Michael H. Buonocore

The Amygdala Is Enlarged in Children But Not Adolescents with Autism; the Hippocampus Is Enlarged at All Ages

Autism is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction, deficits in verbal and nonverbal communication, and a restricted repertoire of activities or interests. We performed a magnetic resonance imaging study to better define the neuropathology of autistic spectrum disorders. Here we report findings on the amygdala and the hippocampal formation. Borders of the amygdala, hippocampus, and cerebrum were defined, and their volumes were measured in male children (7.5-18.5 years of age) in four diagnostic groups: autism with mental retardation, autism without mental retardation, Asperger syndrome, and age-matched typically developing controls. Although there were no differences between groups in terms of total cerebral volume, children with autism (7.5-12.5 years of age) had larger right and left amygdala volumes than control children. There were no differences in amygdala volume between the adolescent groups (12.75-18.5 years of age). Interestingly, the amygdala in typically developing children increases substantially in volume from 7.5 to 18.5 years of age. Thus, the amygdala in children with autism is initially larger, but does not undergo the age-related increase observed in typically developing children. Children with autism, with and without mental retardation, also had a larger right hippocampal volume than typically developing controls, even after controlling for total cerebral volume. Children with autism but without mental retardation also had a larger left hippocampal volume relative to controls. These cross-sectional findings indicate an abnormal program of early amygdala development in autism and an abnormal pattern of hippocampal development that persists through adolescence. The cause of amygdala and hippocampal abnormalities in autism is currently unknown.

Posterior cingulate cortex activation by emotional words: fMRI evidence from a valence decision task

Functional imaging studies consistently find that emotional stimuli activate the posterior cingulate cortex, a region that appears to have memory‐related functions. However, prior imaging studies have not controlled for non‐emotional stimulus features that might activate this region by engaging memory processes unrelated to emotion. This study examined whether emotional words activated the posterior cingulate cortex when these potentially confounding factors were controlled. Sixty‐four pleasant and 64 unpleasant words were matched with neutral words on non‐emotional features known to influence memory. Eight subjects underwent block‐designed functional magnetic resonance imaging scans while evaluating the valence of these words. The posterior cingulate cortex was significantly activated bilaterally during both unpleasant and pleasant compared to neutral words. The strongest activation peak with both unpleasant and pleasant words was observed in the left subgenual cingulate cortex. Anteromedial orbital and left inferior and middle frontal cortices were also activated by both pleasant and unpleasant words. Right amygdala and auditory cortex were activated only by unpleasant words, while left frontal pole was activated only by pleasant words. The results show that activation of the posterior cingulate cortex by emotional stimuli cannot be attributed to the memory‐enhancing effects of non‐emotional stimulus features. The findings are consistent with the suggestion that this region may mediate interactions of emotional and memory‐related processes. The results also extend prior findings that evaluating emotional words consistently activates the subgenual cingulate cortex, and suggest a means of probing this region in patients with mood disorders. Hum. Brain Mapping 18:30–41, 2003.

REMEMBERING FAMILIAR PEOPLE: THE POSTERIOR CINGULATE CORTEX AND AUTOBIOGRAPHICAL MEMORY RETRIEVAL

Most functional imaging studies of memory retrieval investigate memory for standardized laboratory stimuli. However, naturally acquired autobiographical memories differ from memories of standardized stimuli in important ways. Neuroimaging studies of natural memories may reveal distinctive patterns of brain activation and may have particular value in assessing clinical disorders of memory. This study used functional magnetic resonance imaging to investigate brain activation during successful retrieval of autobiographical memories elicited by name-cued recall of family members and friends. The caudal part of the left posterior cingulate cortex was the most strongly activated region and was significantly activated in all eight subjects studied. Most subjects also showed significant activation of the left anterior orbitomedial, anterior middle frontal, precuneus, cuneus, and posterior inferior parietal cortices, and the right posterior cingulate and motor cortices.Our findings are consistent with prior studies showing posterior cingulate cortex activation during autobiographical memory retrieval. This region is also consistently activated during retrieval of standardized memory stimuli when experimental designs emphasizing successful retrieval are employed. Our results support the hypothesis that the posterior cingulate cortex plays an important role in successful memory retrieval. The posterior cingulate cortex has strong reciprocal connections with entorhinal and parahippocampal cortices. Studies of early Alzheimers disease, temporal lobectomy, and hypoxic amnesia show that hypometabolism of the posterior cingulate cortex is an early and prominent indicator of pathology in these patients. Our findings suggest that autobiographical memory retrieval tasks could be used to probe the functional status of the posterior cingulate cortex in patients with early Alzheimers disease or at risk for that condition.

