Christine Ecker

Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression

BACKGROUND Bipolar disorder (BD) is characterised by abnormalities in mood and emotional processing, but the neural correlates of these, their relationship to depressive symptoms, and the similarities with deficits in major depressive disorder (MDD) remain unclear. We compared responses within subcortical and prefrontal cortical regions to emotionally salient material in patients with BP and MDD using functional magnetic resonance imaging. METHODS We measured neural responses to mild and intense expressions of fear, happiness, and sadness in euthymic and depressed BD patients, healthy control subjects, and depressed MDD patients. RESULTS Bipolar disorder patients demonstrated increased subcortical (ventral striatal, thalamic, hippocampal) and ventral prefrontal cortical responses particularly to mild and intense fear, mild happy, and mild sad expressions. Healthy control subjects demonstrated increased subcortical responses to intense happy and mild fear, and increased dorsal prefrontal cortical responses to intense sad expressions. Overall, MDD patients showed diminished neural responses to all emotional expressions except mild sadness. Depression severity correlated positively with hippocampal response to mild sadness in both patient groups. CONCLUSIONS Compared with healthy controls and MDD patients, BD patients demonstrated increased subcortical and ventral prefrontal cortical responses to both positive and negative emotional expressions.

Describing the Brain in Autism in Five Dimensions—Magnetic Resonance Imaging-Assisted Diagnosis of Autism Spectrum Disorder Using a Multiparameter Classification Approach

Autism spectrum disorder (ASD) is a neurodevelopmental condition with multiple causes, comorbid conditions, and a wide range in the type and severity of symptoms expressed by different individuals. This makes the neuroanatomy of autism inherently difficult to describe. Here, we demonstrate how a multiparameter classification approach can be used to characterize the complex and subtle structural pattern of gray matter anatomy implicated in adults with ASD, and to reveal spatially distributed patterns of discriminating regions for a variety of parameters describing brain anatomy. A set of five morphological parameters including volumetric and geometric features at each spatial location on the cortical surface was used to discriminate between people with ASD and controls using a support vector machine (SVM) analytic approach, and to find a spatially distributed pattern of regions with maximal classification weights. On the basis of these patterns, SVM was able to identify individuals with ASD at a sensitivity and specificity of up to 90% and 80%, respectively. However, the ability of individual cortical features to discriminate between groups was highly variable, and the discriminating patterns of regions varied across parameters. The classification was specific to ASD rather than neurodevelopmental conditions in general (e.g., attention deficit hyperactivity disorder). Our results confirm the hypothesis that the neuroanatomy of autism is truly multidimensional, and affects multiple and most likely independent cortical features. The spatial patterns detected using SVM may help further exploration of the specific genetic and neuropathological underpinnings of ASD, and provide new insights into the most likely multifactorial etiology of the condition.

Biological sex affects the neurobiology of autism

In autism, heterogeneity is the rule rather than the exception. One obvious source of heterogeneity is biological sex. Since autism was first recognized, males with autism have disproportionately skewed research. Females with autism have thus been relatively overlooked, and have generally been assumed to have the same underlying neurobiology as males with autism. Growing evidence, however, suggests that this is an oversimplification that risks obscuring the biological base of autism. This study seeks to answer two questions about how autism is modulated by biological sex at the level of the brain: (i) is the neuroanatomy of autism different in males and females? and (ii) does the neuroanatomy of autism fit predictions from the ‘extreme male brain’ theory of autism, in males and/or in females? Neuroanatomical features derived from voxel-based morphometry were compared in a sample of equal-sized high-functioning male and female adults with and without autism (n = 120, n = 30/group). The first question was investigated using a 2 × 2 factorial design, and by spatial overlap analyses of the neuroanatomy of autism in males and females. The second question was tested through spatial overlap analyses of specific patterns predicted by the extreme male brain theory. We found that the neuroanatomy of autism differed between adult males and females, evidenced by minimal spatial overlap (not different from that occurred under random condition) in both grey and white matter, and substantially large white matter regions showing significant sex × diagnosis interactions in the 2 × 2 factorial design. These suggest that autism manifests differently by biological sex. Furthermore, atypical brain areas in females with autism substantially and non-randomly (P < 0.001) overlapped with areas that were sexually dimorphic in neurotypical controls, in both grey and white matter, suggesting neural ‘masculinization’. This was not seen in males with autism. How differences in neuroanatomy relate to the similarities in cognition between males and females with autism remains to be understood. Future research should stratify by biological sex to reduce heterogeneity and to provide greater insight into the neurobiology of autism.

