Test-retest reliability of subjective supra-threshold scaling of multiple pressure-pain sensations among healthy individuals: a study using hydraulic pressure algometry.

BACKGROUND: Supra-threshold scaling of multiple pressure-pain sensations involves delivery of varied stimulus intensities, either via stimulus-dependent or response-dependent manner, and recording of subjective pain ratings by participants. The focus of this study was to determine the intra- and inter-session reliability of pain intensity and pain unpleasantness ratings related to pressure-pain thresholds (PPTs) of just noticeable pain (JNP), weak pain (WP) and moderate pain (MP) among healthy individuals. METHODS: Fourteen healthy participants (eight women, six men) participated in three sessions of testing at varied intervals over the course of 72 h. In session one, a multiple random staircase method using hydraulic pressure algometry was used to measure PPT of JNP, WP and MP on thumbnail bed. In session 2, ratings of pain intensity and pain unpleasantness were recorded when stimuli at levels corresponding to PPT of JNP, WP and MP were repeatedly applied before and after 20 min of no intervention. RESULTS: Interclass correlation coefficient (ICC) values for pain ratings of JNP, WP and MP in intra-session reliability were 0.810, 0.826 and 0.881, respectively, whereas the values were 0.817, 0.792 and 0.910, respectively, for inter-session reliability. ICC values for pain unpleasantness were also highly consistent and repeatable. Temporal summation of pain intensity and pain unpleasantness were not related to the repeated application of pressure stimuli. CONCLUSIONS: The findings indicate that the pain intensity and pain unpleasantness ratings for stimuli at levels equal to the thresholds of JNP, WP and MP have good intra- and inter-session reliability. SIGNIFICANCE: This study showed that both pain intensity and pain unpleasantness of JNP, WP and MP have good intra- and inter-session reliability and agreement. Furthermore, the temporal summation of pain or unpleasantness is not related to repeated application of pressure stimuli. ABBREVIATIONS: JNP: Just noticeable pain; WP: Weak pain; MP: Moderate pain; PPTs: pressure-pain thresholds; HPA: Hydraulic pressure algometry; MRSM: multiple random staircase method.

Biomedical journals lack a consistent method to detect outcome reporting bias: a cross-sectional analysis.

WHAT IS KNOWN AND OBJECTIVE: An increasing amount of recently published literature has implicated outcome reporting bias (ORB) as a major contributor to skewing data in both randomized controlled trials and systematic reviews; however, little is known about the current methods in place to detect ORB. This study aims to gain insight into the detection and management of ORB by biomedical journals. METHODS: This was a cross-sectional analysis involving standardized questions via email or telephone with the top 30 biomedical journals (2012) ranked by impact factor. The Cochrane Database of Systematic Reviews was excluded leaving 29 journals in the sample. RESULTS: Of 29 journals, 24 (83%) responded to our initial inquiry of which 14 (58%) answered our questions and 10 (42%) declined participation. Five (36%) of the responding journals indicated they had a specific method to detect ORB, whereas 9 (64%) did not have a specific method in place. The prevalence of ORB in the review process seemed to differ with 4 (29%) journals indicating ORB was found commonly, whereas 7 (50%) indicated ORB was uncommon or never detected by their journal previously. The majority (n = 10/14, 72%) of journals were unwilling to report or make discrepancies found in manuscripts available to the public. Although the minority, there were some journals (n = 4/14, 29%) which described thorough methods to detect ORB. WHAT IS NEW AND CONCLUSION: Many journals seemed to lack a method with which to detect ORB and its estimated prevalence was much lower than that reported in literature suggesting inadequate detection. There exists a potential for overestimation of treatment effects of interventions and unclear risks. Fortunately, there are journals within this sample which appear to utilize comprehensive methods for detection of ORB, but overall, the data suggest improvements at the biomedical journal level for detecting and minimizing the effect of this bias are needed.

