Jason Bruggemann

Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume.

Previous studies on schizophrenia have detected elevated cytokines in both brain and blood, suggesting neuroinflammation may contribute to the pathophysiology in some cases. We aimed to determine the extent to which elevated peripheral cytokine messenger RNA (mRNA) expression: (1) characterizes a subgroup of people with schizophrenia and (2) shows a relationship to cognition, brain volume and/or symptoms. Forty-three outpatients with schizophrenia or schizoaffective disorder and matched healthy controls were assessed for peripheral cytokine mRNAs (interleukin (IL)-1β, IL-2, IL-6, IL-8 and IL-18), intelligence quotient, memory and verbal fluency, symptom severity and cortical brain volumes integral to language (that is, Broca’s and Wernicke’s areas). IL-1β mRNA levels were 28% increased in schizophrenia compared with controls (t(82)=2.64, P<0.01). Using a two-step clustering procedure, we identified a subgroup of people displaying relatively elevated cytokine mRNA levels (17/43 people with schizophrenia and 9/42 controls). Individuals with schizophrenia in the elevated cytokine subgroup performed significantly worse than the low-cytokine subgroup on verbal fluency (F(1,40)=15.7, P<0.001). There was a 17% volume reduction of the left pars opercularis (POp) (Broca’s area) in patients with elevated cytokines compared with patients with lower cytokines (F(1,29)=9.41, P=0.005). Negative linear relationships between IL-1β mRNA levels and both verbal fluency and left POp volume were found in schizophrenia. This study is among the first to link blood biomarkers of inflammation with both cognitive deficits and brain volume reductions in people with schizophrenia, supporting that those with elevated cytokines represent a neurobiologically meaningful subgroup. These findings raise the possibility that targeted anti-inflammatory treatments may ameliorate cognitive and brain morphological abnormalities in some people with schizophrenia.

Acute atomoxetine effects on the EEG of children with attention-deficit/hyperactivity disorder.

Although stimulant medications are the most commonly-used treatments for Attention-Deficit/Hyperactivity Disorder (AD/HD), as many as 20% of treated children do not respond clinically to stimulants. This study investigated the effects of an acute dose of atomoxetine, a selective noradrenaline reuptake inhibitor (SNRI), on the electroencephalogram (EEG) and performance of children with AD/HD. An initial pre-medication EEG was recorded during an eyes-closed resting condition. Within two weeks, a second EEG was recorded 1 h after ingestion of 20 mg of atomoxetine. Data were Fourier transformed to provide absolute and relative power estimates for the delta, theta, alpha, beta and gamma bands. Compared to controls, the unmedicated AD/HD children had significantly elevated global absolute and relative delta, with reduced global relative alpha, and absolute and relative gamma, and many topographic differences. Atomoxetine produced significant global increases in absolute and relative beta, with several topographic changes in other bands, and a significant reduction in omission errors on a Continuous Performance Task. These results indicate that SNRIs can produce substantial normalisation of the AD/HD EEG profile, together with behavioural performance improvements. Although EEG changes induced by acute administration of psychostimulants (methylphenidate/dexamphetamine) and atomoxetine are not identical, both classes of AD/HD drugs produce similar EEG band changes. Further analysis of EEG responses to SNRIs and psychostimulants could reveal common neurophysiological processes closely linked to clinical improvement of AD/HD symptoms in response to pharmacotherapy, providing translational markers for clinical efficacy studies and potential translational biomarkers for AD/HD drug discovery.

Voxel-based morphometry in the detection of dysplasia and neoplasia in childhood epilepsy: Combined grey/white matter analysis augments detection

PURPOSE Analysis of grey matter on MRI utilising voxel-based morphometry (VBM) may have insufficient sensitivity for routine clinical application. The aim of this exploratory study was to evaluate combined analysis of grey and white matter using VBM for detecting focal lesions underlying childhood epilepsy, and to establish the optimal statistical parameters in this context. METHODS The patients were 16 children (10 boys) aged 5.9-15.2 years (11.3+/-2.8 years; mean+/-S.D.) with epilepsy and focal cortical dysplasia (FCD) or neoplasia. The control group comprised 24 normal children (12 boys), age matched to the patients. VBM was used to spatially normalise MRI volumes to a custom template and segment them into grey matter (GM) and white matter (WM). The combined GM/WM segments from each patient were contrasted with the control group. Three different VBM post-processing techniques of combined GM/WM were evaluated along with GM-only analysis. Maps showing increased/decreased GM or GM/WM concentration were generated and compared with visually identified lesions. Rates of detection and true/false positives voxels were calculated. RESULTS The GM-only lesion detection rate was equal for FCD and neoplasia at 5/8, whereas the best combined GM/WM technique detected 8/8 FCD and 6/8 neoplasia. The combined technique also produced a higher overall rate of true positives (87%) than GM-only (44%) with a similar low rate of false positives. CONCLUSIONS These preliminary data suggest that VBM is ineffective for precise delineation of lesion margins, but could potentially be used to detect subtle dysplasia in MRI negative and equivocal cases.

