Differential amygdala response during facial recognition in patients with schizophrenia: an fMRI study

Human lesion or neuroimaging studies suggest that amygdala is involved in facial emotion recognition. Although impairments in recognition of facial and/or emotional expression have been reported in schizophrenia, there are few neuroimaging studies that have examined differential brain activation during facial recognition between patients with schizophrenia and normal controls. To investigate amygdala responses during facial recognition in schizophrenia, we conducted a functional magnetic resonance imaging (fMRI) study with 12 right-handed medicated patients with schizophrenia and 12 age- and sex-matched healthy controls. The experiment task was a type of emotional intensity judgment task. During the task period, subjects were asked to view happy (or angry/disgusting/sad) and neutral faces simultaneously presented every 3 s and to judge which face was more emotional (positive or negative face discrimination). Imaging data were investigated in voxel-by-voxel basis for single-group analysis and for between-group analysis according to the random effect model using Statistical Parametric Mapping (SPM). No significant difference in task accuracy was found between the schizophrenic and control groups. Positive face discrimination activated the bilateral amygdalae of both controls and schizophrenics, with more prominent activation of the right amygdala shown in the schizophrenic group. Negative face discrimination activated the bilateral amygdalae in the schizophrenic group whereas the right amygdala alone in the control group, although no significant group difference was found. Exaggerated amygdala activation during emotional intensity judgment found in the schizophrenic patients may reflect impaired gating of sensory input containing emotion.     

Differential brain responses to cries of infants with autistic disorder and typical development: An fMRI study

This study used fMRI to measure brain activity during adult processing of cries of infants with autistic disorder (AD) compared to cries of typically developing (TD) infants. Using whole brain analysis, we found that cries of infants with AD compared to those of TD infants elicited enhanced activity in brain regions associated with verbal and prosodic processing, perhaps because altered acoustic patterns of AD cries render them especially difficult to interpret, and increased activity in brain regions associated with emotional processing, indicating that AD cries also elicit more negative feelings and may be perceived as more aversive and/or arousing. Perceived distress engendered by AD cries related to increased activation in brain regions associated with emotional processing. This study supports the hypothesis that cry is an early and meaningful anomaly displayed by children with AD. It could be that cries associated with AD alter parent-child interactions much earlier than the time that reliable AD diagnosis normally occurs.     

Emotional responses associated with self-face processing in individuals with autism spectrum disorders: An fMRI study

Individuals with autism spectrum disorders (ASD) show impaired emotional responses to self-face processing, but the underlying neural bases are unclear. Using functional magnetic resonance imaging, we investigated brain activity when 15 individuals with high-functioning ASD and 15 controls rated the photogenicity of self-face images and photographs of others' faces. Controls showed a strong correlation between photogenicity ratings and extent of embarrassment evoked by self-face images; this correlation was weaker among ASD individuals, indicating a decoupling between the cognitive evaluation of self-face images and emotional responses. Individuals with ASD demonstrated relatively low self-related activity in the posterior cingulate cortex (PCC), which was related to specific autistic traits. There were significant group differences in the modulation of activity by embarrassment ratings in the right insular (IC) and lateral orbitofrontal cortices. Task-related activity in the right IC was lower in the ASD group. The reduced activity in the right IC for self-face images was associated with weak coupling between cognitive evaluation and emotional responses to self-face images. The PCC is responsible for self-referential processing, and the IC plays a role in emotional experience. Dysfunction in these areas could contribute to the lack of self-conscious behaviors in response to self-reflection in ASD individuals.     

An fMRI investigation of detection of semantic incongruities in autistic spectrum conditions

The aim of this study was to investigate differences in the brain's haemodynamic response to semantically incongruent and congruent sentences in adults with an autistic spectrum condition (ASC) and a typically developing Control group. We used functional magnetic resonance imaging to measure regional variations in neural activity during detection of semantic incongruities within written sentences. Whilst the 12 controls showed a pattern of activity extending from posterior cingulate cortices bilaterally and the left occipitotemporal region to the left superior and inferior temporal lobes, right anterior cingulate and right inferior frontal gyrus, the 12 participants with an ASC presented a more spatially restricted activation pattern, including the left inferior frontal gyrus, left anterior cingulate cortex and right middle frontal gyrus. These results are coherent with the hypothesis that impaired integration of multiple neural networks in people with an ASC is related to previous observations that this group have difficulties in the use of context to predict the final word of sentences.     

