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1.  The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) study protocol: a cross-sectional, lifespan, multidisciplinary examination of healthy cognitive ageing 
BMC Neurology  2014;14(1):204.
As greater numbers of us are living longer, it is increasingly important to understand how we can age healthily. Although old age is often stereotyped as a time of declining mental abilities and inflexibility, cognitive neuroscience reveals that older adults use neural and cognitive resources flexibly, recruiting novel neural regions and cognitive processes when necessary. Our aim in this project is to understand how age-related changes to neural structure and function interact to support cognitive abilities across the lifespan.
We are recruiting a population-based cohort of 3000 adults aged 18 and over into Stage 1 of the project, where they complete an interview including health and lifestyle questions, a core cognitive assessment, and a self-completed questionnaire of lifetime experiences and physical activity. Of those interviewed, 700 participants aged 18-87 (100 per age decile) continue to Stage 2 where they undergo cognitive testing and provide measures of brain structure and function. Cognition is assessed across multiple domains including attention and executive control, language, memory, emotion, action control and learning. A subset of 280 adults return for in-depth neurocognitive assessment in Stage 3, using functional neuroimaging experiments across our key cognitive domains.
Formal statistical models will be used to examine the changes that occur with healthy ageing, and to evaluate age-related reorganisation in terms of cognitive and neural functions invoked to compensate for overall age-related brain structural decline. Taken together the three stages provide deep phenotyping that will allow us to measure neural activity and flexibility during performance across a number of core cognitive functions. This approach offers hypothesis-driven insights into the relationship between brain and behaviour in healthy ageing that are relevant to the general population.
Our study is a unique resource of neuroimaging and cognitive measures relevant to change across the adult lifespan. Because we focus on normal age-related changes, our results may contribute to changing views about the ageing process, lead to targeted interventions, and reveal how normal ageing relates to frail ageing in clinicopathological conditions such as Alzheimer’s disease.
PMCID: PMC4219118  PMID: 25412575
Healthy ageing; Brain ageing; Brain imaging; Epidemiology; Cognition; Magnetoencephalography; Functional MRI; Structural MRI; Brain networks; Lifespan
2.  Perceptual cues in non-verbal vocal expressions of emotion 
Work on facial expressions of emotions (Calder et al, 2001) and emotionally inflected speech (Banse & Scherer, 1996) has successfully delineated some of the physical properties that underlie emotion recognition. To identify the acoustic cues used in the perception of non-verbal emotional expressions like laugher and screams, an investigation was conducted into vocal expressions of emotion, using non-verbal vocal analogues of the ‘basic’ emotions (anger, fear, disgust, sadness and surprise; Ekman & Friesen, 1971; Scott et al, 1997), and of positive affective states (Ekman, 1992, 2003; Sauter & Scott, 2007). First, the emotional stimuli were categorized and rated to establish that listeners could identify and rate the sounds reliably, and to provide confusion matrices. A principal components analysis of the rating data yielded two underlying dimensions, correlating with the perceived valence and arousal of the sounds. Second, acoustic properties of the amplitude, pitch and spectral profile of the stimuli were measured. A discriminant analysis procedure established that these acoustic measures provided sufficient discrimination between expressions of emotional categories to permit accurate statistical classification. Multiple linear regressions with participants’ subjective ratings of the acoustic stimuli showed that all classes of emotional ratings could be predicted by some combination of acoustic measures, and that most emotion ratings were predicted by different constellations of acoustic features. The results demonstrate that, similarly to affective signals in facial expressions and emotionally inflected speech, the perceived emotional character of affective vocalizations can be predicted on the basis of their physical features.
PMCID: PMC4178283  PMID: 20437296
emotion; voice; vocalizations; acoustics; non-verbal behaviour
3.  Obesity-Associated Melanocortin-4 Receptor Mutations Are Associated With Changes in the Brain Response to Food Cues 
Mutations in the melanocortin-4 receptor (MC4R) represent the commonest genetic form of obesity and are associated with hyperphagia.
The aim of this study was to investigate whether melanocortin signaling modulates anticipatory food reward by studying the brain activation response to food cues in individuals with MC4R mutations.
Design/Setting/Participants/Main Outcome Measure:
We used functional magnetic resonance imaging to measure blood oxygen level-dependent responses to images of highly palatable, appetizing foods, bland foods, and non-food objects in eight obese individuals with MC4R mutations, 10 equally obese controls, and eight lean controls with normal MC4R genotypes. Based on previous evidence, we performed a region-of-interest analysis centered on the caudate/putamen (dorsal striatum) and ventral striatum.
