Felix D.C.C. Beacher

Emotional Appraisal Is Influenced by Cardiac Afferent Information

Influential models highlight the central integration of bodily arousal with emotion. Some emotions, notably disgust, are more closely coupled to visceral state than others. Cardiac baroreceptors, activated at systole within each cardiac cycle, provide short-term visceral feedback. Here we explored how phasic baroreceptor activation may alter the appraisal of brief emotional stimuli and consequent cardiovascular reactions. We used functional MRI (fMRI) to measure brain responses to emotional face stimuli presented before and during cardiac systole. We observed that the processing of emotional stimuli was altered by concurrent natural baroreceptor activation. Specifically, facial expressions of disgust were judged as more intense when presented at systole, and rebound heart rate increases were attenuated after expressions of disgust and happiness. Neural activity within prefrontal cortex correlated with emotionality ratings. Activity within periaqueductal gray matter reflected both emotional ratings and their interaction with cardiac timing. Activity within regions including prefrontal and visual cortices correlated with increases in heart rate evoked by the face stimuli, while orbitofrontal activity reflected both evoked heart rate change and its interaction with cardiac timing. Our findings demonstrate that momentary physiological fluctuations in cardiovascular afferent information (1) influence specific emotional judgments, mediated through regions including the periaqueductal gray matter, and (2) shape evoked autonomic responses through engagement of orbitofrontal cortex. Together these findings highlight the close coupling of visceral and emotional processes and identify neural regions mediating bodily state influences on affective judgment.

Autism attenuates sex differences in brain structure: a combined voxel-based morphometry and diffusion tensor imaging study

BACKGROUND AND PURPOSE: It has been proposed that autism spectrums condition may represent a form of extreme male brain (EMB), a notion supported by psychometric, behavioral, and endocrine evidence. Yet, limited data are presently available evaluating this hypothesis in terms of neuroanatomy. Here, we investigated sex-related anatomic features in adults with AS, a “pure” form of autism not involving major developmental delay. MATERIALS AND METHODS: Males and females with AS and healthy controls (n = 28 and 30, respectively) were recruited. Structural MR imaging was performed to measure overall gray and white matter volume and to assess regional effects by means of VBM. DTI was used to investigate the integrity of the main white matter tracts. RESULTS: Significant interactions were found between sex and diagnosis in total white matter volume, regional gray matter volume in the right parietal operculum, and fractional anisotropy (FA) in the body of the CC, cingulum, and CR. Post hoc comparisons indicated that the typical sexual dimorphism found in controls, whereby males have larger FA and total white matter volume, was absent or attenuated in participants with AS. CONCLUSIONS: Our results point to a fundamental role of the factors that underlie sex-specific brain differentiation in the etiology of autism.

Sex differences and autism: brain function during verbal fluency and mental rotation

Autism spectrum conditions (ASC) affect more males than females. This suggests that the neurobiology of autism: 1) may overlap with mechanisms underlying typical sex-differentiation or 2) alternately reflect sex-specificity in how autism is expressed in males and females. Here we used functional magnetic resonance imaging (fMRI) to test these alternate hypotheses. Fifteen men and fourteen women with Asperger syndrome (AS), and sixteen typically developing men and sixteen typically developing women underwent fMRI during performance of mental rotation and verbal fluency tasks. All groups performed the tasks equally well. On the verbal fluency task, despite equivalent task-performance, both males and females with AS showed enhanced activation of left occipitoparietal and inferior prefrontal activity compared to controls. During mental rotation, there was a significant diagnosis-by-sex interaction across occipital, temporal, parietal, middle frontal regions, with greater activation in AS males and typical females compared to AS females and typical males. These findings suggest a complex relationship between autism and sex that is differentially expressed in verbal and visuospatial domains.

Brain structure and joint hypermobility: relevance to the expression of psychiatric symptoms

Joint hypermobility is overrepresented among people with anxiety and can be associated with abnormal autonomic reactivity. We tested for associations between regional cerebral grey matter and hypermobility in 72 healthy volunteers using voxel-based morphometry of structural brain scans. Strikingly, bilateral amygdala volume distinguished those with from those without hypermobility. The hypermobility group scored higher for interoceptive sensitivity yet were not significantly more anxious. Our findings specifically link hypermobility to the structural integrity of a brain centre implicated in normal and abnormal emotions and physiological responses. Our observations endorse hypermobility as a multisystem phenotype and suggest potential mechanisms mediating clinical vulnerability to neuropsychiatric symptoms.