Hippocampal, parahippocampal and occipital-temporal contributions to associative and item recognition memory: an fMRI study.

The temporal lobe regions involved in memory retrieval were examined using fMRI. During an associative recognition test, participants made memory judgments about the study color of previously presented drawings of objects, and during item recognition tests they made old/new judgments about previously studied objects or new objects. Associative recognition compared with old item recognition led to activations in bilateral hippocampal and parahippocampal regions, as well as in the left middle occipital gyrus. Old item recognition compared with new item recognition led to activation in the left middle occipital gyrus and the left middle temporal gyrus, and relative deactivations in bilateral hippocampal regions. The results indicate that partially distinct temporal lobe regions are involved during recognition memory for item and associative information.

ERP and fMRI measures of visual spatial selective attention

In two prior studies, we investigated the neural mechanisms of spatial attention using a combined event‐related potential (ERP) and positron emission tomography (PET) approach (Heinze et al. [1994]: Nature 392:543–546; Mangun et al. [1997]: Hum Brain Mapp 5:273–279). Neural activations in extrastriate cortex were observed in the PET measures for attended stimuli, and these effects were related to attentional modulations in the ERPs at specific latencies. The present study used functional magnetic resonance imaging (fMRI) and ERPs in single subjects to investigate the intersubject variability in extrastriate spatial attention effects, and to qualitatively compare this to variations in ERP attention effects. Activations in single subjects replicated our prior group‐averaged PET findings, showing attention‐related increases in blood flow in the posterior fusiform and middle occipital gyri in the hemisphere contralateral to attended visual stimuli. All subjects showed attentional modulations of the occipital P1 component of the ERPs. These findings in single subjects demonstrate the consistency of extrastriate attention effects, and provide information about the feasibility of this approach for integration of electrical and functional imaging data. Hum. Brain Mapping 6:383–389, 1998.

4D magnetic resonance velocity mapping of blood flow patterns in the aorta in young vs. elderly normal subjects.

Four‐dimensional magnetic resonance MR velocity mapping was developed to study normal flow patterns in the thoracic aorta using time‐resolved cardiac gated three‐directional velocity data. Sixteen normal subjects were studied, one young group (average age 31 years) and one group with elderly people (average age 72 years). Blood flowed in a right‐handed helix from the ascending aorta to the aortic arch. A straight flow pattern or a left‐handed helix was seen in the descending aorta. Blood flow was never parabolic. Blood flowed forward in early systole, retrograde in mid‐to‐end systole, and forward again in diastole in all subjects as a basic pattern. Continuous retrograde flow over a long distance was not seen, but blood entered a retrograde flow column at various levels. In young people blood passed from the aortic valve to the mid‐descending aorta in less than one heartbeat. In people in their sixties it took two heartbeats and in people older than 78 years, it took three heartbeats. The maximum systolic forward velocities were higher in young subjects than in elderly while the retrograde velocities were lower. J. Magn. Reson. Imaging 1999;10:861–869.

