Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion.

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.

Serotonin and the neural processing of facial emotions in adults with autism: an fMRI study using acute tryptophan depletion.

CONTEXT: People with autism spectrum disorders (ASDs) have lifelong deficits in social behavior and differences in behavioral as well as neural responses to facial expressions of emotion. The biological basis to this is incompletely understood, but it may include differences in the role of neurotransmitters such as serotonin, which modulate facial emotion processing in health. While some individuals with ASD have significant differences in the serotonin system, to our knowledge, no one has investigated its role during facial emotion processing in adults with ASD and control subjects using acute tryptophan depletion (ATD) and functional magnetic resonance imaging. OBJECTIVE: To compare the effects of ATD on brain responses to primary facial expressions of emotion in men with ASD and healthy control subjects. DESIGN: Double-blind, placebo-controlled, crossover trial of ATD and functional magnetic resonance imaging to measure brain activity during incidental processing of disgust, fearful, happy, and sad facial expressions. SETTING: Institute of Psychiatry, King's College London, and South London and Maudsley National Health Service Foundation Trust, England. PARTICIPANTS: Fourteen men of normal intelligence with autism and 14 control subjects who did not significantly differ in sex, age, or overall intelligence. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent response to facial expressions of emotion. RESULTS: Brain activation was differentially modulated by ATD depending on diagnostic group and emotion type within regions of the social brain network. For example, processing of disgust faces was associated with interactions in medial frontal and lingual gyri, whereas processing of happy faces was associated with interactions in middle frontal gyrus and putamen. CONCLUSIONS: Modulation of the processing of facial expressions of emotion by serotonin significantly differs in people with ASD compared with control subjects. The differences vary with emotion type and occur in social brain regions that have been shown to be associated with group differences in serotonin synthesis/receptor or transporter density.

In vivo brain anatomy of adult males with Fragile X syndrome: an MRI study.

Fragile X Syndrome (FraX) is caused by the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and is a leading cause of learning disability (mental retardation) worldwide. Relatively few studies, however, have examined the neuroanatomical abnormalities associated with FraX. Of those that are available many included mixed gender populations, combined FraX children and adults into one sample, and employed manual tracing techniques which measures bulk volume of particular regions. Hence, there is relatively little information on differences in grey and white matter content across whole brain. We employed magnetic resonance imaging to investigate brain anatomy in 17 adult males with FraX and 18 healthy controls that did not differ significantly in age. Data were analysed using stereology and VBM to compare (respectively) regional brain bulk volume, and localised grey/white matter content. Using stereology we found that FraX males had a significant increase in bulk volume bilaterally of the caudate nucleus and parietal lobes and of the right brainstem, but a significant decrease in volume of the left frontal lobe. Our complimentary VBM analysis revealed an increased volume of grey matter in fronto-striatal regions (including bilaterally in the caudate nucleus), and increased white matter in regions extending from the brainstem to the parahippocampal gyrus, and from the left cingulate cortex extending into the corpus callosum. People with FraX have regionally specific differences in brain anatomy from healthy controls with enlargement of the caudate nuclei that persists into adulthood.

Effects of acute tryptophan depletion on neural processing of facial expressions of emotion in humans.

INTRODUCTION: Acute tryptophan depletion (ATD) temporarily lowers brain serotonin (5-HT) synthesis, and behavioral studies have shown that this alters the processing of facial expressions of emotion. MATERIALS AND METHODS: The neural basis for these alterations is not known. Therefore, we employed ATD and event-related functional magnetic resonance imaging (fMRI) to examine neural responses during incidental processing of fearful, happy, sad, and disgusted facial expressions. Fourteen healthy male controls (age, 28 +/- 10) were scanned under both placebo (SHAM) and depletion (ATD) conditions. RESULTS AND DISCUSSION: We predicted that ATD would be associated with changes in neural activity within facial emotion-processing networks. We found that serotonergic modulation did not affect performance on the fMRI tasks, but was associated with widespread effects on neural response to components of face processing networks for fearful, disgusted, and happy but not sad expressions across differing intensities. CONCLUSION: Hence, the 5-HT system affects brain function (in 'limbic' and 'face processing' regions) during incidental processing of emotional facial expressions; but this varies with emotion type and intensities.