Compared to non-foods, appetizing foods were associated with activation in the dorsal and ventral striatum in lean controls and in MC4R-deficient individuals. Surprisingly, we observed reduced activation of the dorsal and ventral striatum in obese controls relative to MC4R-deficient patients and lean controls. There were no group differences for the contrast of disgusting foods with bland foods or non-foods, suggesting that the effects observed in response to appetizing foods were not related to arousal.
We identified differences in the striatal response to food cues between two groups of obese individuals, those with and those without MC4R mutations. These findings are consistent with a role for central melanocortinergic circuits in the neural response to visual food cues.
PMCID: PMC4258603  PMID: 25062455
4.  Changes in “Top-Down” Connectivity Underlie Repetition Suppression in the Ventral Visual Pathway 
Repetition of the same stimulus leads to a reduction in neural activity known as repetition suppression (RS). In functional magnetic resonance imaging (fMRI), RS is found for multiple object categories. One proposal is that RS reflects locally based “within-region” changes, such as neural fatigue. Thus, if a given region shows RS across changes in stimulus size or view, then it is inferred to hold size- or view-invariant representations. An alternative hypothesis characterizes RS as a consequence of “top-down” between-region modulation. Differentiating between these accounts is central to the correct interpretation of fMRI RS data. It is also unknown whether the same mechanisms underlie RS to identical stimuli and RS across changes in stimulus size or view. Using fMRI, we investigated RS within a body-sensitive network in human visual cortex comprising the extrastriate body area (EBA) and the fusiform body area (FBA). Both regions showed RS to identical images of the same body that was unaffected by changes in body size or view. Dynamic causal modeling demonstrated that changes in backward, top-down (FBA-to-EBA) effective connectivity play a critical role in RS. Furthermore, only repetition of the identical image showed additional changes in forward connectivity (EBA-to-FBA). These results suggest that RS is driven by changes in top-down modulation, whereas the contribution of “feedforward” changes in connectivity is dependent on the precise nature of the repetition. Our results challenge previous interpretations regarding the underlying nature of neural representations made using fMRI RS paradigms.
PMCID: PMC3759805  PMID: 21490204
5.  Atypical Neural Responses During Face Processing in Female Adolescents With Conduct Disorder 
Conduct disorder (CD) in females is associated with negative adult outcomes including mental health problems and personality disorders. Although recent neuroimaging studies have reported changes in neural activity during facial emotion processing in males with CD or callous-unemotional (CU) traits, there have been no neuroimaging studies specifically assessing females with CD. We addressed this gap by investigating whether female adolescents with CD show atypical neural activation when processing emotional or neutral faces.
We acquired functional magnetic resonance imaging (fMRI) data from 20 female adolescents with CD and 20 female control participants while they viewed angry, sad, and neutral faces.
An omnibus group (CD, control) by facial emotion (angry, sad, neutral) analysis of variance (ANOVA) revealed main effects of facial emotion in superior temporal cortex, fusiform gyrus, ventrolateral prefrontal cortex and insula, and main effects of group in medial orbitofrontal cortex (OFC) and right anterior insula. Female participants with CD showed reduced medial OFC and increased anterior insula responses relative to healthy controls. There were no significant group × facial emotion interactions. Lifetime CD symptoms were negatively correlated with amygdala, superior temporal cortex, fusiform gyrus, and dorsolateral prefrontal cortex activity for the contrast “all-faces versus fixation.” CU traits were negatively correlated with fusiform gyrus activity for the contrast sad versus neutral faces.
Females with CD showed atypical neural activation during the processing of all facial expressions, irrespective of valence. Our results demonstrate that severity of CD symptoms and CU traits is important in explaining abnormal patterns of neural activity.
PMCID: PMC4032577  PMID: 24839886
CD; CU traits; females; face processing; fMRI
6.  Eye gaze is not coded by cardinal mechanisms alone 
Gaze is an important social cue in regulating human and non-human interactions. In this study, we employed an adaptation paradigm to examine the mechanisms underlying the perception of another's gaze. Previous research has shown that the interleaved presentation of leftwards and rightwards gazing adaptor stimuli results in observers judging a wider range of gaze deviations as being direct. We applied a similar paradigm to examine how human observers encode oblique (e.g. upwards and to the left) directions of gaze. We presented observers with interleaved gaze adaptors and examined whether adaptation differed between congruent (adaptor and test along same axis) and incongruent conditions. We find greater adaptation in congruent conditions along cardinal (horizontal and vertical) and non-cardinal (oblique) directions suggesting gaze is not coded alone by cardinal mechanisms. Our results suggest that the functional aspects of gaze processing might parallel that of basic visual features such as orientation.
