Brain activation during face perception: evidence of a developmental change.

Behavioral studies suggest that children under age 10 process faces using a piecemeal strategy based on individual distinctive facial features, whereas older children use a configural strategy based on the spatial relations among the face's features. The purpose of this study was to determine whether activation of the fusiform gyrus, which is involved in face processing in adults, is greater during face processing in older children (12-14 years) than in younger children (8-10 years). Functional MRI scans were obtained while children viewed faces and houses. A developmental change was observed: Older children, but not younger children, showed significantly more activation in bilateral fusiform gyri for faces than for houses. Activation in the fusiform gyrus correlated significantly with age and with a behavioral measure of configural face processing. Regions believed to be involved in processing basic facial features were activated in both younger and older children. Some evidence was also observed for greater activation for houses versus faces for the older children than for the younger children, suggesting that processing of these two stimulus types becomes more differentiated as children age. The current results provide biological insight into changes in visual processing of faces that occur with normal development.

Onset and rate of striatal atrophy in preclinical Huntington disease.

BACKGROUND: Huntington disease (HD) is characterized by striatal atrophy that begins long before the onset of motor symptoms. OBJECTIVE: To determine when striatal atrophy begins, the extent and rate of atrophy before diagnosis of motor symptoms, and whether striatal atrophy can predict when symptom onset will occur. METHODS: Caudate and putamen volumes were measured on MRI scans of 19 preclinical subjects with the HD gene expansion who were very far (9 to 20 years) from estimated onset, and on serial scans from 17 preclinical subjects, six of whom were diagnosed with HD within 5 years after the initial scan. RESULTS: Striatal volumes were significantly smaller for the subjects who were very far from estimated onset than for age-matched control subjects. Statistical models fit to the longitudinal data suggest that rate of caudate atrophy becomes significant when subjects are approximately 11 years from estimated onset and rate of putamen atrophy becomes significant approximately 9 years prior to onset. In the six incident cases, caudate and putamen were approximately one-third to one-half of normal volume at diagnosis, and caudate volume alone was able to predict with 100% accuracy those subjects who would be diagnosed within 2 years of imaging. CONCLUSIONS: Striatal atrophy begins many years prior to diagnosable HD, and assessment of atrophy on MRI may be very useful in both predicting HD onset and in tracking progression in future therapeutic trials in preclinical subjects.

Caudate volume as an outcome measure in clinical trials for Huntington's disease: a pilot study.

Previous research has demonstrated that longitudinal change in caudate volume could be observed over a period of 3 years in subjects with Huntington's disease (HD). The current pilot study was designed to determine whether measurement of caudate change on magnetic resonance imaging (MRI) is a feasible and valid outcome measure in an actual clinical trial situation. We measured caudate volumes on pre- and post-treatment MRI scans from 19 patients at two sites who were participating in CARE-HD (Co-enzyme Q10 and Remacemide: Evaluation in Huntington's Disease), a 30-month clinical trial of remacemide and co-enzyme Q(10) in symptomatic patients with HD. Results from this pilot study indicated that decrease in caudate volume was significant over time. Power analysis indicated that relatively small numbers of subjects would be needed in clinical trials using caudate volume as an outcome measure. Advantages and disadvantages of using MRI caudate volume as an outcome measure are presented. We recommend the adoption of quantitative neuroimaging of caudate volume as an outcome measure in future clinical trials for treatments of HD.

Instructional treatment associated with changes in brain activation in children with dyslexia.