EEG From a Single-Channel Dry-Sensor Recording Device

While a laboratory setting and research-grade electroencephalogram (EEG) equipment allow control of variables and high-quality multiple-channel EEG recording, there are situations and populations for which this is not suitable. The present studies examined the validity of a new method of single-channel EEG measurement that is portable and uses dry-sensor technology. In study 1, EEG was recorded simultaneously from the portable device and 4 standard EEG electrodes from a research system, during eyes open (EO) and eyes closed (EC) resting conditions, with 20 adult participants. Average correlations with the research system frequency spectra were highest at site F3 for portable device data processed onboard of the device (r = .90), and for device data processed in a standard manner (r = .89). Further, predictable variations in EO versus EC comparisons were observed. In study 2, twenty-three healthy children had EEGs recorded from the portable device during EO and EC resting conditions, and 3 EO active conditions (ie, relaxation, attention, and cognitive load). Absolute and relative EEG band power differed between conditions in predicted ways, including a reduction in relative theta power and an increase in relative alpha power in EC compared to EO resting conditions. Overall, the results suggest that, while limited in terms of scalp recording locations, the portable device has potential utility in certain EEG recording situations where ease of use is a priority.

Association of serum VEGF levels with prefrontal cortex volume in schizophrenia

A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=−0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.

Caffeine effects on resting-state arousal in children

From previous work in our laboratory, increases in skin conductance level (SCL), together with global (across-scalp) decreases in electroencephalogram (EEG) alpha power and increases in alpha frequency, are useful indices of arousal increase, and here we sought to identify changes in these indices with caffeine ingestion in children. We explored the effects of a single oral dose of caffeine (80 mg) in a randomised double-blind placebo-controlled repeated-measures cross-over study. Thirty healthy children aged between 8 and 13 years (mean age 10.5 years; 11 females) participated in two sessions, 1 week apart. EEG and SCL from a 3 min eyes-closed epoch, commencing approximately 30 min after ingestion of caffeine or placebo, were examined. Caffeine was associated with increased SCL, and a global reduction in EEG power in the theta and alpha bands, as well as topographically-focused reductions in delta and beta power, and a focal increase in alpha frequency. Only global alpha level demonstrated the expected inverse relationship with SCL in both placebo and caffeine conditions. These results are generally consistent with recent electrodermal and EEG studies of arousal. Together with our previous adult data, they indicate that caffeine can be used to increase arousal in both adults and children, without the potential confounds associated with varying task demands. Caffeine appears useful as a simple tool for manipulating arousal in studies exploring its role in physiological and behavioural functioning. This may be helpful in determining the role of hypothetical arousal anomalies in syndromes such as attention-deficit/hyperactivity disorder.

Voxel-based morphometry in the detection of dysplasia and neoplasia in childhood epilepsy: limitations of grey matter analysis.

The purpose of this exploratory investigation was to evaluate voxel-based morphometry (VBM) in detecting lesions underlying childhood epilepsy, and to establish the optimal image processing and statistical parameters in this context. The patients were 16 children (10 boys) aged 5.9 to 15.2 years (mean 11.3 years) with epilepsy and focal cortical dysplasia (FCD) or neoplasia. The control group comprised 24 normal children (12 boys), age matched to the patients. MRI volumes were spatially normalised to a custom template and segmented into grey matter (GM) and white matter. Using statistical parametric mapping, the GM segment from each patient was then contrasted with the mean GM segment of the control group utilising different VBM post-processing methods. Maps showing increased/decreased areas of GM concentration or volume were generated and compared with visually identified lesions. The results indicated that conservative VBM parameters of linear normalisation with no modulation produced the highest rates of lesion detection, which were identical for FCD and neoplasia at 5/8 lesions. These preliminary data suggest that VBM analysis of GM using conservative parameters can usually detect FCD and neoplasia in the MRI of children with epilepsy, but sensitivity may be inadequate for routine clinical application. Further refinement of the technique may be necessary.