PMCID: PMC3712425  PMID: 23782886
gaze; adaptation; cardinal; non-cardinal
7.  Reduced gaze aftereffects are related to difficulties categorising gaze direction in children with autism 
Neuropsychologia  2013;51(8):1504-1509.
Perceptual mechanisms are generally flexible or “adaptive”, as evidenced by perceptual aftereffects: distortions that arise following exposure to a stimulus. We examined whether adaptive mechanisms for coding gaze direction are atypical in children diagnosed with an autism spectrum condition. Twenty-four typical children and 24 children with autism, of similar age and ability, were administered a developmentally sensitive eye-gaze adaptation task. In the pre-adaptation phase, children judged whether target faces showing subtle deviations in eye-gaze direction were looking leftwards, rightwards or straight-ahead. Next, children were adapted to faces gazing in one consistent direction (25° leftwards/rightwards) before categorising the direction of the target faces again. Children with autism showed difficulties in judging whether subtle deviations in gaze were directed to the left, right or straight-ahead relative to typical children. Although adaptation to leftward or rightward gaze resulted in reduced sensitivity to gaze on the adapted side for both groups, the aftereffect was significantly reduced in children with autism. Furthermore, the magnitude of children's gaze aftereffects was positively related to their ability to categorise gaze direction. These results show that the mechanisms coding gaze are less flexible in autism and offer a potential new explanation for these children's difficulties discriminating subtle deviations in gaze direction.
•Adaptive mechanisms are fundamental for perceptual coding.•We found adaptation to gaze direction was significantly attenuated in autism.•The degree of adaptation was also linked to children's gaze acuity.•This study provides potential evidence for the functional benefits of adaptation.
PMCID: PMC3708125  PMID: 23583965
Autism; Gaze; Adaptation; Aftereffect; Vision
8.  Humans Have an Expectation That Gaze Is Directed Toward Them 
Current Biology  2013;23(8):717-721.
Many animals use cues from another animal’s gaze to help distinguish friend from foe [1–3]. In humans, the direction of someone’s gaze provides insight into their focus of interest and state of mind [4] and there is increasing evidence linking abnormal gaze behaviors to clinical conditions such as schizophrenia and autism [5–11]. This fundamental role of another’s gaze is buoyed by the discovery of specific brain areas dedicated to encoding directions of gaze in faces [12–14]. Surprisingly, however, very little is known about how others’ direction of gaze is interpreted. Here we apply a Bayesian framework that has been successfully applied to sensory and motor domains [15–19] to show that humans have a prior expectation that other people’s gaze is directed toward them. This expectation dominates perception when there is high uncertainty, such as at night or when the other person is wearing sunglasses. We presented participants with synthetic faces viewed under high and low levels of uncertainty and manipulated the faces by adding noise to the eyes. Then, we asked the participants to judge relative gaze directions. We found that all participants systematically perceived the noisy gaze as being directed more toward them. This suggests that the adult nervous system internally represents a prior for gaze and highlights the importance of experience in developing our interpretation of another’s gaze.
► A novel application of a Bayesian framework to gaze perception ► We tend to perceive others’ gaze as directed toward us when not certain ► Head orientation influences perceived eye direction, even when only the eye region is visible
PMCID: PMC3918857  PMID: 23562265
9.  The amygdala response to images with impact 
Effective photojournalism provokes an emotional reaction and leaves a lasting impression upon the viewer. Striking and memorable images are often said to possess ’impact’. Within cognitive neuroscience memorable emotional images evoke a greater amygdala response. Research to date has focused on arousal as a causative factor, while the contribution of appraisal dimensions relating to salience of an item, goal relevance, or impact are yet to be addressed. We explored how differences in ratings of impact influenced amygdala activity to negative emotional images matched for valence, arousal and other factors. Increased amygdala activation was found to high impact when compared to neutral images, or high impact when compared to low impact images (matched for arousal). Our findings demonstrate that the amygdala response to emotional stimuli is not a function of arousal (or valence) alone and accord more with the proposal that the amygdala responds to the significance or relevance of an event.