Medication treatment in subjects with autistic spectrum disorders

Autism is a pervasive developmental disorder that is aetiologically and clinically heterogeneous. Twin and family genetic studies provide evidence for strong genetic components. An international consortium using an affected sib pair strategy has found a promising linkage to a region on chromosome 7. In 10–15% of the cases autism is due to associated medical conditions that affect normal brain functioning. Post-mortem studies on small case series report cellular abnormalities in the limbic system and cerebellum. Between 10 and 20% of subjects with autism have macrocephalia, which is in accordance with MRI findings of an increased total brain tissue volume and enlargement most prominent in the occipital and parietal lobes. The most robust and well-replicated neurobiological abnormality in autism is an elevation of whole blood serotonin found in over 30% of the patients. Pharmacological interventions with serotonin reuptake blockers or with atypical neuroleptics that block both dopamine (D₂) and serotonin (5-HT₂) receptors seem to offer clinical benefit and merit further study.

     

Differential response in the human amygdala to racial outgroup vs ingroup face stimuli

Here we describe response in the human amygdala to the presentation of racial outgroup vs ingroup faces. Functional magnetic resonance imaging (fMRI) measures of brain activity were acquired while subjects who identified themselves as White or Black viewed photographs of both White and Black faces. Across all subjects, we observed significantly greater blood oxygen-level-dependent (BOLD) signal in the amygdala to outgroup vs ingroup faces, but only during later stimulus presentations. A region of interest (ROI)-based analysis of these voxels revealed a significant interaction between amygdala response to outgroup and ingroup faces over time. Specifically, the greater amygdala activation to outgroup faces during later stimulus presentations was the result of amygdala response habituation to repeated presentations of ingroup faces with sustained responses to outgroup faces. The present results suggest that amygdala responses to human face stimuli are affected by the relationship between the perceived race of the stimulus face and that of the subject. Results are discussed as consistent with a role for the amygdala in encoding socially and/or biologically relevant information. We conclude that researchers seeking to study brain responses to face stimuli in human subjects should consider the relationship between the race of subjects and stimuli as a significant potential source of variance. Moreover, these data provide a foundation for future related studies in the neuroscience of social cognition and race.     

An fMRI investigation of responses to peer rejection in adolescents with autism spectrum disorders

Peer rejection is particularly pervasive among adolescents with autism spectrum disorders (ASD). However, how adolescents with ASD differ from typically developing adolescents in their responses to peer rejection is poorly understood. The goal of the current investigation was to examine neural responses to peer exclusion among adolescents with ASD compared to typically developing adolescents. Nineteen adolescents with ASD and 17 typically developing controls underwent fMRI as they were ostensibly excluded by peers during an online game called Cyberball. Afterwards, participants reported their distress about the exclusion. Compared to typically developing adolescents, those with ASD displayed less activity in regions previously linked with the distressing aspect of peer exclusion, including the subgenual anterior cingulate and anterior insula, as well as less activity in regions previously linked with the regulation of distress responses during peer exclusion, including the ventrolateral prefrontal cortex and ventral striatum. Interestingly, however, both groups self-reported equivalent levels of distress. This suggests that adolescents with ASD may engage in differential processing of social experiences at the neural level, but be equally aware of, and concerned about, peer rejection. Overall, these findings contribute new insights about how this population may differentially experience negative social events in their daily lives.     

Etiologic yield of autistic spectrum disorders: a prospective study.

At present, the etiologic yield in community-derived samples of young children with an autistic spectrum disorder is not known. To address this question, all young children (under 5 years of age) referred for an initial assessment to ambulatory pediatric neurology or developmental pediatric clinics at a tertiary university center over an 18-month period for a suspected developmental delay were prospectively identified. Specific diagnostic testing was left to the discretion of the evaluating physician. In all, 50 children with an autistic spectrum disorder were assessed. Detailed history or physical examination was informative with respect to suggesting the possibility of an underlying etiology in a minority (10/50,20%). Genetic studies (FMR-1, karyotype), electroencephalography (EEG), and neuroimaging were carried out in a majority (42/50, 34/50, and 33/50, respectively) of the children, for the most part on a screening rather than an indicated basis (31/42, 34/34, and 28/33, respectively). Etiologic yield was low (1/50, 2%), with only a single child identified with a possible Landau-Kleffner variant on sleep EEG tracing. The results suggest an evaluation paradigm with reference to etiologic determination for young children with autistic spectrum disorder that does not presently justify metabolic or neuroimaging on a screening basis. Recurrence risk and treatment implications, however, suggest that strong consideration be given to genetic (FMR-1, karyotype) testing and EEG study despite a relatively low yield.     