RIPK3 promotes islet amyloid-induced ß-cell loss and glucose intolerance in a humanized mouse model of type 2 diabetes.

OBJECTIVE: Aggregation of human islet amyloid polypeptide (hIAPP), a ß-cell secretory product, leads to islet amyloid deposition, islet inflammation and ß-cell loss in type 2 diabetes (T2D), but the mechanisms that underlie this process are incompletely understood. Receptor interacting protein kinase 3 (RIPK3) is a pro-death signaling molecule that has recently been implicated in amyloid-associated brain pathology and ß-cell cytotoxicity. Here, we evaluated the role of RIPK3 in amyloid-induced ß-cell loss using a humanized mouse model of T2D that expresses hIAPP and is prone to islet amyloid formation. METHODS: We quantified amyloid deposition, cell death and caspase 3/7 activity in islets isolated from WT, Ripk3-/-, hIAPP and hIAPP; Ripk3-/- mice in real time, and evaluated hIAPP-stimulated inflammation in WT and Ripk3-/- bone marrow derived macrophages (BMDMs) in vitro. We also characterized the role of RIPK3 in glucose stimulated insulin secretion (GSIS) in vitro and in vivo. Finally, we examined the role of RIPK3 in high fat diet (HFD)-induced islet amyloid deposition, ß-cell loss and glucose homeostasis in vivo. RESULTS: We found that amyloid-prone hIAPP mouse islets exhibited increased cell death and caspase 3/7 activity compared to amyloid-free WT islets in vitro, and this was associated with increased RIPK3 expression. hIAPP; Ripk3-/- islets were protected from amyloid-induced cell death compared to hIAPP islets in vitro, although amyloid deposition and caspase 3/7 activity were not different between genotypes. We observed that macrophages are a source of Ripk3 expression in isolated islets, and that Ripk3-/- BMDMs were protected from hIAPP-stimulated inflammatory gene expression (Tnf, Il1b, Nos2). Following 52 weeks of HFD feeding, islet amyloid-prone hIAPP mice exhibited impaired glucose tolerance and decreased ß-cell area compared to WT mice in vivo, whereas hIAPP; Ripk3-/- mice were protected from these impairments. CONCLUSIONS: In conclusion, loss of RIPK3 protects from amyloid-induced inflammation and islet cell death in vitro and amyloid-induced ß-cell loss and glucose intolerance in vivo. We propose that therapies targeting RIPK3 may reduce islet inflammation and ß-cell loss and improve glucose homeostasis in the pathogenesis of T2D.

Manganese-enhanced MRI reflects seizure outcome in a model for mesial temporal lobe epilepsy.

The neurobiological processes resulting in epilepsy, known as epileptogenesis, are incompletely understood. Manganese-enhanced MRI (MEMRI) can potentially aide in this quest as it provides superior tissue contrast, particularly of the hippocampal subregions. This longitudinal study aims to characterise the changes in the hippocampus of the post kainic acid-induced status epilepticus (KASE) rat model of mesial temporal lobe epilepsy using MEMRI in vivo. Serial acquisition of T(1)-weighted MEMRI images were taken before, 2 days and 6 weeks after KASE (10-30 mg/kg, i.p.) in 14 rats and in 11 control rats, while a second cohort of control (N=6) and epileptic animals (N=10) was imaged at 2 months post KASE only. MnCl(2) (50 mM, 10 µl) was administered in the right lateral ventricle 1 day before scanning. Regions of interest were drawn around the hippocampus and several subregions of the hippocampus (CA1, CA3 and dentate gyrus). Markers of epilepsy such as spontaneous recurrent seizures, hippocampal neuronal loss and mossy fiber sprouting were quantified. A persistent increase in MEMRI signal intensity was found in the hippocampus, CA1 and dentate gyrus in the KASE group compared to the control group (ANOVA P<0.05). The intensity signal in the hippocampus and subregions correlated inversely with the frequency of spontaneous recurrent seizures in the chronic epileptic phase, however there was no relationship observed between histopathological changes such as cell loss and mossy fiber sprouting with seizures. This study demonstrates that MEMRI is able to detect imaging changes in the hippocampus during the course of epileptogenesis relevant for seizure expression. These data strongly indicate a relationship between manganese enhancement and spontaneous seizure outcome, suggesting that MEMRI could provide a preclinical biomarker for the severity of epileptogenesis in vivo in animal models.