PMCID: PMC2686226  PMID: 19151376
Emotion; Arousal; Attention; Appraisal; fMRI
10.  The Interaction Between Gaze and Facial Expression in the Amygdala and Extended Amygdala is Modulated by Anxiety 
Behavioral evidence indicates that angry faces are seen as more threatening, and elicit greater anxiety, when directed at the observer, whereas the influence of gaze on the processing of fearful faces is less consistent. Recent research has also found inconsistent effects of expression and gaze direction on the amygdala response to facial signals of threat. However, such studies have failed to consider the important influence of anxiety on the response to signals of threat; an influence that is well established in behavioral research and recent neuroimaging studies. Here, we investigated the way in which individual differences in anxiety would influence the interactive effect of gaze and expression on the response to angry and fearful faces in the human extended amygdala. Participants viewed images of fearful, angry and neutral faces, either displaying an averted or direct gaze. We found that state anxiety predicted an increased response in the dorsal amygdala/substantia innominata (SI) to angry faces when gazing at, relative to away from the observer. By contrast, high state anxious individuals showed an increased amygdala response to fearful faces that was less dependent on gaze. In addition, the relationship between state anxiety and gaze on emotional intensity ratings mirrored the relationship between anxiety and the amygdala/SI response. These results have implications for understanding the functional role of the amygdala and extended amygdala in processing signals of threat, and are consistent with the proposed role of this region in coding the relevance or significance of a stimulus to the observer.
PMCID: PMC2906373  PMID: 20661452
emotion; anxiety; fMRI; face processing; amygdala; expression; gaze
11.  Connectivity Analysis Reveals a Cortical Network for Eye Gaze Perception 
Cerebral Cortex (New York, NY)  2009;20(8):1780-1787.
Haxby et al. (Haxby JV, Hoffman EA, Gobbini MI. 2000. The distributed human neural system for face perception. Trends Cogn Sci. 4:223–233.) proposed that eye gaze processing results from an interaction between a “core” face-specific system involved in visual analysis and an “extended” system involved in spatial attention, more generally. However, the full gaze perception network has remained poorly specified. In the context of a functional magnetic resonance imaging study, we used psychophysiological interactions (PPIs) to identify brain regions that showed differential connectivity (correlation) with core face perception structures (posterior superior temporal sulcus [pSTS] and fusiform gyrus [FG]) when viewing gaze shifts relative to control eye movements (opening/closing the eyes). The PPIs identified altered connectivity between the pSTS and MT/V5, intraparietal sulcus, frontal eye fields, superior temporal gyrus (STG), supramarginal gyrus, and middle frontal gyrus (MFG). The FG showed altered connectivity with the same areas of the STG and MFG, demonstrating the contribution of both dorsal and ventral core face areas to gaze perception. We propose that this network provides an interactive system that alerts us to seen changes in other agents’ gaze direction, makes us aware of their altered focus of spatial attention, and prepares a corresponding shift in our own attention.
PMCID: PMC2901016  PMID: 20016001
attention; effective connectivity; face perception; fMRI; social attention
12.  Anxiety and Sensitivity to Gaze Direction in Emotionally Expressive Faces 
Emotion (Washington, D.C.)  2007;7(3):478-486.
This study investigated the role of neutral, happy, fearful, and angry facial expressions in enhancing orienting to the direction of eye gaze. Photographs of faces with either direct or averted gaze were presented. A target letter (T or L) appeared unpredictably to the left or the right of the face, either 300 ms or 700 ms after gaze direction changed. Response times were faster in congruent conditions (i.e., when the eyes gazed toward the target) relative to incongruent conditions (when the eyes gazed away from the target letter). Facial expression did influence reaction times, but these effects were qualified by individual differences in self-reported anxiety. High trait-anxious participants showed an enhanced orienting to the eye gaze of faces with fearful expressions relative to all other expressions. In contrast, when the eyes stared straight ahead, trait anxiety was associated with slower responding when the facial expressions depicted anger. Thus, in anxiety-prone people attention is more likely to be held by an expression of anger, whereas attention is guided more potently by fearful facial expressions.
PMCID: PMC2757723  PMID: 17683204
emotion; facial expression; gaze direction; anxiety; attentional orienting
13.  Direct Gaze Elicits Atypical Activation of the Theory-of-Mind Network in Autism Spectrum Conditions 
Cerebral Cortex (New York, NY)  2013;24(6):1485-1492.
Eye contact plays a key role in social interaction and is frequently reported to be atypical in individuals with autism spectrum conditions (ASCs). Despite the importance of direct gaze, previous functional magnetic resonance imaging in ASC has generally focused on paradigms using averted gaze. The current study sought to determine the neural processing of faces displaying direct and averted gaze in 18 males with ASC and 23 matched controls. Controls showed an increased response to direct gaze in brain areas implicated in theory-of-mind and gaze perception, including medial prefrontal cortex, temporoparietal junction, posterior superior temporal sulcus region, and amygdala. In contrast, the same regions showed an increased response to averted gaze in individuals with an ASC. This difference was confirmed by a significant gaze direction × group interaction. Relative to controls, participants with ASC also showed reduced functional connectivity between these regions. We suggest that, in the typical brain, perceiving another person gazing directly at you triggers spontaneous attributions of mental states (e.g. he is “interested” in me), and that such mental state attributions to direct gaze may be reduced or absent in the autistic brain.