Iron deficiency in preschool children with autistic spectrum disorders

Iron deficiency (ID) cause negative outcomes on psychomotor and behavioral development of infants and young children. Children with autistic spectrum disorders (ASD) are under risk for ID and this condition may increase the severity of psychomotor and behavioral problems, some of which already inherently exist in these children. In the present study, the frequency of ID and the association between ID and autistic symptoms, developmental level, and behavioral problems in preschool children attending a clinic for ASD (N = 31) were evaluated. No association was observed between ID and the severity of autistic symptoms, developmental level and behavioral problems. ID was detected in 32.3% (N = 10) of the children based on serum ferritin level. In this study, the negative impact of low serum ferritin in ASD has not been confirmed. On the other hand, the rate of ID was considerably high in this sample of children with ASD compared to normative data of preschool children. Further studies with larger samples are needed to clarify the relationship between ID and clinical variables associated with ASD.     

Association between amygdala response to emotional faces and social anxiety in autism spectrum disorders

Difficulty interpreting facial expressions has been reported in autism spectrum disorders (ASD) and is thought to be associated with amygdala abnormalities. To further explore the neural basis of abnormal emotional face processing in ASD, we conducted an fMRI study of emotional face matching in high-functioning adults with ASD and age, IQ, and gender matched controls. In addition, we investigated whether there was a relationship between self-reported social anxiety and fMRI activation. During fMRI scanning, study participants were instructed to match facial expressions depicting fear or anger. The control condition was a comparable shape-matching task. The control group evidenced significantly increased left prefrontal activation and decreased activation in the occipital lobes compared to the ASD group during emotional face matching. Further, within the ASD group, greater social anxiety was associated with increased activation in right amygdala and left middle temporal gyrus, and decreased activation in the fusiform face area. These results indicate that level of social anxiety mediates the neural response to emotional face perception in ASD.     

Double-blind,placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders

L-Carnosine, a dipeptide, can enhance frontal lobe function or be neuroprotective. It can also correlate with gamma-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable changes versus placebo. Outcome measures were the Childhood Autism Rating Scale, the Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the enterorhinal or temporal cortex.     

Prefrontal hyperactivation during a working memory task in early-onset schizophrenia spectrum disorders: An fMRI study

Working memory (WM) dysfunction is increasingly recognized as a core feature of schizophrenia, but few studies have investigated prefrontal activation during WM tasks in early-onset schizophrenia spectrum disorder (EOS). Our aim was to explore prefrontal activation during a WM-task in EOS patients compared to healthy controls using functional magnetic resonance imaging (fMRI). Fifteen patients with EOS and 15 matched healthy controls performed a 0-back and a 2-back task while fMRI data were acquired. Results indicated that even though performance between patients and controls was comparable on both tasks, there was a hyperactivation in patients' ventrolateral prefrontal cortex (VLPFC) during the 2-back task compared to healthy controls. This pattern of activation suggests that, in patients with EOS, the VLPFC compensated in order to match performance of the controls. The activations in the EOS group may reflect the use of a compensatory, cognitive strategy while solving WM-tasks.     

Fluoxetine response in children with autistic spectrum disorders: correlation with familial major affective disorder and intellectual achievement

One hundred and twenty-nine children, 2 to 8 years old, with idiopathic autistic spectrum disorder diagnosed by standard instruments (Childhood Austim Ratings Scale and Autism Diagnostic Observation Schedule) were treated with fluoxetine (0.15 to 0.5mg/kg) for 5 to 76 months (mean 32 to 36 months), with discontinuation trials. Response criteria are described. Family histories were obtained using the family history method in repeated interviews. Fluoxetine response, family history of major affective disorder, and unusual intellectual achievement, pretreatment language, and hyperlexia were used to define a coherent subgroup of autistic spectrum disorder. Statistical analyses were post hoc. Of the children, 22 (17%) had an excellent response, 67 (52%) good, and 40 (31%) fair/poor. Treatment age did not correlate with response. Fluoxetine response correlated robustly with familial major affective disorder and unusual intellectual achievement, and with hyperlexia in the child. Family history of bipolar disorder and of unusual intellectual achievement correlated strongly. Five children developed bipolar disorder during follow-up. Fluoxetine response, family history of major affective disorder (especially bipolar), unusual achievement, and hyperlexia in the children appear to define a homogeneous autistic subgroup. Bipolar disorder, unusual intellectual achievement, and autistic spectrum disorders cluster strongly in families and may share genetic determinants.     