Automated differentiation of pre-diagnosis Huntington's disease from healthy control individuals based on quadratic discriminant analysis of the basal ganglia: the IMAGE-HD study.

We investigated two measures of neural integrity, T1-weighted volumetric measures and diffusion tensor imaging (DTI), and explored their combined potential to differentiate pre-diagnosis Huntington's disease (pre-HD) individuals from healthy controls. We applied quadratic discriminant analysis (QDA) to discriminate pre-HD individuals from controls and we utilised feature selection and dimension reduction to increase the robustness of the discrimination method. Thirty six symptomatic HD (symp-HD), 35 pre-HD, and 36 control individuals participated as part of the IMAGE-HD study and underwent T1-weighted MRI, and DTI using a Siemens 3 Tesla scanner. Volume and DTI measures [mean diffusivity (MD) and fractional anisotropy (FA)] were calculated for each group within five regions of interest (ROI; caudate, putamen, pallidum, accumbens and thalamus). QDA was then performed in a stepwise manner to differentiate pre-HD individuals from controls, based initially on unimodal analysis of motor or neurocognitive measures, or on volume, MD or FA measures from within the caudate, pallidum and putamen. We then tested for potential improvements to this model, by examining multi-modal MRI classifications (volume, FA and MD), and also included motor and neurocognitive measures, and additional brain regions (i.e., accumbens and thalamus). Volume, MD and FA differed across the three groups, with pre-HD characterised by significant volumetric reductions and increased FA within caudate, putamen and pallidum, relative to controls. The QDA results demonstrated that the differentiation of pre-HD from controls was highly accurate when both volumetric and diffusion data sets from basal ganglia (BG) regions were used. The highest discriminative accuracy however was achieved in a multi-modality approach and when including all available measures: motor and neurocognitive scores and multi-modal MRI measures from the BG, accumbens and thalamus. Our QDA findings provide evidence that combined multi-modal imaging measures can accurately classify individuals up to 15 years prior to onset when therapeutic intervention is likely to have maximal effects in slowing the trajectory of disease development.

Rural and urban distribution of trauma incidents in Scotland.

BACKGROUND: Trauma systems reduce mortality and improve functional outcomes from injury. Regional trauma networks have been established in several European regions to address longstanding deficiencies in trauma care. A perception of the geography and population distribution as challenging has delayed the introduction of a trauma system in Scotland. The characteristics of trauma incidents attended by the Scottish Ambulance Service were analysed, to gain a better understanding of the geospatial characteristics of trauma in Scotland. METHODS: Data on trauma incidents collected by the Scottish Ambulance Service between November 2008 and October 2010 were obtained. Incident location was analysed by health board region, rurality and social deprivation. The results are presented as number of patients, average annual incidence rates and relative risks. RESULTS: Of the 141,668 incidents identified, 72·1 per cent occurred in urban regions. The risk of being involved in an incident was similar across the most populous regions, and decreased slightly with increasing rurality. Social deprivation was associated with greater numbers and risk. A total of 53·1 per cent of patients were taken to a large general hospital, and 38·6 per cent to a teaching hospital; the distribution was similar for the subset of incidents involving patients with physiological derangements. CONCLUSION: The majority of trauma incidents in Scotland occur in urban and deprived areas. A regionalized system of trauma care appears plausible, although the precise configuration of such a system requires further study.

The relationship between long-term blood pressure variability and cortical thickness in older adults.