PMCID: PMC4014180  PMID: 23324559
autism; connectivity; eye gaze; theory-of-mind
14.  Failure to deactivate the default mode network indicates a possible endophenotype of autism 
Molecular Autism  2012;3:15.
Reduced activity during cognitively demanding tasks has been reported in the default mode network in typically developing controls and individuals with autism. However, no study has investigated the default mode network (DMN) in first-degree relatives of those with autism (such as siblings) and it is not known whether atypical activation of the DMN is specific to autism or whether it is also present in unaffected relatives. Here we use functional magnetic resonance imaging to investigate the pattern of task-related deactivation during completion of a visual search task, the Embedded Figures Task, in teenagers with autism, their unaffected siblings and typically developing controls.
We identified striking reductions in deactivation during the Embedded Figures Task in unaffected siblings compared to controls in brain regions corresponding to the default mode network. Adolescents with autism and their unaffected siblings similarly failed to deactivate regions, including posterior cingulate and bilateral inferior parietal cortex.
This suggests that a failure to deactivate these regions is a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings.
PMCID: PMC3539860  PMID: 23206727
Autism; Default mode network; Functional MRI; Endophenotype
15.  5-HTTLPR–environment interplay and its effects on neural reactivity in adolescents 
Neuroimage  2012;63-248(3):1670-1680.
It is not known how 5-HTTLPR genotype × childhood adversity (CA) interactions that are associated with an increased risk for affective disorders in population studies operate at the neural systems level. We hypothesized that healthy adolescents at increased genetic and environmental risk for developing mood disorders (depression and anxiety) would demonstrate increased amygdala reactivity to emotional stimuli compared to those with only one such risk factor or those with none. Participants (n = 67) were classified into one of 4 groups dependent on being homozygous for the long or short alleles within the serotonin-transporter-linked polymorphic region (5-HTTLPR) of the SLC6A4 gene and exposure to CA in the first 11 years of life (present or absent). A functional magnetic resonance imaging investigation was undertaken which involved viewing emotionally-salient face stimuli. In addition, we assessed the role of other variables hypothesized to influence amygdala reactivity, namely recent negative life-events (RNLE) assessed at ages 14 and 17, current anxiety symptoms and psychiatric history. We replicated prior findings demonstrating moderation by gene variants in 5-HTTLPR, but found no support for an effect of CA on amygdala reactivity. We also found a significant effect of RNLE aged 17 with amygdala reactivity demonstrating additive, but not interactive effects with 5-HTTLPR. A whole-brain analysis found a 5-HTTLPR × CA interaction in the lingual gyrus whereby CA appears to differentially modify neural reactivity depending on genotype. These results demonstrate that two different forms of environmental adversities interplay with 5-HTTLPR and thereby differentially impact amygdala and cortical reactivity.
► Tested hypothesis that amygdala is neural locus for 5-HTTLPR × environment interaction ► Additive effects of 5-HTTLPR genotype and recent life events on amygdala reactivity ► Genotype × childhood adversity interaction on neural reactivity in lingual gyrus ► Two forms of environmental adversities interplay with 5-HTTLPR and neural reactivity. ► No support for hypothesized G × E interaction on amygdala reactivity
PMCID: PMC3480648  PMID: 23034517
5-HTTLPR, (serotonin-transporter-linked polymorphic region); SLC6A4, (Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4); CA, (Childhood adversity); PH, (Psychiatric history); RNLE, (Recent negative life events); CAMEEI, (Cambridge Early Experience Interview); fMRI, (functional magnetic resonance imaging); MFQ, (Mood and Feelings Questionnaire); SAI, (Spielberger Anxiety Inventory); K-SADS-PL, (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime version; 5-HTTLPR; Childhood adversity; Recent negative life events; Amygdala; Functional magnetic resonance imaging; Faces
16.  Facial Expressions of Threat Influence Perceived Gaze Direction in 8 Year-Olds 
PLoS ONE  2012;7(11):e49317.
Adults show reciprocal influences between the perception of gaze direction and emotional expression. These facilitate the understanding of facial signals, because the meaning of one cue can vary considerably depending on the value of the other. Here we ask whether children show similar reciprocal influences in the perception of gaze and expression. A previous study has demonstrated that gaze direction affects the perception of emotional expression in children. Here we demonstrate the opposite direction of influence, showing that expression affects the perception of gaze direction. Specifically, we show that the cone of gaze, i.e., range of gaze deviations perceived as direct, is larger for angry than neutral or fearful faces in 8 year-old children. Therefore, we conclude that children, like adults, show reciprocal influences in the perception of gaze and expression. An unexpected finding was that, compared with adults, children showed larger effects of expression on gaze perception. This finding raises the possibility that it is the ability to process cues independently, rather than sensitivity to combinations, that matures during development. Alternatively, children may be particularly sensitive to anger in adult faces.