OBJECTIVE: To assess the effects of reading instruction on fMRI brain activation in children with dyslexia. BACKGROUND: fMRI differences between dyslexic and control subjects have most often involved phonologic processing tasks. However, a growing body of research documents the role of morphologic awareness in reading and reading disability. METHODS: The authors developed tasks to probe brain activation during phoneme mapping (assigning sounds to letters) and morpheme mapping (understanding the relationship of suffixed words to their roots). Ten children with dyslexia and 11 normal readers performed these tasks during fMRI scanning. Children with dyslexia then completed 28 hours of comprehensive reading instruction. Scans were repeated on both dyslexic and control subjects using the same tasks. RESULTS: Before treatment, children with dyslexia showed less activation than controls in left middle and inferior frontal gyri, right superior frontal gyrus, left middle and inferior temporal gyri, and bilateral superior parietal regions for phoneme mapping. Activation was significantly reduced for children with dyslexia on the initial morpheme mapping scan in left middle frontal gyrus, right superior parietal, and fusiform/occipital region. Treatment was associated with improved reading scores and increased brain activation during both tasks, such that quantity and pattern of activation for children with dyslexia after treatment closely resembled that of controls. The elimination of group differences at follow-up was due to both increased activation for the children with dyslexia and decreased activation for controls, presumably reflecting practice effects. CONCLUSION: These results suggest that behavioral gains from comprehensive reading instruction are associated with changes in brain function during performance of language tasks. Furthermore, these brain changes are specific to different language processes and closely resemble patterns of neural processing characteristic of normal readers.

Effects of age on brain volume and head circumference in autism.

OBJECTIVE: To determine whether brain volume, as assessed on MRI scans, differs between individuals with autism and control subjects, and whether such differences are affected by age. BACKGROUND: Previous studies have found increased brain weight, head circumference, and MRI brain volume in children with autism. However, studies of brain size in adults with autism have yielded conflicting results. The authors hypothesize that enlargement of the brain may be a feature of brain development during early childhood in autism that normalizes with maturational processes. METHODS: The authors measured total brain volumes from 1.5-mm coronal MRI scans in 67 non-mentally retarded children and adults with autism and 83 healthy community volunteers, ranging in age from 8 to 46 years. Head circumference was also measured. Groups did not differ on age, sex, verbal IQ, or socioeconomic status. RESULTS: Brain volumes were significantly larger for children with autism 12 years old and younger compared with normally developing children, when controlling for height. Brain volumes for individuals older than age 12 did not differ between the autism and control groups. Head circumference was increased in both younger and older groups of subjects with autism, suggesting that those subjects older than age 12 had increased brain volumes as children. CONCLUSIONS: Brain development in autism follows an abnormal pattern, with accelerated growth in early life that results in brain enlargement in childhood. Brain volume in adolescents and adults with autism is, however, normal, and appears to be due to a slight decrease in brain volume for these individuals at the same time that normal children are experiencing a slight increase.

Brain structural abnormalities in young children with autism spectrum disorder.

OBJECTIVE: To explore the specific gross neuroanatomic substrates of this brain developmental disorder, the authors examine brain morphometric features in a large sample of carefully diagnosed 3- to 4-year-old children with autism spectrum disorder (ASD) compared with age-matched control groups of typically developing (TD) children and developmentally delayed (DD) children. METHODS: Volumes of the cerebrum, cerebellum, amygdala, and hippocampus were measured from three-dimensional coronal MR images acquired from 45 children with ASD, 26 TD children, and 14 DD children. The volumes were analyzed with respect to age, sex, volume of the cerebrum, and clinical status. RESULTS: Children with ASD were found to have significantly increased cerebral volumes compared with TD and DD children. Cerebellar volume for the ASD group was increased in comparison with the TD group, but this increase was proportional to overall increases in cerebral volume. The DD group had smaller cerebellar volumes compared with both of the other groups. Measurements of amygdalae and hippocampi in this group of young children with ASD revealed enlargement bilaterally that was proportional to overall increases in total cerebral volume. There were similar findings of cerebral enlargement for both girls and boys with ASD. For subregion analyses, structural abnormalities were observed primarily in boys, although this may reflect low statistical power issues because of the small sample (seven girls with ASD) studied. Among the ASD group, structural findings were independent of nonverbal IQ. In a subgroup of children with ASD with strictly defined autism, amygdalar enlargement was in excess of increased cerebral volume. CONCLUSIONS: These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

Test battery for the diagnosis of dementia in individuals with intellectual disability. Working Group for the Establishment of Criteria for the Diagnosis of Dementia in Individuals with Intellectual Disability.