High blood pressure variability (BPV) is a risk factor for cognitive decline and dementia, but its association with cortical thickness is not well understood. Here we use a topographical approach, to assess links between long-term BPV and cortical thickness in 478 (54% men at baseline) community dwelling older adults (70-88 years) from the ASPirin in Reducing Events in the Elderly NEURO sub-study. BPV was measured as average real variability, based on annual visits across three years. Higher diastolic BPV was significantly associated with reduced cortical thickness in multiple areas, including temporal (banks of the superior temporal sulcus), parietal (supramarginal gyrus, post-central gyrus), and posterior frontal areas (pre-central gyrus, caudal middle frontal gyrus), while controlling for mean BP. Higher diastolic BPV was associated with faster progression of cortical thinning across the three years. Diastolic BPV is an important predictor of cortical thickness, and trajectory of cortical thickness, independent of mean blood pressure. This finding suggests an important biological link in the relationship between BPV and cognitive decline in older age.

Decreased functional brain activation in Friedreich ataxia using the Simon effect task.

The present study applied the Simon effect task to examine the pattern of functional brain reorganization in individuals with Friedreich ataxia (FRDA), using functional magnetic resonance imaging (fMRI). Thirteen individuals with FRDA and 14 age and sex matched controls participated, and were required to respond to either congruent or incongruent arrow stimuli, presented either to the left or right of a screen, via laterally-located button press responses. Although the Simon effect (incongruent minus congruent stimuli) showed common regions of activation in both groups, including the superior and middle prefrontal cortices, insulae, superior and inferior parietal lobules (LPs, LPi), occipital cortex and cerebellum, there was reduced functional activation across a range of brain regions (cortical, subcortical and cerebellar) in individuals with FRDA. The greater Simon effect behaviourally in individuals with FRDA, compared with controls, together with concomitant reductions in functional brain activation and reduced functional connectivity between cortical and sub-cortical regions, implies a likely disruption of cortico-cerebellar loops and ineffective engagement of cognitive/attention regions required for response suppression.

Cortical activation and lamina terminalis functional connectivity during thirst and drinking in humans.

The pattern of regional brain activation in humans during thirst associated with dehydration, increased blood osmolality, and decreased blood volume is not known. Furthermore, there is little information available about associations between activation in osmoreceptive brain regions such as the organum vasculosum of the lamina terminalis and the brain regions implicated in thirst and its satiation in humans. With the objective of investigating the neuroanatomical correlates of dehydration and activation in the ventral lamina terminalis, this study involved exercise-induced sweating in 15 people and measures of regional cerebral blood flow (rCBF) using a functional magnetic resonance imaging technique called pulsed arterial spin labeling. Regional brain activations during dehydration, thirst, and postdrinking were consistent with the network previously identified during systemic hypertonic infusions, thus providing further evidence that the network is involved in monitoring body fluid and the experience of thirst. rCBF measurements in the ventral lamina terminalis were correlated with whole brain rCBF measures to identify regions that correlated with the osmoreceptive region. Regions implicated in the experience of thirst were identified including cingulate cortex, prefrontal cortex, striatum, parahippocampus, and cerebellum. Furthermore, the correlation of rCBF between the ventral lamina terminalis and the cingulate cortex and insula was different for the states of thirst and recent drinking, suggesting that functional connectivity of the ventral lamina terminalis is a dynamic process influenced by hydration status and ingestive behavior.

Impaired inhibition of prepotent motor tendencies in Friedreich ataxia demonstrated by the Simon interference task.