PMCID: PMC3498150  PMID: 23166638
17.  Abnormal Anatomical Connectivity between the Amygdala and Orbitofrontal Cortex in Conduct Disorder 
PLoS ONE  2012;7(11):e48789.
Previous research suggested that structural and functional abnormalities within the amygdala and orbitofrontal cortex contribute to the pathophysiology of Conduct Disorder (CD). Here, we investigated whether the integrity of the white-matter pathways connecting these regions is abnormal and thus may represent a putative neurobiological marker for CD.
Diffusion Tensor Imaging (DTI) was used to investigate white-matter microstructural integrity in male adolescents with childhood-onset CD, compared with healthy controls matched in age, sex, intelligence, and socioeconomic status. Two approaches were employed to analyze DTI data: voxel-based morphometry of fractional anisotropy (FA), an index of white-matter integrity, and virtual dissection of white-matter pathways using tractography.
Adolescents with CD displayed higher FA within the right external capsule relative to controls (T = 6.08, P<0.05, Family-Wise Error, whole-brain correction). Tractography analyses showed that FA values within the uncinate fascicle (connecting the amygdala and orbitofrontal cortex) were abnormally increased in individuals with CD relative to controls. This was in contrast with the inferior frontal-occipital fascicle, which showed no significant group differences in FA. The finding of increased FA in the uncinate fascicle remained significant when factoring out the contribution of attention-deficit/hyperactivity disorder symptoms. There were no group differences in the number of streamlines in either of these anatomical tracts.
These results provide evidence that CD is associated with white-matter microstructural abnormalities in the anatomical tract that connects the amygdala and orbitofrontal cortex, the uncinate fascicle. These results implicate abnormal maturation of white-matter pathways which are fundamental in the regulation of emotional behavior in CD.
PMCID: PMC3492256  PMID: 23144970
18.  Atypical activation during the Embedded Figures Task as a functional magnetic resonance imaging endophenotype of autism 
Brain  2012;135(11):3469-3480.
Atypical activation during the Embedded Figures Task has been demonstrated in autism, but has not been investigated in siblings or related to measures of clinical severity. We identified atypical activation during the Embedded Figures Task in participants with autism and unaffected siblings compared with control subjects in a number of temporal and frontal brain regions. Autism and sibling groups, however, did not differ in terms of activation during this task. This suggests that the pattern of atypical activation identified may represent a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings. We also found that reduced activation in autism relative to control subjects in regions including associative visual and face processing areas was strongly correlated with the clinical severity of impairments in reciprocal social interaction. Behavioural performance was intact in autism and sibling groups. Results are discussed in terms of atypical information processing styles or of increased activation in temporal and frontal regions in autism and the broader phenotype. By separating the aspects of atypical activation as markers of familial risk for the condition from those that are autism-specific, our findings offer new insight into the factors that might cause the expression of autism in families, affecting some children but not others.
PMCID: PMC3501969  PMID: 23065480
autism; Embedded Figures Task; siblings; functional MRI; endophenotype
19.  Reduced functional connectivity within and between ‘social’ resting state networks in autism spectrum conditions 
Individuals with Autism Spectrum Conditions (ASC) have difficulties in social interaction and communication, which is reflected in hypoactivation of brain regions engaged in social processing, such as medial prefrontal cortex (mPFC), amygdala and insula. Resting state studies in ASC have identified reduced connectivity of the default mode network (DMN), which includes mPFC, suggesting that other resting state networks incorporating ‘social’ brain regions may also be abnormal. Using Seed-based Connectivity and Group Independent Component Analysis (ICA) approaches, we looked at resting functional connectivity in ASC between specific ‘social’ brain regions, as well as within and between whole networks incorporating these regions. We found reduced functional connectivity within the DMN in individuals with ASC, using both ICA and seed-based approaches. Two further networks identified by ICA, the salience network, incorporating the insula and a medial temporal lobe network, incorporating the amygdala, showed reduced inter-network connectivity. This was underlined by reduced seed-based connectivity between the insula and amygdala. The results demonstrate significantly reduced functional connectivity within and between resting state networks incorporating ‘social’ brain regions. This reduced connectivity may result in difficulties in communication and integration of information across these networks, which could contribute to the impaired processing of social signals in ASC.
PMCID: PMC3739917  PMID: 22563003
autism; resting state; fMRI
20.  Social cognitive deficits and their neural correlates in progressive supranuclear palsy 
Brain  2012;135(7):2089-2102.