Comorbidity of autistic spectrum disorders in children with Down syndrome

The aim of the study was to identify the comorbidity of autistic spectrum disorders in a population of children with Down syndrome (DS). All children with DS within a defined population of South Birmingham were identified. The Asperger Syndrome Screening Questionnaire and the Child Autism Rating Scale were completed and diagnosis made according to ICD-10 criteria following interview and observation. Thirty-three of 58 identified children completed the measures, four of whom received a diagnosis of an autistic spectrum disorder. This is equivalent to a minimum comorbid rate of 7%. The questionnaire items concerning social withdrawal, restricted or repetitive interests, clumsiness, and unusual eye contact were associated with an autistic disorder. Of the remaining 29 participating children, 11 also displayed marked obsessional and ritualistic behaviours. The comorbid occurrence of autism and DS is at least 7%. It is important that these children are identified and receive appropriate education and support. A full assessment of social, language, and communication skills and behaviour is crucial, particularly in children with DS who appear different from other children with DS. Potential mechanisms accounting for this comorbidity are discussed.     

Impairment in movement skills of children with autistic spectrum disorders

Aim  We undertook this study to explore the degree of impairment in movement skills in children with autistic spectrum disorders (ASD) and a wide IQ range.
Method  Movement skills were measured using the Movement Assessment Battery for Children (M-ABC) in a large, well defined, population-derived group of children ( n =101: 89 males,12 females; mean age 11y 4mo, SD 10mo; range 10y–14y 3mo) with childhood autism and broader ASD and a wide range of IQ scores. Additionally, we tested whether a parent-completed questionnaire, the Developmental Coordination Disorder Questionnaire (DCDQ), was useful in identifying children who met criteria for movement impairments after assessment ( n =97 with complete M-ABCs and DCDQs).
Results  Of the children with ASD, 79% had definite movement impairments on the M-ABC; a further 10% had borderline problems. Children with childhood autism were more impaired than children with broader ASD, and children with an IQ less than 70 were more impaired than those with IQ more than 70. This is consistent with the view that movement impairments may arise from a more severe neurological impairment that also contributes to intellectual disability and more severe autism. Movement impairment was not associated with everyday adaptive behaviour once the effect of IQ was controlled for. The DCDQ performed moderately well as a screen for possible motor difficulties.
Interpretation  Movement impairments are common in children with ASD. Systematic assessment of movement abilities should be considered a routine investigation.     

5-HTTLPR variants not associated with autistic spectrum disorders

To determine whether there is an association of polymorphic variants of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) and autistic spectrum disorders, we analyzed the 5-HTTLPR genotypes of 72 autistic subjects, 11 fragile X syndrome patients with autistic behavior, 43 normal subjects, and 49 fragile X syndrome non-autistic subjects. The distribution frequency of 5-HTTLPR long allele (L) and the short allele (S) variants showed no differences between subjects. Our findings do not support the hypothesis that polymorphic 5-HTTLPR variants are a susceptibility factor for autistic disorders. Received: August 5, 1998 / Accepted: December 22, 1998 / Published online: March 11, 1999     

Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study.

BACKGROUND: The amygdala has a central role in processing emotions, particularly fear. During functional magnetic resonance imaging (fMRI) amygdala activation has been demonstrated outside of conscious awareness using masked emotional faces. METHODS: We applied the masked faces paradigm to patients with major depression (n = 11) and matched control subjects (n = 11) during fMRI to compare amygdala activation in response to masked emotional faces before and after antidepressant treatment. Data were analyzed using left and right amygdala a priori regions of interest, in an analysis of variance block analysis and random effects model. RESULTS: Depressed patients had exaggerated left amygdala activation to all faces, greater for fearful faces. Right amygdala did not differ from control subjects. Following treatment, patients had bilateral reduced amygdala activation to masked fearful faces and bilateral reduced amygdala activation to all faces. Control subjects had no differences between the two scanning sessions. CONCLUSIONS: Depressed patients have left amygdala hyperarousal, even when processing stimuli outside conscious awareness. Increased amygdala activation normalizes with antidepressant treatment.