Reduced activation and inter-regional functional connectivity of fronto-striatal networks in adults with childhood Attention-Deficit Hyperactivity Disorder (ADHD) and persisting symptoms during tasks of motor inhibition and cognitive switching

Attention-Deficit Hyperactivity Disorder (ADHD) in children has been associated with fronto-striatal functional abnormalities during tasks of inhibitory control. In adults with ADHD, however, hardly any functional magnetic resonance imaging (fMRI) studies have investigated the neurofunctional correlates of the most compromised cognitive functions of motor response inhibition and no study has investigated cognitive flexibility. In this study we used fMRI to compare brain function and task-relevant inter-regional functional connectivity between 11 medication-naïve adults with persistent inattentive/hyperactive behaviours, followed up from childhood when they had been diagnosed with ADHD, and 14 age-matched healthy controls during a Stop and a cognitive Switch tasks. Whole-brain regression MR analyses were conducted within patients to correlate symptoms with brain activation. Despite comparable task performance, adults with childhood ADHD showed reduced activation compared to controls in bilateral inferior prefrontal cortex, caudate and thalamus during both tasks, as well as in left parietal lobe during the Switch task. Within patients, the severity of the behavioural symptoms was negatively correlated with more extensive activation of similar regions in fronto-striatal, parietal and cerebellar brain areas. In the Stop task, patients showed reduced inter-regional functional connectivity between right inferior fronto-frontal, fronto-striatal and fronto-parietal neural networks. The findings demonstrate that adults with childhood ADHD and persisting behavioural symptoms show strikingly similar patterns of fronto-striatal and parietal dysfunction to those observed in childhood ADHD during the same tasks of inhibitory control. This suggests that neuro-functional abnormalities in ADHD patients are likely to continue between childhood and early adulthood.

Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with Autism

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share behavioural-cognitive abnormalities in sustained attention. A key question is whether this shared cognitive phenotype is based on common or different underlying pathophysiologies. To elucidate this question, we compared 20 boys with ADHD to 20 age and IQ matched ASD and 20 healthy boys using functional magnetic resonance imaging (fMRI) during a parametrically modulated vigilance task with a progressively increasing load of sustained attention. ADHD and ASD boys had significantly reduced activation relative to controls in bilateral striato–thalamic regions, left dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex. Both groups also displayed significantly increased precuneus activation relative to controls. Precuneus was negatively correlated with the DLPFC activation, and progressively more deactivated with increasing attention load in controls, but not patients, suggesting problems with deactivation of a task-related default mode network in both disorders. However, left DLPFC underactivation was significantly more pronounced in ADHD relative to ASD boys, which furthermore was associated with sustained performance measures that were only impaired in ADHD patients. ASD boys, on the other hand, had disorder-specific enhanced cerebellar activation relative to both ADHD and control boys, presumably reflecting compensation. The findings show that ADHD and ASD boys have both shared and disorder-specific abnormalities in brain function during sustained attention. Shared deficits were in fronto–striato–parietal activation and default mode suppression. Differences were a more severe DLPFC dysfunction in ADHD and a disorder-specific fronto–striato–cerebellar dysregulation in ASD.

Brain Surface Anatomy in Adults With Autism: The Relationship Between Surface Area, Cortical Thickness, and Autistic Symptoms

CONTEXT Neuroimaging studies of brain anatomy in autism spectrum disorder (ASD) have mostly been based on measures of cortical volume (CV). However, CV is a product of 2 distinct parameters, cortical thickness (CT) and surface area (SA), that in turn have distinct genetic and developmental origins. OBJECTIVE To investigate regional differences in CV, SA, and CT as well as their relationship in a large and well-characterized sample of men with ASD and matched controls. DESIGN Multicenter case-control design using quantitative magnetic resonance imaging. SETTING Medical Research Council UK Autism Imaging Multicentre Study. PARTICIPANTS A total of 168 men, 84 diagnosed as having ASD and 84 controls who did not differ significantly in mean (SD) age (26 [7] years vs 28 [6] years, respectively) or full-scale IQ (110 [14] vs 114 [12], respectively). MAIN OUTCOME MEASURES Between-group differences in CV, SA, and CT investigated using a spatially unbiased vertex-based approach; the degree of spatial overlap between the differences in CT and SA; and their relative contribution to differences in regional CV. RESULTS Individuals with ASD differed from controls in all 3 parameters. These mainly consisted of significantly increased CT within frontal lobe regions and reduced SA in the orbitofrontal cortex and posterior cingulum. These differences in CT and SA were paralleled by commensurate differences in CV. The spatially distributed patterns for CT and SA were largely nonoverlapping and shared only about 3% of all significantly different locations on the cerebral surface. CONCLUSIONS Individuals with ASD have significant differences in CV, but these may be underpinned by (separable) variations in its 2 components, CT and SA. This is of importance because both measures result from distinct developmental pathways that are likely modulated by different neurobiological mechanisms. This finding may provide novel targets for future studies into the etiology of the condition and a new way to fractionate the disorder.