Although progressive supranuclear palsy is defined by its akinetic rigidity, vertical supranuclear gaze palsy and falls, cognitive impairments are an important determinant of patients’ and carers’ quality of life. Here, we investigate whether there is a broad deficit of modality-independent social cognition in progressive supranuclear palsy and explore the neural correlates for these. We recruited 23 patients with progressive supranuclear palsy (using clinical diagnostic criteria, nine with subsequent pathological confirmation) and 22 age- and education-matched controls. Participants performed an auditory (voice) emotion recognition test, and a visual and auditory theory of mind test. Twenty-two patients and 20 controls underwent structural magnetic resonance imaging to analyse neural correlates of social cognition deficits using voxel-based morphometry. Patients were impaired on the voice emotion recognition and theory of mind tests but not auditory and visual control conditions. Grey matter atrophy in patients correlated with both voice emotion recognition and theory of mind deficits in the right inferior frontal gyrus, a region associated with prosodic auditory emotion recognition. Theory of mind deficits also correlated with atrophy of the anterior rostral medial frontal cortex, a region associated with theory of mind in health. We conclude that patients with progressive supranuclear palsy have a multimodal deficit in social cognition. This deficit is due, in part, to progressive atrophy in a network of frontal cortical regions linked to the integration of socially relevant stimuli and interpretation of their social meaning. This impairment of social cognition is important to consider for those managing and caring for patients with progressive supranuclear palsy.
PMCID: PMC3381722  PMID: 22637582
progressive supranuclear palsy; voxel-based morphometry; social cognition; theory of mind; emotion perception
21.  Different Neural Mechanisms within Occipitotemporal Cortex Underlie Repetition Suppression across Same and Different-Size Faces 
Cerebral Cortex (New York, NY)  2012;23(5):1073-1084.
Repetition suppression (RS) (or functional magnetic resonance imaging adaptation) refers to the reduction in blood oxygen level–dependent signal following repeated presentation of a stimulus. RS is frequently used to investigate the role of face-selective regions in human visual cortex and is commonly thought to be a “localized” effect, reflecting fatigue of a neuronal population representing a given stimulus. In contrast, predictive coding theories characterize RS as a consequence of “top-down” changes in between-region modulation. Differentiating between these accounts is crucial for the correct interpretation of RS effects in the face-processing network. Here, dynamic causal modeling revealed that different mechanisms underlie different forms of RS to faces in occipitotemporal cortex. For both familiar and unfamiliar faces, repetition of identical face images (same size) was associated with changes in “forward” connectivity between the occipital face area (OFA) and the fusiform face area (FFA) (OFA-to-FFA). In contrast, RS across image size was characterized by altered “backward” connectivity (FFA-to-OFA). In addition, evidence was higher for models in which information projected directly into both OFA and FFA, challenging the role of OFA as the input stage of the face-processing network. These findings suggest “size-invariant” RS to faces is a consequence of interactions between regions rather than being a localized effect.
PMCID: PMC3615345  PMID: 22510534
adaptation; DCM; face-processing; fMRI; predictive-coding
22.  Autism spectrum traits predict the neural response to eye gaze in typical individuals 
Neuroimage  2012;59(4-4):3356-3363.
Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterised by impaired social interaction and communication, restricted interests and repetitive behaviours. The severity of these characteristics are posited to lie on a continuum extending into the typical population, and typical adults' performance on behavioural tasks that are impaired in ASD is correlated with the extent to which they display autistic traits (as measured by Autism Spectrum Quotient, AQ). Individuals with ASD also show structural and functional differences in brain regions involved in social perception. Here we show that variation in AQ in typically developing individuals is associated with altered brain activity in the neural circuit for social attention perception while viewing others' eye gaze. In an fMRI experiment, participants viewed faces looking at variable or constant directions. In control conditions, only the eye region was presented or the heads were shown with eyes closed but oriented at variable or constant directions. The response to faces with variable vs. constant eye gaze direction was associated with AQ scores in a number of regions (posterior superior temporal sulcus, intraparietal sulcus, temporoparietal junction, amygdala, and MT/V5) of the brain network for social attention perception. No such effect was observed for heads with eyes closed or when only the eyes were presented. The results demonstrate a relationship between neurophysiology and autism spectrum traits in the typical (non-ASD) population and suggest that changes in the functioning of the neural circuit for social attention perception is associated with an extended autism spectrum in the typical population.
► Autistic spectrum might extend to typically developing (TD) individuals. ► We studied TD individuals with varying Autism Spectrum Quotient (AQ). ► AQ correlated with BOLD response to viewing variable vs. constant eye gaze. ► AQ did not correlate with response to directional control stimuli. ► Neurophysiology and autism spectrum traits are associated in non-AS individuals.