Vulnerability to simple faints is predicted by regional differences in brain anatomy

Neurocardiogenic syncope (NCS, simple fainting) is a common and typically benign familial condition, which rarely may result in traumatic injury or hypoxic convulsions. NCS is associated with emotional triggers, anxiety states and stress. However, the etiology of NCS, as a psychophysiological process, is poorly understood. We therefore investigated the relationship between NCS and brain anatomy. We studied a non-clinical sample of eighteen individuals with histories characteristic of NCS, and nineteen matched controls who had never fainted. We recorded fainting frequency, resting heart rate variability measures and anxiety levels. Structural T1-weighted magnetic resonance images (MRI) were acquired at 1.5 T. Associations between brain morphometry (regional gray and white matter volumes) and NCS, resting physiology and anxiety were tested using voxel-based morphometry (VBM). Compared to controls, NCS participants had lower regional brain volume within medulla and midbrain (a priori regions of interest). Moreover, across NCS individuals, lower gray matter volume in contiguous regions of left caudate nucleus predicted enhanced parasympathetic cardiac tone, fainting frequency and anxiety levels. Our findings provide preliminary evidence for a hierarchical anatomical basis to NCS. First, differences in the volume of brainstem centers supporting cardiovascular homeostasis may relate to constitutional predisposition to NCS. Second, differences in the structural organization of the caudate nucleus in NCS individuals may relate to fainting frequency via interactions between emotional state and parasympathetic control of the heart. These observations highlight the application of VBM to the identification of neurovisceral mechanisms relevant to psychosomatic medicine and the neuroscience of emotion.

Small-world network properties in prefrontal cortex correlate with predictors of psychopathology risk in young children: A NIRS study

Near infrared spectroscopy (NIRS) is an emerging imaging technique that is relatively inexpensive, portable, and particularly well suited for collecting data in ecological settings. Therefore, it holds promise as a potential neurodiagnostic for young children. We set out to explore whether NIRS could be utilized in assessing the risk of developmental psychopathology in young children. A growing body of work indicates that temperament at young age is associated with vulnerability to psychopathology later on in life. In particular, it has been shown that low effortful control (EC), which includes the focusing and shifting of attention, inhibitory control, perceptual sensitivity, and a low threshold for pleasure, is linked to conditions such as anxiety, depression and attention deficit hyperactivity disorder (ADHD). Physiologically, EC has been linked to a control network spanning among other sites the prefrontal cortex. Several psychopathologies, such as depression and ADHD, have been shown to result in compromised small-world network properties. Therefore we set out to explore the relationship between EC and the small-world properties of PFC using NIRS. NIRS data were collected from 44 toddlers, ages 3-5, while watching naturalistic stimuli (movie clips). Derived complex network measures were then correlated to EC as derived from the Childrens Behavior Questionnaire (CBQ). We found that reduced levels of EC were associated with compromised small-world properties of the prefrontal network. Our results suggest that the longitudinal NIRS studies of complex network properties in young children hold promise in furthering our understanding of developmental psychopathology.

Abnormalities in fronto-striatal connectivity within language networks relate to differences in grey-matter heterogeneity in Asperger syndrome

Asperger syndrome (AS) is an Autism Spectrum Disorder (ASD) characterised by qualitative impairment in the development of emotional and social skills with relative preservation of general intellectual abilities, including verbal language. People with AS may nevertheless show atypical language, including rate and frequency of speech production. We previously observed that abnormalities in grey matter homogeneity (measured with texture analysis of structural MR images) in AS individuals when compared with controls are also correlated with the volume of caudate nucleus. Here, we tested a prediction that these distributed abnormalities in grey matter compromise the functional integrity of brain networks supporting verbal communication skills. We therefore measured the functional connectivity between caudate nucleus and cortex during a functional neuroimaging study of language generation (verbal fluency), applying psycho-physiological interaction (PPI) methods to test specifically for differences attributable to grey matter heterogeneity in AS participants. Furthermore, we used dynamic causal modelling (DCM) to characterise the causal directionality of these differences in interregional connectivity during word production. Our results revealed a diagnosis-dependent influence of grey matter heterogeneity on the functional connectivity of the caudate nuclei with right insula/inferior frontal gyrus and anterior cingulate, respectively with the left superior frontal gyrus and right precuneus. Moreover, causal modelling of interactions between inferior frontal gyri, caudate and precuneus, revealed a reliance on bottom-up (stimulus-driven) connections in AS participants that contrasted with a dominance of top-down (cognitive control) connections from prefrontal cortex observed in control participants. These results provide detailed support for previously hypothesised central disconnectivity in ASD and specify discrete brain network targets for diagnosis and therapy in ASD.

Gray matter textural heterogeneity as a potential in-vivo biomarker of fine structural abnormalities in Asperger syndrome

Brain imaging studies contribute to the neurobiological understanding of Autism Spectrum Conditions (ASC). Herein, we tested the prediction that distributed neurodevelopmental abnormalities in brain development impact on the homogeneity of brain tissue measured using texture analysis (TA; a morphological method for surface pattern characterization). TA was applied to structural magnetic resonance brain scans of 54 adult participants (24 with Asperger syndrome (AS) and 30 controls). Measures of mean gray-level intensity, entropy and uniformity were extracted from gray matter images at fine, medium and coarse textures. Comparisons between AS and controls identified higher entropy and lower uniformity across textures in the AS group. Data reduction of texture parameters revealed three orthogonal principal components. These were used as regressors-of-interest in a voxel-based morphometry analysis that explored the relationship between surface texture variations and regional gray matter volume. Across the AS but not control group, measures of entropy and uniformity were related to the volume of the caudate nuclei, whereas mean gray-level was related to the size of the cerebellar vermis. Similar to neuropathological studies, our study provides evidence for distributed abnormalities in the structural integrity of gray matter in adults with ASC, in particular within corticostriatal and corticocerebellar networks. Additionally, this in-vivo technique may be more sensitive to fine microstructural organization than other more traditional magnetic resonance approaches and serves as a future testable biomarker in AS and other neurodevelopmental disorders.