MR spectroscopic studies of the brain in psychiatric disorders

The measurement of brain metabolites with magnetic resonance spectroscopy (MRS) provides a unique perspective on the brain bases of neuropsychiatric disorders. As a context for interpreting MRS studies of neuropsychiatric disorders, we review the characteristic MRS signals, the metabolic dynamics,and the neurobiological significance of the major brain metabolites that can be measured using clinical MRS systems. These metabolites include N-acetylaspartate(NAA), creatine, choline-containing compounds, myo-inositol, glutamate and glutamine, lactate, and gamma-amino butyric acid (GABA). For the major adult neuropsychiatric disorders (schizophrenia, bipolar disorder, major depression, and the anxiety disorders), we highlight the most consistent MRS findings, with an emphasis on those with potential clinical or translational significance. Reduced NAA in specific brain regions in schizophrenia, bipolar disorder, post-traumatic stress disorder, and obsessive–compulsive disorder corroborate findings of reduced brain volumes in the same regions. Future MRS studies may help determine the extent to which the neuronal dysfunction suggested by these findings is reversible in these disorders. Elevated glutamate and glutamine (Glx) in patients with bipolar disorder and reduced Glx in patients with unipolar major depression support models of increased and decreased glutamatergic function, respectively, in those conditions. Reduced phosphomonoesters and intracellular pH in bipolar disorder and elevated dynamic lactate responses in panic disorder are consistent with metabolic models of pathogenesis in those disorders. Preliminary findings of an increased glutamine/glutamate ratio and decreased GABA in patients with schizophrenia are consistent with a model of NMDA hypofunction in that disorder. As MRS methods continue to improve, future studies may further advance our understanding of the natural history of psychiatric illnesses, improve our ability to test translational models of pathogenesis, clarify therapeutic mechanisms of action,and allow clinical monitoring of the effects of interventions on brain metabolicmarkers

Activation of left posterior cingulate gyrus by the auditory presentation ofthreat-related words: an fMRI study

This study investigated the cortical response to hearing threat-related and neutral words using functional magnetic resonance imaging (fMRI) in 16 coronal planes. Right-handed volunteers listened to (i) neutral words alternating with no words as the control condition, and (ii) neutral words alternating with threat-related words as the experimental condition. Threat-related words compared to neutral words activated left posterior cingulate gyrus in eight of 10 subjects with activation most prominent in the retrosplenial region. Patterns of activation produced by neutral words compared to no words included bilateral temporal and frontal regions but not posterior cingulate. The retrosplenial cingulate region has recently been implicated in episodic memory processes. We discuss the possible role of the posterior cingulate cortex in processes involving emotion and memory and in anxiety disorders.

Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders

Autism is a heterogeneous disorder with multiple behavioral and biological phenotypes. Accelerated brain growth during early childhood is a well-established biological feature of autism. Onset pattern, i.e., early onset or regressive, is an intensely studied behavioral phenotype of autism. There is currently little known, however, about whether, or how, onset status maps onto the abnormal brain growth. We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism. Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4–6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism.

Brain structure and cognition in a community sample of elderly Latinos

BackgroundPrevious studies have found that hippocampal atrophy and white matter hyperintensities (WMH) on MRI are linked to cognitive impairment and dementia. The authors measured these variables in a population-based cohort of older Mexican Americans with a wide spectrum of cognitive ability, ranging from normal cognition to dementia. ObjectiveTo investigate whether these structural brain changes were seen in individuals prior to the development of dementia and how these changes were related to the presence of dementia. MethodsA sample of 122 subjects was selected from the Sacramento Area Latino Study on Aging, and subjects were categorized into four groups of increasing levels of cognitive impairment: normal, memory impaired (MI), cognitively impaired but not demented (CIND), and demented. Hippocampal volume was quantified using a region of interest approach. WMH was rated on a semiquantitative scale as the percent of total volume of white matter. ResultsHippocampal volume was significantly reduced in CIND and demented individuals, and WMH were significantly increased in demented subjects. MI subjects did not have any significant changes in hippocampal volume or WMH. The risk for developing dementia was significantly and comparably increased in subjects with either hippocampal atrophy or high WMH. However, the risk for dementia increased dramatically in subjects with both hippocampal atrophy and a high degree of WMH. ConclusionReductions in hippocampal volume may be present before dementia but not until cognitive impairment is relatively severe. Because there is a synergistic effect between high WMH and hippocampal atrophy, interactions between vascular and degenerative processes may be important determinants of dementia.