PMCID: PMC3315678  PMID: 22062191
Eye gaze; fMRI; Autism spectrum; Attention; Face perception
23.  Effects of Acute Tryptophan Depletion on Prefrontal-Amygdala Connectivity While Viewing Facial Signals of Aggression 
Biological Psychiatry  2012;71(1):36-43.
Reduced levels of serotonin (5-HT) within prefrontal cortex (PFC)–amygdala circuits have long been implicated in impulsive aggression. However, whether lowering 5-HT alters the dynamic interplay between the PFC and the amygdala has not been directly tested in humans. It is known that manipulating 5-HT via acute tryptophan depletion (ATD) causes variable effects on brain responses to a variety of emotional stimuli, but it remains unclear whether ATD affects functional connectivity in neural networks involved in processing social signals of aggression (e.g., angry faces).
Thirty healthy individuals were enrolled in a randomized, double-blind, placebo-controlled ATD study. On each treatment, brain responses to angry, sad, and neutral faces were measured with functional magnetic resonance imaging. Two methods (psycho-physiological-interaction in a general linear model and dynamic causal modeling) were used to assess the impact of ATD on the functional connectivity between PFC and amygdala.
Data from 19 subjects were available for the final analyses. A whole-brain psycho-physiological-interaction in a general linear model showed that ATD significantly modulated the connectivity between the amygdala and two PFC regions (ventral anterior cingulate cortex and ventrolateral PFC) when processing angry vs. neutral and angry vs. sad but not sad vs. neutral faces. Dynamic causal modeling corroborated and extended these findings by showing that 5-HT depletion reduced the influence of processing angry vs. neutral faces on circuits within PFC and on PFC–amygdala pathways.
We provide strong support for neurobiological accounts positing that 5-HT significantly influences PFC–amygdala circuits implicated in aggression and other affective behaviors.
PMCID: PMC3368260  PMID: 21920502
5-HT; amygdala; anterior cingulate cortex; effective connectivity; fMRI; violence
24.  Disgust Enhances the Recollection of Negative Emotional Images 
PLoS ONE  2011;6(11):e26571.
Memory is typically better for emotional relative to neutral images, an effect generally considered to be mediated by arousal. However, this explanation cannot explain the full pattern of findings in the literature. Two experiments are reported that investigate the differential effects of categorical affective states upon emotional memory and the contributions of stimulus dimensions other than pleasantness and arousal to any memory advantage. In Experiment 1, disgusting images were better remembered than equally unpleasant frightening ones, despite the disgusting images being less arousing. In Experiment 2, regression analyses identified affective impact – a factor shown previously to influence the allocation of visual attention and amygdala response to negative emotional images – as the strongest predictor of remembering. These findings raise significant issues that the arousal account of emotional memory cannot readily address. The term impact refers to an undifferentiated emotional response to a stimulus, without requiring detailed consideration of specific dimensions of image content. We argue that ratings of impact relate to how the self is affected. The present data call for further consideration of the theoretical specifications of the mechanisms that lead to enhanced memory for emotional stimuli and their neural substrates.
PMCID: PMC3217922  PMID: 22110588
25.  A Head View-Invariant Representation of Gaze Direction in Anterior Superior Temporal Sulcus 
Current Biology  2011;21(21-2):1817-1821.
Humans show a remarkable ability to discriminate others' gaze direction, even though a given direction can be conveyed by many physically dissimilar configurations of different eye positions and head views. For example, eye contact can be signaled by a rightward glance in a left-turned head or by direct gaze in a front-facing head. Such acute gaze discrimination implies considerable perceptual invariance. Previous human research found that superior temporal sulcus (STS) responds preferentially to gaze shifts [1], but the underlying representation that supports such general responsiveness remains poorly understood. Using multivariate pattern analysis (MVPA) of human functional magnetic resonance imaging (fMRI) data, we tested whether STS contains a higher-order, head view-invariant code for gaze direction. The results revealed a finely graded gaze direction code in right anterior STS that was invariant to head view and physical image features. Further analyses revealed similar gaze effects in left anterior STS and precuneus. Our results suggest that anterior STS codes the direction of another's attention regardless of how this information is conveyed and demonstrate how high-level face areas carry out fine-grained, perceptually relevant discrimination through invariance to other face features.
► Response patterns in superior temporal sulcus (STS) code perceived gaze direction ► Gaze codes are invariant to head view and physical image features in anterior STS ► However, such socially irrelevant features do influence gaze codes in posterior STS ► Anterior STS represents where others attend, regardless of how this is conveyed
PMCID: PMC3267037  PMID: 22036180

Results 1-25 (43)