A functional magnetic resonance imaging study of inhibitory control in obsessive-compulsive disorder.

People with obsessive-compulsive disorder (OCD) have abnormalities in cognitive and motor inhibition, and it has been proposed that these are related to dysfunction of fronto-striatal circuits. However, nobody has investigated neuro-functional abnormalities during a range of inhibition tasks in adults with OCD. The aims of the study were to compare brain activation of people with OCD and controls during three tasks of inhibitory control. Ten unmedicated adults with OCD and 11 healthy controls performed three different tasks of motor and cognitive inhibitory control during event-related functional magnetic resonance imaging: a Go/No-go task (motor inhibition), a motor Stroop task (interference inhibition) and a Switch task (cognitive flexibility). People with OCD displayed significantly different patterns of brain activation compared to controls during all three tasks. During the Go/No-go and Switch experiments, people with OCD had underactivation in task-relevant orbitofrontal/dorsolateral prefrontal, striatal and thalamic regions. During the motor Stroop and Switch tasks, people with OCD also displayed underactivation in temporo-parietal areas. In the Go/No-go and motor Stroop tasks the OCD group showed increased activation compared to controls in cerebellum and predominantly posterior brain regions. OCD is associated with task-relevant fronto-striatal dysfunction during motor inhibition and cognitive switching. In addition, parieto-temporal dysfunction was observed during tasks with a higher attentional load.

Psychosis and autism: magnetic resonance imaging study of brain anatomy.

BACKGROUND: Autism-spectrum disorder is increasingly recognised, with recent studies estimating that 1% of children in South London are affected. However, the biology of comorbid mental health problems in people with autism-spectrum disorder is poorly understood. AIMS: To investigate the brain anatomy of people with autism-spectrum disorder with and without psychosis. METHOD: We used in vivo magnetic resonance imaging and compared 30 adults with autism-spectrum disorder (14 with a history psychosis) and 16 healthy controls. RESULTS: Compared with controls both autism-spectrum disorder groups had significantly less grey matter bilaterally in the temporal lobes and the cerebellum. In contrast, they had increased grey matter in striatal regions. However, those with psychosis also had a significant reduction in grey matter content of frontal and occipital regions. Contrary to our expectation, within autism-spectrum disorder, comparisons revealed that psychosis was associated with a reduction in grey matter of the right insular cortex and bilaterally in the cerebellum extending into the fusiform gyrus and the lingual gyrus. CONCLUSIONS: The presence of neurodevelopmental abnormalities normally associated with autism-spectrum disorder might represent an alternative 'entry-point' into a final common pathway of psychosis.

Brain structural differences associated with the behavioural phenotype in children with Williams syndrome.

BACKGROUND: We investigated structural brain morphology of intellectually disabled children with Williams (WS) syndrome and its relationship to the behavioural phenotype. METHODS: We compared the neuroanatomy of 15 children (mean age:13+/-2) with WS and 15 age/gender-matched healthy children using a manual region-of-interest analysis to measure bulk (white+grey) tissue volumes and unbiased fully-automated voxel-based morphometry to assess differences in grey/white matter throughout the brain. Ratings of abnormal behaviours were correlated with brain structure. RESULTS: Compared to controls, the brains of children with WS had a decreased volume of the right parieto-occipital regions and basal ganglia. We identified reductions of grey matter of the parieto-occipital regions, left putamen/globus pallidus and thalamus; and in white matter of the basal ganglia and right posterior cingulate gyrus. In contrast, significant increases of grey matter were identified in the frontal lobes, anterior cingulate gyrus, left temporal lobe, and of white matter bilaterally in the anterior cingulate. Inattention in WS was correlated with volumetric differences in the frontal lobes, caudate nucleus and cerebellum, and hyperactivity was related to differences in the left temporal and parietal lobes and cerebellum. Finally, ratings of peer problems were related to differences in the temporal lobes, right basal ganglia and frontal lobe. CONCLUSIONS: In one of the first studies of brain structure in intellectually disabled children with WS using voxel-based morphometry, our findings suggest that this group has specific differences in grey/white matter morphology. In addition, it was found that structural differences were correlated to ratings of inattention, hyperactivity and peer problems in children with WS.