A working battery of tests for the diagnosis of dementia, which is applicable to most adults with intellectual disability, is proposed by an international Working Group. The battery, reflecting contemporary research and practice findings, includes scales for informant report of functioning and tests for direct assessment. The Working Group recommends the international use of the battery both as part of ongoing and new longitudinal research, and in clinical practice. The widespread use of a common battery will enhance communication and collaborative opportunities among researchers and clinicians at various sites, and will help to standardize diagnostic protocols and research findings. The collaborative evaluation of such a battery will address one of the greatest challenges in the field, that of differentiating change associated with ageing from that associated with dementia.

Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington's disease.

Previous research by our group demonstrated a longitudinal change in caudate volume for symptomatic subjects with Huntington's disease (HD), and suggested that volume of the caudate may be a useful outcome measure for therapeutic studies in symptomatic patients. The current study was designed to determine whether longitudinal change in caudate atrophy could be documented in presymptomatic carriers of the HD gene mutation, and to compare rate of change in these subjects with rate of change in mildly and moderately affected symptomatic patients. We measured caudate volumes on serial magnetic resonance image scans from 30 patients at three stages of HD: 10 presymptomatic; 10 with mild symptoms, as indicated by scores on the Quantified Neurological Exam (QNE) < or =35; and 10 with moderate symptoms (QNE >45). The mean interscan interval was 36 months. When analyzed separately, both symptomatic groups and the presymptomatic group demonstrated a significant change in caudate volume over time. Amount of change over time did not differ significantly among the three groups. We conclude that change in caudate volume may be a useful outcome measure for assessing treatment effectiveness in both presymptomatic and symptomatic subjects.

Elucidating the contributions of processing speed, executive ability, and frontal lobe volume to normal age-related differences in fluid intelligence.

One theory of normal cognitive aging asserts that decreases in simple processing speed mediate the age-related decline of fluid intelligence. Another possibility is that age-related atrophic changes in frontal brain structures undermine the functioning of executive abilities, thereby producing the same decline. In this study, we used principal components analysis to derive a measure of fluid-spatial intelligence in 197 normal adults between 20 and 92 years of age. Measures of perceptual comparison speed, working memory, and executive ability, as well as regional brain volumes based on high resolution magnetic resonance imaging were obtained from a subsample of 112 participants. We then conducted a series of hierarchical multiple regression analyses to test whether (1) the processing speed theory, (2) frontal-executive theory, or (3) some combination of these best accounted for age-related variation in fluid intelligence. The results showed that perceptual comparison speed, executive ability, and frontal lobe volume each made significant contributions to a regression equation that explained 57% of the variance in fluid intelligence. These findings suggest that both the processing speed and frontal-executive theory of cognitive aging are partially correct and complement one another.

Neurocognitive functioning in children with mild and moderate asthma in the childhood asthma management program. The Childhood Asthma Management Program (CAMP) Research Group.

BACKGROUND: The Childhood Asthma Management Program (CAMP) is a multicenter double-blind, randomized, placebo-controlled, clinical trial of two anti-inflammatory agents and placebo in children with mild and moderate asthma. OBJECTIVE: The interrelationship between asthma severity and neurocognitive functioning among 1041 children (age range, 5-12 years) enrolled in the CAMP trial was examined. METHODS: Asthma severity was established at baseline with a clinical history of asthma symptomatology and measures of lung function (spirometry and methacholine challenge). Diary cards were used in a screening to record nighttime awakenings and doctor contacts caused by asthma symptoms, symptom severity, and number of puffs from a rescue inhaler. All children received a comprehensive neurocognitive assessment at the end of the 28-day screening period (before randomization), including measures of intelligence, attention, memory, and academic achievement. RESULTS: Significant differences were found between children with mild and moderate asthma on lung function and symptom outcome variables (log(e)FEV(1)PC(20), DeltaFEV(1) percent predicted, change in peak flow percent predicted, nighttime awakenings caused by asthma, average symptom severity score, and average daily number of puffs from a rescue inhaler) but not on neurocognitive variables. Multiple regression analyses revealed that asthma outcomes could not be predicted by neurocognitive variables despite controlling for socioeconomic status. The prevalence of neurocognitive dysfunction, as indicated by the use of psychostimulant medication, was found to be consistent with that found in the existing literature. CONCLUSION: Mild and moderate asthma symptoms are not related to neurocognitive functioning in the children enrolled in CAMP. Mean performance on neurocognitive variables was found to be similar to that of national normative data.

MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults.

OBJECTIVE: To determine whether volumes of hippocampus and amygdala are abnormal in people with autism. BACKGROUND: Neuropathologic studies of the limbic system in autism have found decreased neuronal size, increased neuronal packing density, and decreased complexity of dendritic arbors in hippocampus, amygdala, and other limbic structures. These findings are suggestive of a developmental curtailment in the maturation of the neurons and neuropil. METHODS: Measurement of hippocampus, amygdala, and total brain volumes from 1.5-mm coronal, spoiled gradient-recalled echo MRI scans in 14 non-mentally retarded autistic male adolescents and young adults and 14 individually matched, healthy community volunteers. RESULTS: Amygdala volume was significantly smaller in the autistic subjects, both with (p = 0.006) and without (p = 0.01) correcting for total brain volume. Total brain volume and absolute hippocampal volume did not differ significantly between groups, but hippocampal volume, when corrected for total brain volume, was significantly reduced (p = 0.04) in the autistic subjects. CONCLUSIONS: There is a reduction in the volume of amygdala and hippocampus in people with autism, particularly in relation to total brain volume. The histopathology of autism suggests that these volume reductions are related to a reduction in dendritic tree and neuropil development, and likely reflect the underdevelopment of the neural connections of limbic structures with other parts of the brain, particularly cerebral cortex.

MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia.

OBJECTIVE: This study sought to determine whether volumes of the hippocampus and amygdala are disproportionately smaller in subjects with Down's syndrome than in normal comparison subjects and whether volume reduction is greater in Down's syndrome subjects with dementia. METHOD: The subjects were 25 adults with Down's syndrome (eight with dementia) and 25 cognitively normal adults who were individually matched on age, sex, and race. Magnetic resonance imaging measures included volumes of the hippocampus, amygdala, and total brain. Nineteen of the Down's syndrome subjects had follow-up scans (interscan interval = 9-41 months). RESULTS: Nondemented Down's syndrome subjects had significantly smaller volumes of the hippocampus, but not the amygdala, than their comparison subjects, even when total brain volume was controlled for. Volumes of both the hippocampus and the amygdala were smaller in the demented Down's syndrome subjects than in their comparison subjects, even when total brain volume was controlled for. Age was not correlated with volume of the hippocampus or amygdala among the nondemented Down's syndrome subjects and the comparison subjects; age was correlated with volume of the amygdala, but not the hippocampus, among the Down's syndrome subjects with dementia. Changes in volume over time were not statistically significant for either the demented or the nondemented subjects. CONCLUSIONS: Hippocampal volume, while disproportionately small for brain size in individuals with Down's syndrome, remains fairly constant through the fifth decade of life in those without dementia. All subjects over age 50 who had Down's syndrome demonstrated volume reduction in the hippocampus as well as clinical signs of dementia. Dementia was also associated with volume reductions in the amygdala that exceeded reductions in total brain volume.

MRI brain changes in subjects with Down syndrome with and without dementia.

Individuals with Down syndrome (DS), a disorder of known genetic etiology (trisomy of chromosome 21), exhibit several types of structural brain abnormalities that are detectable pathologically and by MRI. In addition, in middle age, individuals with DS develop histological and, in some cases, clinical features of Alzheimer's disease (AD). Abnormalities in MRI scans of 50 adults with DS, 11 of whom had clinical dementia, are described and compared with those of 23 cognitively normal, healthy subjects who were matched for age, sex, and race. Qualitative visual analogue scale (VAS) ratings on MRI hard copies for all subjects and computer-aided volume measures for a subsample of subjects were carried out. On VAS, subjects with DS had larger lateral ventricles, a higher frequency of posterior fossa arachnoid cysts/megacisterna magna and fewer scans rated as normal compared with controls. Quantitatively, total brain and gray-matter volumes were reduced in DS, as were the volumes of the left hippocampus and amygdala; ventricle volumes were larger. Post hoc comparisons of subjects with DS with and without dementia revealed that on VAS the former had more generalized atrophy for age, mesial temporal shrinkage, and third ventricular enlargement. Similarly, total brain, left hippocampus, and left amygdala volumes were reduced quantitatively in subjects with DS with dementia, while ventricular volumes were increased.

