterns was associated with increased temporal MMN and decreased fronto-central MMN. Larger temporal MMN at baseline was a significant predictor of greater alcohol use at follow-up. Conclusions: Results suggest risky alcohol use in BD may further compound pre-existing NMDA receptor abnormalities and, importantly, reducing alcohol use early in stages of illness is associated with changes in MMN. This highlights the importance of monitoring alcohol use from first presentation. In addition, preliminary results present an exciting potential for utility of MMN as a neurobiological marker used to determine risk for alcohol misuse in BD.

Risky alcohol use predicts temporal mismatch negativity impairments in young people with bipolar disorder

Alcohol misuse in bipolar disorder (BD) has a negative impact on illness progression. The NMDA/glutamatergic system is implicated in BD pathophysiology and is critically involved in the effects of alcohol on the brain. Mismatch negativity (MMN) is purported to reflect NMDA receptor output, providing a measure for investigating this association. Forty-two patients and 34 controls (16-30 years) were split into low and high-risk drinkers (based on the Alcohol Use Disorders Identification Test) and underwent a two-tone passive auditory oddball, duration deviant MMN paradigm. Multiple regression models revealed risky drinking and BD diagnosis were predictors of impaired temporal MMN. Potentially reflecting an additive effect of alcohol on a perturbed NMDA/glutamatergic system in BD, these findings highlight alcohol as both a modifiable risk factor of neurobiological impairments and as a potential confounder in MMN studies. Given the increasing use of glutamatergic agents for BD treatment, this finding is important clinically.