Neuroimaging in autism spectrum disorder: brain structure and function across the lifespan

Over the past decade, in-vivo MRI studies have provided many invaluable insights into the neural substrates underlying autism spectrum disorder (ASD), which is now known to be associated with neurodevelopmental variations in brain anatomy, functioning, and connectivity. These systems-level features of ASD pathology seem to develop differentially across the human lifespan so that the cortical abnormalities that occur in children with ASD differ from those noted at other stages of life. Thus, investigation of the brain in ASD poses particular methodological challenges, which must be addressed to enable the comparison of results across studies. Novel analytical approaches are also being developed to facilitate the translation of findings from the research to the clinical setting. In the future, the insights provided by human neuroimaging studies could contribute to biomarker development for ASD and other neurodevelopmental disorders, and to new approaches to diagnosis and treatment.

Neural responses to dynamic expressions of fear in schizophrenia.

Abnormalities in social functioning are a significant feature of schizophrenia. One critical aspect of these abnormalities is the difficulty these individuals have with the recognition of facial emotions, particularly negative expressions such as fear. The present work focuses on fear perception and its relationship to the paranoid symptoms of schizophrenia, specifically, how underlying limbic system structures (i.e. the amygdala) react when probed with dynamic fearful facial expressions. Seven paranoid and eight non-paranoid subjects (all males) with a diagnosis of schizophrenia took part in functional magnetic resonance imaging study (1.5T) examining neural responses to emerging fearful expressions contrasted with dissipating fearful expressions. Subjects viewed emerging and dissipating expressions while completing a gender discrimination task. Their brain activation was compared to that of 10 healthy male subjects. Increased hippocampal activation was seen in the non-paranoid group, while abnormalities in the bilateral amygdalae were observed only in the paranoid individuals. These patterns may represent trait-related hippocampal dysfunction, coupled with state (specifically paranoia) related amygdala abnormalities. The findings are discussed in light of models of paranoia in schizophrenia.

Human attachment security is mediated by the amygdala: Evidence from combined fMRI and psychophysiological measures

The neural basis of human attachment security remains unexamined. Using event‐related functional magnetic resonance imaging (fMRI) and simultaneous recordings of skin conductance levels, we measured neural and autonomic responses in healthy adult individuals during a semantic conceptual priming task measuring human attachment security “by proxy”. Performance during a stress but not a neutral prime condition was associated with response in bilateral amygdalae. Furthermore, levels of activity within bilateral amygdalae were highly positively correlated with attachment insecurity and autonomic response during the stress prime condition. We thereby demonstrate a key role of the amygdala in mediating autonomic activity associated with human attachment insecurity. Hum Brain Mapp, 2005.

Effects of age and gender on neural networks of motor response inhibition: From adolescence to mid-adulthood ☆

Functional inhibitory neural networks mature progressively with age. However, nothing is known about the impact of gender on their development. This study employed functional magnetic resonance imaging (fMRI) to investigate the effects of age, sex, and sex by age interactions on the brain activation of 63 healthy males and females, between 13 and 38 years, performing a Stop task. Increasing age was associated with progressively increased activation in typical response inhibition areas of right inferior and dorsolateral prefrontal and temporo-parietal regions. Females showed significantly enhanced activation in left inferior and superior frontal and striatal regions relative to males, while males showed increased activation relative to females in right inferior and superior parietal areas. Importantly, left frontal and striatal areas that showed increased activation in females, also showed significantly increased functional maturation in females relative to males, while the right inferior parietal activation that was increased in males showed significantly increased functional maturation relative to females. The findings demonstrate for the first time that sex-dimorphic activation patterns of enhanced left fronto-striatal activation in females and enhanced right parietal activation in males during motor inhibition appear to be the result of underlying gender differences in the functional maturation of these brain regions.