Frontal lobe volume in patients with Huntington's disease.

Neuropathologic and neuroimaging studies have suggested that frontal lobes are affected in Huntington's disease (HD), and that atrophy in this region may be associated with some of the cognitive impairment and clinical decline observed in patients with HD. We measured gray and white matter volumes within the frontal lobes on MRI for 20 patients with HD (10 mildly affected and 10 moderately affected) and 20 age- and sex-matched control subjects. We also correlated frontal lobe measurements with measures of symptom severity and cognitive function. Patients who were mildly affected had frontal lobe volumes (both gray and white matter) essentially identical to those of control subjects, despite clearly abnormal basal ganglia. Patients who were moderately affected demonstrated significant reductions in total frontal lobe volume (17%) and frontal white matter volume (28%). Frontal lobe white matter volume reductions, but not total frontal lobe volume reductions, were disproportionately greater than overall brain volume reductions (17%). Frontal lobe volume correlated with symptom severity and general cognitive function, but these correlations did not remain significant after taking into account total brain volume. We conclude that cognitive impairment and symptom severity are associated with frontal lobe atrophy, but this association is not specific to the frontal lobes. Frontal lobe atrophy (like total brain atrophy) occurs in later stages of increasing HD symptom severity and this atrophy primarily involves white matter.

Measurement of frontal lobe volume on magnetic resonance imaging scans.

This article describes rules for measurement of the frontal lobe on thin SPGR (spoiled gradient recalled echo in steady state) MRI (magnetic resonance imaging) scans. Measurements were performed using a locally-developed software program that allows 3-dimensional reconstruction of images, 'painting' of landmarks on the surface of the brain, and reconstruction of 2-dimensional images in any plane with landmark 'paint' remaining on the surface of the brain. Excellent inter-rater reliability has been achieved for this method. The approach may be particularly useful for studies involving groups of patients whose brains are known to be dysmorphic and who may not, therefore, be appropriate for measurement methods that involve image warping or dependence on arbitrary landmarks for defining the posterior boundary of the frontal lobe.

Basal ganglia volume in adults with Down syndrome.

This study was designed to determine the effects of aging on the volume of the basal ganglia in individuals with Down syndrome (DS) and to examine the relationship between basal ganglia volumes, neuropsychological test performance, and dementia status in this population. Subjects were 32 adults with DS. Basal ganglia volumes from 22 of these subjects were compared with those of 22 cognitively-normal individuals, who were individually matched on age, sex, and race. Performance on neuropsychological tests was correlated with basal ganglia volumes for 32 individuals with DS, and basal ganglia volumes of five demented DS subjects were compared with those of 14 non-demented DS subjects. Results indicated larger putamen volumes in the DS subjects, despite significantly smaller total brain volumes. Volumes of caudate and globus pallidus did not differ between DS and control subjects. Although there were some significant correlations between basal ganglia volumes and age, neuropsychological test performance, and dementia status in the DS subjects, these associations appeared to be a reflection of neurodevelopmental or atrophic reductions in overall brain volume rather than a reflection of specific basal ganglia abnormality. Correlations between age and volumes of basal ganglia and total brain were not significantly greater in non-demented DS subjects than in control subjects. Results suggest that volume reductions of the basal ganglia are not a salient feature of aging or of the dementia associated with DS.

Diagnosis of dementia in individuals with intellectual disability.

The foremost impediment to progress in the understanding and treatment of dementia in adults with intellectual disability is the lack of standardized criteria and diagnostic procedures. Standardized criteria for the diagnosis of dementia in individuals with intellectual disability are proposed, and their application is discussed. In addition, procedures for determining whether or not criteria are met in individual cases are outlined. It is the intention of the authors, who were participants of an International Colloquium on Alzheimer Disease and Mental Retardation, that these criteria be appropriate for use by both clinicians and researchers. Their use will improve communication among clinicians and researchers, and will allow researchers to test hypotheses concerning discrepancies in findings among research groups (e.g. dementia prevalence ranges and age of onset).