Friedreich ataxia (FRDA) is the most common of the genetically inherited ataxias. We recently demonstrated that people with FRDA have impairment in motor planning - most likely because of pathology affecting the cerebral cortex and/or cerebello-cortical projections. We used the Simon interference task to examine how effective 13 individuals with FRDA were at inhibiting inappropriate automatic responses associated with stimulus-response incompatibility in comparison with control participants. Participants had to respond to arrow targets according to two features which were either congruent or incongruent. We found that individuals with FRDA were differentially affected in reaction time to incongruent, compared with congruent stimuli, when compared with control participants. There was a significant negative correlation between age of onset and the incongruency effect, suggesting an impact of FRDA on the developmental unfolding of motor cognition, independent of the effect of disease duration. Future neuroimaging studies will be required to establish whether this dysfunction is due to cerebellar impairment disrupting cerebro-ponto-cerebello-thalamo-cerebral loops (and thus cortical function), direct primary cortical pathology, or a possible combination of the two.

Effect of aging on regional cerebral blood flow responses associated with osmotic thirst and its satiation by water drinking: a PET study.

Levels of thirst and ad libitum drinking decrease with advancing age, making older people vulnerable to dehydration. This study investigated age-related changes in brain responses to thirst and drinking in healthy men. Thirst was induced with hypertonic infusions (3.1 ml/kg 0.51M NaCl) in young (Y) and older (O) subjects. Regional cerebral blood flow (rCBF) was measured with positron emission tomography (PET). Thirst activations were identified by correlating rCBF with thirst ratings. Average rCBF was measured from regions of interest (ROI) corresponding to activation clusters in each group. The effects of drinking were examined by correlating volume of water drunk with changes in ROI rCBF from maximum thirst to postdrinking. There were increases in blood osmolality (Y, 2.8 +/- 1.8%; O, 2.2 +/- 1.4%) and thirst ratings (Y, 3.1 +/- 2.1; O, 3.7 +/- 2.8) from baseline to the end of the hypertonic infusion. Older subjects drank less water (1.9 +/- 1.6 ml/kg) than younger subjects (3.9 +/- 1.9 ml/kg). Thirst-related activation was evident in S1/M1, prefrontal cortex, anterior midcingulate cortex (aMCC), premotor cortex, and superior temporal gyrus in both groups. Postdrinking changes of rCBF in the aMCC correlated with drinking volumes in both groups. There was a greater reduction in aMCC rCBF relative to water drunk in the older group. Aging is associated with changes in satiation that militate against adequate hydration in response to hyperosmolarity, although it is unclear whether these alterations are due to changes in primary afferent inflow or higher cortical functioning.

Reduced connectivity of the auditory cortex in patients with auditory hallucinations: a resting state functional magnetic resonance imaging study.

BACKGROUND: Previous research has reported auditory processing deficits that are specific to schizophrenia patients with a history of auditory hallucinations (AH). One explanation for these findings is that there are abnormalities in the interhemispheric connectivity of auditory cortex pathways in AH patients; as yet this explanation has not been experimentally investigated. We assessed the interhemispheric connectivity of both primary (A1) and secondary (A2) auditory cortices in n=13 AH patients, n=13 schizophrenia patients without auditory hallucinations (non-AH) and n=16 healthy controls using functional connectivity measures from functional magnetic resonance imaging (fMRI) data. METHOD: Functional connectivity was estimated from resting state fMRI data using regions of interest defined for each participant based on functional activation maps in response to passive listening to words. Additionally, stimulus-induced responses were regressed out of the stimulus data and the functional connectivity was estimated for the same regions to investigate the reliability of the estimates. RESULTS: AH patients had significantly reduced interhemispheric connectivity in both A1 and A2 when compared with non-AH patients and healthy controls. The latter two groups did not show any differences in functional connectivity. Further, this pattern of findings was similar across the two datasets, indicating the reliability of our estimates. CONCLUSIONS: These data have identified a trait deficit specific to AH patients. Since this deficit was characterized within both A1 and A2 it is expected to result in the disruption of multiple auditory functions, for example, the integration of basic auditory information between hemispheres (via A1) and higher-order language processing abilities (via A2).

A novel method for contrast-to-noise ratio (CNR) evaluation of digital mammography detectors.