Real-time compositing framework for interactive stereo fMRI displays

This research concentrates on providing high fidelity animation, only achievable with offline rendering solutions, for interactive fMRI-based experiments. Virtual characters are well established within the film, game and research worlds, yet much remains to be learned about which design, stylistic or behavioural factors combine to make a believable character. The definition of believability depends on context. When designing and implementing characters for entertainment, the concern is making believable characters that the audience will engage with. When using virtual characters in experiments, the aim is to create characters and synthetic spaces that people respond to in a similar manner to their real world counterparts. Research has shown that users show empathy for virtual characters. However, uncanny valley effects -- ie dips in user impressions -- can arise: behavioural fidelity expectations increase alongside increases in visual fidelity and vice versa. Often, characters used within virtual environments tend to be of fairly low fidelity due to technological constraints including rendering in real-time (Garau et al. 2003). This problem is addressed here by using non-linear playback and compositing of pre-rendered high fidelity sequences.

The acute effect of tryptophan depletion on serum neurotrophin levels (BDNF, FGF2, and S100B) in healthy subjects

There is compelling preclinical evidence for involvement of neurotrophin systems in the etiology and treatment of depressive disorders (Duman and Monteggia 2006). Antidepressants cause trophic changes (neurogenesis and synaptogenesis) within brain regions such as hippocampus; processes that are proposed to be essential to antidepressant effects (Perera et al. 2007) and likely to be neurotrophin-mediated. Human evidence is limited but serum brain-derived neurotrophic factor (BDNF) is reduced in depressed patients (Sen et al. 2008); basic fibroblast growth factor (FGF2) is enhanced by chronic antidepressant treatment (Bachis et al. 2008) and the glial neurotrophin S100B is increased in serum of patients with depressive disorder which is normalized by antidepressant treatment (Schroeter et al. 2008). Reduced serotonin neurotransmission is established in depressive disorder and linked to reduced neurotrophin expression via attenuated intracellular signal transduction (Duman 1998). Neumeister et al. (2005) however, demonstrated a paradoxical enhancement of serum BDNF expression 24 h following experimentally reduced central serotonergic neurotransmission using tryptophan depletion (TD) in healthy volunteers. We reexamined this effect on BDNF over a shorter time period and explored the acute effect of TD on serum FGF2 and S100B expression in healthy women. Twenty healthy female volunteers (mean age 23.36 years) free of personal or family history of depression and psychotropic medication were recruited. TD was induced by standard method using an 85g amino acid mixture. The control mixture additionally contained tryptophan (1.92 g). Participants attended the lab on two occasions, separated by mean 9 days receiving either TD or control in a balanced order, cross-over, and randomized manner. Blood samples were taken at baseline and 4 h later. Ethical approval for the study was granted through national process and participants consented to the procedure. Serum levels of BDNF, FGF2, and S100B were measured using enzyme-linked immunosorbent assay and total serum tryptophan measured by fluorimetry using standard method. The intraand interassay coefficients of variation were all less than 10%. Biochemical results for 12 participants were available for analysis (four did not tolerate the mixture). All data were normally distributed. Serum tryptophan levels were reliably reduced by depleted vs. control mixture: mean change± SEM −12.4±0.7 vs. 18.4±2.3 μg/ml, respectively (t=−12.5, p<0.001). There was a subthreshold trend for TD to increase levels of all neurotrophins vs. control (Fig. 1). Mean change±SEM in serum neurotrophin level, baseline to 4 h later, for tryptophan-depleted drink vs. control drink was −231±−475 vs. −632±544 pg/ml for BDNF (t= 0.58, p=0.58); 24.9±6.7 vs. 10.6±5.2 pg/ml for FGF2 (t= 1.5, p=0.16) and 0.0064±0.024 vs. −0.024±0.01 μg/ml for S100B (t=1.56, p=0.15). Within participants, there was no significant relationship between different neurotrophins in the magnitude of change evoked by acute TD. We were unable to demonstrate a robust acute effect of TD on serum concentrations of BDNF, FGF2, or S100B in this group of healthy women. Our observed trend toward Hugo Critchley is supported by the Wellcome Trust. R. Whale (*) : F. Beacher :H. Critchley Brighton and Sussex Medical School, Brighton, Sussex, UK e-mail: Richard.whale@brighton.ac.uk