Accelerated Gray and White Matter Deterioration With Age in Schizophrenia

OBJECTIVE Although brain changes in schizophrenia have been proposed to mirror those found with advancing age, the trajectory of gray matter and white matter changes during the disease course remains unclear. The authors sought to measure whether these changes in individuals with schizophrenia remain stable, are accelerated, or are diminished with age. METHOD Gray matter volume and fractional anisotropy were mapped in 326 individuals diagnosed with schizophrenia or schizoaffective disorder and in 197 healthy comparison subjects aged 20-65 years. Polynomial regression was used to model the influence of age on gray matter volume and fractional anisotropy at a whole-brain and voxel level. Between-group differences in gray matter volume and fractional anisotropy were regionally localized across the lifespan using permutation testing and cluster-based inference. RESULTS Significant loss of gray matter volume was evident in schizophrenia, progressively worsening with age to a maximal loss of 8% in the seventh decade of life. The inferred rate of gray matter volume loss was significantly accelerated in schizophrenia up to middle age and plateaued thereafter. In contrast, significant reductions in fractional anisotropy emerged in schizophrenia only after age 35, and the rate of fractional anisotropy deterioration with age was constant and best modeled with a straight line. The slope of this line was 60% steeper in schizophrenia relative to comparison subjects, indicating a significantly faster rate of white matter deterioration with age. The rates of reduction of gray matter volume and fractional anisotropy were significantly faster in males than in females, but an interaction between sex and diagnosis was not evident. CONCLUSIONS The findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.

The impact of premorbid and current intellect in schizophrenia: cognitive, symptom, and functional outcomes

Background:Cognitive heterogeneity among people with schizophrenia has been defined on the basis of premorbid and current intelligence quotient (IQ) estimates. In a relatively large, community cohort, we aimed to independently replicate and extend cognitive subtyping work by determining the extent of symptom severity and functional deficits in each group.Methods:A total of 635 healthy controls and 534 patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited through the Australian Schizophrenia Research Bank. Patients were classified into cognitive subgroups on the basis of the Wechsler Test of Adult Reading (a premorbid IQ estimate) and current overall cognitive abilities into preserved, deteriorated, and compromised groups using both clinical and empirical (k-means clustering) methods. Additional cognitive, functional, and symptom outcomes were compared among the resulting groups.Results:A total of 157 patients (29%) classified as ‘preserved’ performed within one s.d. of control means in all cognitive domains. Patients classified as ‘deteriorated’ (n=239, 44%) performed more than one s.d. below control means in all cognitive domains except estimated premorbid IQ and current visuospatial abilities. A separate 138 patients (26%), classified as ‘compromised,’ performed more than one s.d. below control means in all cognitive domains and displayed greater impairment than other groups on symptom and functional measures.Conclusions:In the present study, we independently replicated our previous cognitive classifications of people with schizophrenia. In addition, we extended previous work by demonstrating worse functional outcomes and symptom severity in the compromised group.

Eysenck's P as a modulator of affective and electrodermal responses to violent and comic film.

High psychoticism (HP) and low psychoticism (LP) subject groups (matched on E, N and gender) received 10 presentations of a violent video segment alternating with a comic video segment. Each video was preceded by a baseline period and followed by an affective rating period. Skin conductance level (SCL) was recorded continuously throughout the study. The HP group showed a strong preference for violence compared with comedy and perceived the violent video as more comical and enjoyable, and the comic video as less comical and enjoyable, than did the LP group. This, and other indications of inhibited affect in the HP group, corresponded with a faster decline in SCL than in the LP group. The psychoticism (P) groups exhibited distinct patterns of electrodermal response to the violent and comic videos consistent with their respective personality profiles and the obtained behavioural data. The HP group produced the largest initial SCL increment to violence followed by rapid habituation, while the LP group exhibited physiological sensitisation, then rapid habituation. Several results showed that the subjects (as a whole) displayed affective and electrodermal desensitisation to the stimulus videos over trials. The findings provide further insight into general response patterns to film violence and suggest that P may be an important modulator of such response patterns.