The purpose of this study was to test a new, simple method of evaluating the contrast-to-noise ratio (CNR) over the entire image field of a digital detector and to compare different mammography systems. Images were taken under clinical exposure conditions for a range of simulated breast thicknesses using poly(methyl methacrylate) (PMMA). At each PMMA thickness, a second image which included an additional 0.2-mm Al sheet was also acquired. Image processing software was used to calculate the CNR in multiple regions of interest (ROI) covering the entire area of the detector in order to obtain a 'CNR image'. Five detector types were evaluated, two CsI-alphaSi (GE Healthcare) flat panel systems, one alphaSe (Hologic) flat panel system and a two generations of scanning photon counting digital detectors (Sectra). Flat panel detectors exhibit better CNR uniformity compared with the first-generation scanning photon counting detector in terms of mean pixel value variation. However, significant improvement in CNR uniformity was observed for the next-generation scanning detector. The method proposed produces a map of the CNR and a measurement of uniformity throughout the entire image field of the detector. The application of this method enables quality control measurement of individual detectors and a comparison of detectors using different technologies.

The role of primordial emotions in the evolutionary origin of consciousness.

Primordial emotions are the subjective element of the instincts which are the genetically programmed behaviour patterns which contrive homeostasis. They include thirst, hunger for air, hunger for food, pain and hunger for specific minerals etc. There are two constituents of a primordial emotion--the specific sensation which when severe may be imperious, and the compelling intention for gratification by a consummatory act. They may dominate the stream of consciousness, and can have plenipotentiary power over behaviour. It is hypothesized that early in animal evolution complex reflex mechanisms in the basal brain subserving homeostatic responses, in concert with elements of the reticular activating system subserving arousal, melded functionally with regions embodied in the progressive rostral development of the telencephalon. This included the emergent limbic and paralimbic areas, and the insula. This phylogenetically ancient organization subserved the origin of consciousness as the primordial emotion, which signalled that the organisms existence was immediately threatened. Neuroimaging confirms major activations in regions of the basal brain during primordial emotions in humans. The behaviour of decorticate humans and animals is discussed in relation to the possible existence of primitive awareness. Neuroimaging of the primordial emotions reveals that rapid gratification of intention by a consummatory act such as ingestion causes precipitate decline of both the initiating sensation and the intention. There is contemporaneous rapid disappearance of particular regions of brain activation which suggests they may be part of the jointly sufficient and severally necessary activations and deactivations which correlate with consciousness [Crick, F. & Koch, C. (2003). A framework for consciousness. NatureNeuroscience,6, 119-126].

Validation of linear cerebral atrophy markers in multiple sclerosis.

Linear measures of cerebral ventricular enlargement may act as surrogate measures of cerebral atrophy in multiple sclerosis (MS). Linear atrophy markers were measured from routine MRI scans during a population survey of 171 Tasmanian MS patients and 91 healthy controls. Thirty-five Victorian MS clinic patients were recruited as a validation cohort with 14 of these re-assessed 4 years later. In the population survey, we measured three linear brain atrophy markers: inter-caudate distance (ICD), third ventricle width (TVW) and frontal horn width (FHW). TVW (OR 2.0, p=0.001) and ICD (OR 16.1, p<0.001) differentiated between MS cases and controls. In the validation study, we correlated the intercaudate ratio (ICR=ICD/brain width) and third ventricular ratio (TVR=TVW/brain width) with brain parenchymal volume. Cross-sectionally, ICR (R=-0.453, p<0.01) and TVR (R=-0.653, p<0.01) were correlated with brain parenchymal volume. Longitudinally, brain parenchymal volume loss was inversely correlated with increased ICD (R=-0.77, p<0.01) and TVW (R=-0.71, p<0.01). This study shows that ICD measurements obtained from clinical MRI scans are valid brain atrophy measures for use in monitoring MS progression.