A comparative study of cognition and brain anatomy between two neurodevelopmental disorders: 22q11.2 deletion syndrome and Williams syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is associated with intellectual disability, poor social interaction and a high prevalence of psychosis. However, to date there have been no studies comparing cognition and neuroanatomical characteristics of 22q11DS with other syndromes to investigate if the cognitive strengths and difficulties and neuroanatomical differences associated with 22q11DS are specific to the syndrome. Hence, it is difficult to know if the observed features of 22q11DS are simply due to a non-specific effect of having a genetic disorder or are specific to 22q11DS. METHODS: In this study, cognition and brain anatomy of 12 children with 22q11DS were compared to 12 age, gender and full scale IQ (FSIQ) matched children with William syndrome (WS) in order to investigate which cognitive and neuroanatomical features are specific to 22q11DS. We chose WS since the literature suggests that both groups have areas of physical/cognitive/behavioural overlap but as yet there has been no direct comparison of the two groups. RESULTS: Despite being matched on FSIQ the WS group had significantly greater impairment than those with 22q11DS on tests of Performance IQ, while performing significantly better on tasks measuring verbal, social and facial processing skills. Moreover there were significant differences in brain anatomy. Despite similar overall brain volumes, midline anomalies were more common among the 22q11DS group, and regional differences such as increased striatal volumes and reduced cerebellar volumes in the 22q11DS group were detected. CONCLUSIONS: These findings suggest that although the behavioural phenotype is similar in some aspects there are key differences in cognition and neuroanatomy between the two groups. Different neuropsychological profiles need to be considered when designing educational frameworks for working with these children.

Women with autistic-spectrum disorder: magnetic resonance imaging study of brain anatomy.

BACKGROUND: Our understanding of anatomical differences in people with autistic-spectrum disorder, is based on mixed-gender or male samples. AIMS: To study regional grey-matter and white-matter differences in the brains of women with autistic-spectrum disorder. METHOD: We compared the brain anatomy of 14 adult women with autistic-spectrum disorder with 19 controls using volumetric magnetic resonance imaging and voxel-based morphometry. RESULTS: Women with autistic-spectrum disorder had a smaller density bilaterally of grey matter in the fronto-temporal cortices and limbic system, and of white matter in the temporallobes (anterior) and pons. In contrast, they had a larger white-matter density bilaterally in regions of the association and projection fibres of the frontal, parietal, posterior temporal and occipital lobes, in the commissural fibres of the corpus callosum (splenium) and cerebellum (anterior lobe). Further, we found a negative relationship between reduced grey-matter density in right limbic regions and social communication ability. CONCLUSIONS: Women with autistic-spectrum disorder have significant differences in brain anatomy from controls, in brain regions previously reported as abnormal in adult men with the disorder. Some anatomical differences may be related to clinical symptoms.

An event related functional magnetic resonance imaging study of facial emotion processing in Asperger syndrome.

BACKGROUND: People with Asperger syndrome (AS) have life-long deficits in social behavior. The biological basis of this is unknown, but most likely includes impaired processing of facial emotion. Human social communication involves processing different facial emotions, and at different intensities. However nobody has examined brain function in people with AS when implicitly (unconsciously) processing four primary emotions at varying emotional intensities. METHODS: We used event-related functional magnetic resonance imaging (MRI) to examine neural responses when people with AS and controls implicitly processed neutral expressions, and mild (25%) and intense (100%) expressions of fear, disgust, happiness, and sadness. We included 18 right-handed adults; 9 with AS and 9 healthy controls who did not differ significantly in IQ. RESULTS: Both groups significantly activated 'face perception' areas when viewing neutral faces, including fusiform and extrastriate cortices. Further, both groups had significantly increased activation of fusiform and other extrastriate regions to increasing intensities of fear and happiness. However, people with AS generally showed fusiform and extrastriate hyporesponsiveness compared to controls across emotion types and intensities. CONCLUSIONS: Fusiform and extrastriate cortices are activated by facial expressions of four primary emotions in people with AS, but generally to a lesser degree than controls. This may partly explain the social impairments of people with AS.

In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism.