Longitudinal change in basal ganglia volume in patients with Huntington's disease.

Cross-sectional MRI studies demonstrating an association between caudate atrophy and symptom severity and duration of symptoms in patients with Huntington's disease (HD) have been assumed to reflect longitudinal changes in basal ganglia, but such neuropathologic progression has never been directly demonstrated. Subjects in the current study were 23 HD patients at various stages of the disorder who had two MRI images at least 10 months apart (mean interimage interval = 20.8 months). We measured volumes of caudate, putamen, and globus pallidus blind to the order of the images. For each structure, we calculated a change score by subtracting the volume obtained on the follow-up imaging from that obtained on the initial imaging. Results indicated significant decreases over time in caudate, putamen, and total basal ganglia volume. Age at onset and length of trinucleotide repeat correlated significantly with amount of volume change in caudate and total basal ganglia, even after controlling for length of interimage interval, duration of disease, and measures of symptom severity. Amount of change in basal ganglia structures was not significantly correlated with neurologic symptom severity at the time of the initial imaging or duration of symptoms. This is the first longitudinal MRI study to document progressive basal ganglia atrophy in HD, and suggests that quantitative neuroimaging with serial MRI may be useful in monitoring effectiveness of potential treatments. In addition, demonstration of greater rate of basal ganglia atrophy in patients with earlier symptom onset suggests that treatment effects may be more quickly observed in this subgroup of patients than in the general HD population.

Cerebellar volume in adults with Down syndrome.

OBJECTIVES: To determine the effects of aging on cerebellar volume in individuals with Down syndrome (DS). To determine whether volume of cerebellum is associated with dementia or with age-related decline in fine-motor control. DESIGN: Case-control study involving comparison of cerebellar volumes in adults with DS and matched control subjects; survey study involving correlations between cerebellar volume and subjects' age and performance on a test of fine motor control; and longitudinal study assessing change in cerebellar volume in adults with DS. SETTING: The Johns Hopkins University School of Medicine, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 40 adults with DS. Thirty of them were matched on age, sex, and race with cognitively normal subjects. A diagnosis of probable dementia was made for 5 of the subjects with DS. Longitudinal data were available for 23 of the 40 subjects with DS, with a mean interscan interval of 2 years. MAIN OUTCOME MEASURES: Volumes of cerebellum, total brain, and intracranial region were measured on magnetic resonance imaging scans. The Purdue Pegboard, a test of fine-motor control, was administered to 38 of the subjects with DS. RESULTS: Subjects with DS had significantly smaller cerebellar volumes than matched controls, even after adjusting for total brain volume or total intracranial volume. Volume of cerebellum did not correlate significantly with age for either the subjects with DS or controls. Longitudinal change in cerebellar volume in subjects with DS was not significant. Volume of total brain, but not cerebellum, correlated significantly with performance on the Purdue Pegboard. CONCLUSIONS: Although cerebellar volumes are disproportionately small in individuals with DS, they do not diminish significantly with age and do not undergo age-related atrophy that is different from that of normal controls. Volume reduction in the cerebellum does not appear to be specifically responsible for the age-related decline in fine-motor control that is observed in adults with DS.

Quantitative MRI volume changes in late onset schizophrenia and Alzheimer's disease compared to normal controls.

Volumes of medial and lateral temporal lobe structures were assessed using magnetic resonance imaging (MRI) in 11 patients with late-life onset schizophrenia (LOS), 18 normal elderly controls and 12 patients with moderate cognitive impairment due to Alzheimer's disease (AD) who had no non-cognitive symptoms. While both patient groups had smaller volumes of several medial temporal regions (e.g. entorhinal cortex, left hippocampus), schizophrenics had significantly smaller anterior superior temporal gyri (STG) than normal controls, but AD patients did not. We have previously demonstrated anterior STG volume to be reduced in early life onset schizophrenia.