Collaborative decision-making between paramedics and CCU nurses based on 12-lead ECG telemetry expedites the delivery of thrombolysis in ST elevation myocardial infarction.

OBJECTIVES: To describe a prehospital thrombolysis (PHT) and expedited inhospital thrombolysis (IHT) programme in south-east Scotland using prehospital 12-lead ECG recordings transmitted by telemetry and autonomous paramedic-administered thrombolysis with decision support being provided by coronary care nurses. DESIGN: Retrospective observational study. SETTING: Three hospitals in south-east Scotland covering a population of 778,468 served by 54 ambulance vehicles. PATIENTS: 11,840 patients who telephoned the ambulance service with "chest pain" over 20 months, during which 812 patients were admitted with ST segment elevation myocardial infarction (STEMI). MAIN OUTCOME MEASURES: All calls and cardiac/potential cardiac calls to the ambulance service, type/time of patient presentation, symptoms/call/door-to-thrombolysis times. RESULTS: Of the 11,840 calls to the ambulance service for chest pain over 20 months of the initiative, 60% were cardiac/potentially cardiac-related by Scottish Ambulance Service triage. ST segment elevation was present in 8% of the 5150 12-lead ECGs transmitted by paramedics to the ECG receiving station in the CCU. Over the 20 months, 812 patients were admitted to the three hospitals with STEMI and 71% received thrombolysis. Median symptom-to-thrombolysis times were 91, 148 and 184 min, respectively, in the PHT, telemetry-facilitated IHT and self-presenting IHT groups. Median call-to-needle time for the PHT group was 40 min. In 2/146 cases the cardiologists judged that the patient should not have been administered PHT. CONCLUSIONS: Based on prehospital 12-lead ECG telemetry, it is possible for paramedics and CCU nurses to conduct live reperfusion decision-making in patients with STEMI, with resultant benefits in symptoms-to-thrombolysis time.

Functional connectivity of the prefrontal cortex in Huntington's disease.

BACKGROUND: Huntington's disease is a progressive neurodegenerative disorder that results in deterioration and atrophy of various brain regions. AIM: To assess the functional connectivity between prefrontal brain regions in patients with Huntington's disease, compared with normal controls, using functional magnetic resonance imaging. PATIENTS AND METHODS: 20 patients with Huntington's disease and 17 matched controls performed a Simon task that is known to activate lateral prefrontal and anterior cingulate cortical regions. The functional connectivity was hypothesised to be impaired in patients with Huntington's disease between prefrontal regions of interest, selected from both hemispheres, in the anterior cingulate and dorsal lateral prefrontal cortex. RESULTS: Controls showed a dynamic increase in interhemispheric functional connectivity during task performance, compared with the baseline state; patients with Huntington's disease, however, showed no such increase in prefrontal connectivity. Overall, patients with Huntington's disease showed significantly impaired functional connectivity between anterior cingulate and lateral prefrontal regions in both hemispheres compared with controls. Furthermore, poor task performance was predicted by reduced connectivity in patients with Huntington's disease between the left anterior cingulate and prefrontal regions. CONCLUSIONS: This finding represents a loss of synchrony in activity between prefrontal regions in patients with Huntington's disease when engaged in the task, which predicted poor task performance. Results show that functional interactions between critical prefrontal regions, necessary for cognitive performance, are compromised in Huntington's disease. It is speculated whether significantly greater levels of activation in patients with Huntington's disease (compared with controls) observed in several brain regions partially compensate for the otherwise compromised interactions between cortical regions.

Emotional prosodic processing in auditory hallucinations.