OBJECTIVE: The neural basis for autistic spectrum disorders is unclear, but abnormalities in the development of limbic areas and of glutamate have been suggested. Proton magnetic resonance spectroscopy ((1)H-MRS) can be used to measure the concentration of brain metabolites. However, the concentration of glutamate/glutamine in brain regions implicated in autistic spectrum disorders has not yet been examined in vivo. METHOD: The authors used (1)H-MRS to investigate the neuronal integrity of the amygdala-hippocampal complex and a parietal control region in adults with autistic spectrum disorders and healthy subjects. RESULTS: People with autistic spectrum disorders had a significantly higher concentration of glutamate/glutamine and creatine/phosphocreatine in the amygdala-hippocampal region but not in the parietal region. CONCLUSIONS: Abnormalities in glutamate/glutamine may partially underpin the pathophysiology of autistic spectrum disorders, and the authors confirm earlier reports that limbic areas are metabolically aberrant in these disorders.

Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study.

OBJECTIVE: The cause of autistic spectrum disorder (i.e., autism and Asperger's syndrome) is unknown. The serotonergic (5-HT) system may be especially implicated. However, cortical 5-HT2A receptor density in adults with the disorder has not been examined, to the authors' knowledge. METHOD: The authors investigated cortical 5-HT2A receptor binding in eight adults with Asperger's syndrome and in 10 healthy comparison subjects with single photon emission computed tomography and the selective 5-HT2A receptor ligand 123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150). RESULTS: People with Asperger's syndrome had a significant reduction in cortical 5-HT2A receptor binding in the total, anterior, and posterior cingulate; bilaterally in the frontal and superior temporal lobes; and in the left parietal lobe. Also, reduced receptor binding was significantly related to abnormal social communication. CONCLUSIONS: The authors' findings suggest that adults with Asperger's syndrome have abnormalities in cortical 5-HT2A receptor density and that this deficit may underlie some clinical symptoms.

Brain and behaviour in children with 22q11.2 deletion syndrome: a volumetric and voxel-based morphometry MRI study.

In people with velo-cardio-facial syndrome [or 22q11.2 deletion syndrome (22qDS)], a single interstitial deletion of chromosome 22q11.2 causes a wide spectrum of cognitive deficits ranging from global learning difficulties to specific cognitive deficits. People with 22qDS are also at high risk of developing attention-deficit/hyperactivity disorder and autism spectrum disorders in childhood, and schizophrenia in adolescence or adult life. However, the neurobiology of 22qDS, and the relationship between abnormalities in brain anatomy and behaviour, is poorly understood. Thus, we studied the neuroanatomy of 22qDS children using fully automated voxel-based morphometry (VBM) and manually traced single region-of-interest (ROI) analysis. Also, we investigated whether those brain regions that differed significantly between groups were related to behavioural differences within children with 22qDS. We compared the brain morphometry of 39 children and adolescents with 22qDS (mean age: 11 years, SD +/-3, IQ = 67, SD +/-10) and 26 sibling controls (mean age: 11 years, SD +/-3, IQ = 102, SD +/-12). Using VBM, we found, after correction for IQ, that individuals with 22qDS compared with controls had a significant reduction in cerebellar grey matter, and white matter reductions in the frontal lobe, cerebellum and internal capsule. Using single ROI analysis, we found that people with 22qDS had a significant (P < 0.05) reduction in bulk volume bilaterally in the occipital-parietal lobes, but a larger right caudate nucleus and lateral ventricles. Further, within people with 22qDS, there was a significant positive correlation between severity of (i) schizotypy score and grey matter volume of the temporo-occipital regions and the corpus striatum; (ii) emotional problems and grey matter volume of frontostriatal regions; and (iii) social behavioural difficulties and grey matter in frontostriatal regions. Thus, subjects with 22qDS have widespread changes in brain anatomy, particularly affecting white matter, basal ganglia and cerebellum. Also, within 22qDS, regionally specific differences in brain development may partially underpin behavioural differences. We suggest that there is preliminary evidence for specific vulnerability of the frontostriatal and cerebellar-cortical networks in 22qDS.

Autistic-spectrum disorders: lessons from neuroimaging.

Autistic-spectrum disorder is approximately half as common as schizophrenia but its cause remains unknown. Recent studies have begun to clarify the underlying neuroanatomical abnormalities and brain-behaviour relationships in autism. In the past decade, great advances have been made in our understanding of the neurobiological basis of autism.