Deficits in emotional prosodic processing, the expression of emotions in voice, have been widely reported in patients with schizophrenia, not only in comprehending emotional prosody but also expressing it. Given that prosodic cues are important in memory for voice and speaker identity, Cutting has proposed that prosodic deficits may contribute to the misattribution that appears to occur in auditory hallucinations in psychosis. The present study compared hallucinating patients with schizophrenia, non-hallucinating patients and normal controls on an emotional prosodic processing task. It was hypothesised that hallucinators would demonstrate greater deficits in emotional prosodic processing than non-hallucinators and normal controls. Participants were 67 patients with a diagnosis of schizophrenia or schizoaffective disorder (hallucinating=38, non-hallucinating=29) and 31 normal controls. The prosodic processing task used in this study comprised a series of semantically neutral sentences expressed in happy, sad and neutral voices which were rated on a 7-point Likert scale from sad (-3) through neutral (0) to happy (+3). Significant deficits in the prosodic processing tasks were found in hallucinating patients compared to non-hallucinating patients and normal controls. No significant differences were observed between non-hallucinating patients and normal controls. In the present study, patients experiencing auditory hallucinations were not as successful in recognising and using prosodic cues as the non-hallucinating patients. These results are consistent with Cutting's hypothesis, that prosodic dysfunction may mediate the misattribution of auditory hallucinations.

Diminished motor imagery capability in adults with motor impairment: An fMRI mental rotation study.

Recent research has demonstrated that adults with probable Developmental Coordination Disorder (pDCD) show similar behavioural deficits as those observed in children DCD when performing a motor imagery task. The aim of this study was to investigate whether the pattern of neural activation in adults with pDCD during motor imagery differed from adults without motor skill impairment. Twelve adults with pDCD (5 male; age M=24.5 yrs) and 11 adults without pDCD (6 male; age M=26.7 yrs) participated. The hand rotation task was used to assess motor imagery ability, while functional neural images were acquired using a 3T MR scanner. Performance on the hand task in both groups conformed to the biomechanical constraints of real movement, supporting the use of motor imagery to complete the task. Comparisons of response time and accuracy data showed no significant group differences. Comparison of the BOLD signal activation maps identified a significant parametric difference between groups. The% BOLD signal change for increasing angle of rotation showed greater activation in controls compared to the pDCD group in the occipito-parietal and parieto-frontal networks including the middle frontal gyrus bilaterally, the left superior parietal lobe as well as in the cerebellum (lobule VI). The pattern of reduced activation in adults with pDCD is consistent with recent studies of childhood DCD that suggest atypical activation in frontal, parietal and cerebellar areas, and supports the theory that this type of impairment may be associated with disruption of parieto-frontal and parieto-cerebellar networks.

Phase I study of temozolomide in combination with thiotepa and carboplatin with autologous hematopoietic cell rescue in patients with malignant brain tumors with minimal residual disease.

Recurrence of malignant brain tumors results in a poor prognosis with limited treatment options. High-dose chemotherapy with autologous hematopoietic cell rescue (AHCR) has been used in patients with recurrent malignant brain tumors and has shown improved outcomes compared with standard chemotherapy. Temozolomide is standard therapy for glioblastoma and has also shown activity in patients with medulloblastoma/primitive neuro-ectodermal tumor (PNET), particularly those with recurrent disease. Temozolomide was administered twice daily on days -10 to -6, followed by thiotepa 300 mg/m(2) per day and carboplatin dosed using the Calvert formula or body surface area on days -5 to -3, with AHCR day 0. Twenty-seven patients aged 3-46 years were enrolled. Diagnoses included high-grade glioma (n=12); medulloblastoma/PNET (n=9); central nervous system (CNS) germ cell tumor (n=4); ependymoma (n=1) and spinal cord PNET (n=1). Temozolomide doses ranged from 100 mg/m(2) per day to 400 mg/m(2) per day. There were no toxic deaths. Prolonged survival was noted in several patients including those with recurrent high-grade glioma, medulloblastoma and CNS germ cell tumor. Increased doses of temozolomide are feasible with AHCR. A phase II study using temozolomide, carboplatin and thiotepa with AHCR for children with recurrent malignant brain tumors is being conducted through the Pediatric Blood and Marrow Transplant Consortium.