Susan M. Rivera

Dissociating prefrontal and parietal cortex activation during arithmetic processing.

Lesion and brain-imaging studies have implicated the prefrontal and parietal cortices in arithmetic processing, but do not exclude the possibility that these brain areas are also involved in nonarithmetic operations. In the present study, we used functional magnetic resonance imaging to explore which brain areas contribute uniquely to numeric computation. Task difficulty was manipulated in a factorial design by varying the number of operands and the rate of stimulus presentation. Both manipulations increased the number of operations to be performed in unit time. Manipulating the number of operands allowed us to investigate the specific effect of calculation, while manipulating the rate of presentation allowed us to increase task difficulty independent of calculation. We found quantitative changes in activation patterns in the prefrontal and parietal cortices as well as the recruitment of additional brain regions, including the caudate and midcerebellar cortex, with increasing task difficulty. More importantly, the main effect of arithmetic complexity was observed in the left and right angular gyrus, while the main effect of rate of stimulus presentation was observed in the left insular/orbitofrontal cortex. Our findings indicate a dissociation in prefrontal and parietal cortex function during arithmetic processing and further provide the first evidence for a specific role for the angular gyrus in arithmetic computation independent of other processing demands.

Cortical Folding Abnormalities in Autism Revealed by Surface-Based Morphometry

We tested for cortical shape abnormalities using surface-based morphometry across a range of autism spectrum disorders (7.5–18 years of age). We generated sulcal depth maps from structural magnetic resonance imaging data and compared typically developing controls to three autism spectrum disorder subgroups: low-functioning autism, high-functioning autism, and Aspergers syndrome. The low-functioning autism group had a prominent shape abnormality centered on the pars opercularis of the inferior frontal gyrus that was associated with a sulcal depth difference in the anterior insula and frontal operculum. The high-functioning autism group had bilateral shape abnormalities similar to the low-functioning group, but smaller in size and centered more posteriorly, in and near the parietal operculum and ventral postcentral gyrus. Individuals with Aspergers syndrome had bilateral abnormalities in the intraparietal sulcus that correlated with age, intelligence quotient, and Autism Diagnostic Interview-Revised social and repetitive behavior scores. Because of evidence suggesting age-related differences in the developmental time course of neural alterations in autism, separate analyses on children (7.5–12.5 years of age) and adolescents (12.75–18 years of age) were also carried out. All of the cortical shape abnormalities identified across all ages were more pronounced in the children. These findings are consistent with evidence of an altered trajectory of early brain development in autism, and they identify several regions that may have abnormal patterns of connectivity in individuals with autism.

A functional and structural study of emotion and face processing in children with autism

Children with autism exhibit impairment in the processing of socioemotional information. The amygdala, a core structure centrally involved in socioemotional functioning, has been implicated in the neuropathology of autism. We collected structural and functional magnetic resonance images (MRI) in children 8 to 12 years of age with high-functioning autism (n=12) and typical development (n=15). The functional MRI experiment involved matching facial expressions and people. Volumetric analysis of the amygdala was also performed. The results showed that children with autism exhibited intact emotion matching, while showing diminished activation of the fusiform gyrus (FG) and the amygdala. Conversely, the autism group showed deficits in person matching amidst some FG and variable amygdala activation. No significant between-group differences in the volume of the left or right amygdala were found. There were associations between age, social anxiety and amygdala volume in the children with autism such that smaller volumes were generally associated with more anxiety and younger age. In summary, the data are consistent with abnormalities in circuits involved in emotion and face processing reported in studies of older subjects with autism showing reductions in amygdala activation related to emotion processing and reduced fusiform activation involved in face processing.

A Review of Fragile X Premutation Disorders: Expanding the Psychiatric Perspective

CONTEXT Fragile X premutation conditions are associated with a significant degree of psychopathology and thus are of interest to the psychiatrist. Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders. OBJECTIVE The authors review the genetic, molecular, neuroimaging, and clinical (systemic, neurologic, and psychiatric) manifestations of the premutation carrier state (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. DATA SOURCES The search for the psychiatric clinical manifestations of fragile X-associated conditions was accomplished by PubMed for clinical papers published between 1970 and 2008 with the following search terms: Fragile X syndrome, depression, psychosis, anxiety, and dementia. STUDY SELECTION Articles addressing psychiatric symptoms in premutation carriers based on review of the abstracts were reviewed. As the majority of the literature on this topic is based on case reports and small case series, these were included in the database. RESULTS Reported clinical manifestations of psychiatric illness in premutation carriers include an apparently significant rate of cognitive, mood, anxiety, and other psychiatric disorders. Fragile X premutation-associated conditions are part of the clinical differential diagnosis of several psychiatric syndromes, particularly in pedigrees with known fragile X syndrome cases. CONCLUSIONS Fragile X-associated psychiatric manifestations serve as a useful model for a molecular genesis of neuropsychiatric illness. Because of the multigenerational expression of fragile X-associated neuropsychiatric illness, there is a prominent role for genetic testing and genetic counseling of patients and their relatives. Genetic testing is confirmatory of the FMR1 premutation and is an essential component of the clinical evaluation. Psychopharmacologic and psychotherapeutic treatment of fragile X-associated psychiatric illnesses may improve patient function and assist in adaptation to the burden of a genetic neuropsychiatric illness.

A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome

Objective: Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Previous open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial. Method: Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, aged 3.5 years to 16 years (n = 55, mean age 9.2 [SD, 3.6] years). Participants were randomized to minocycline or placebo for 3 months and then switched to the other treatment. Results: Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale—Improvement after minocycline compared with placebo (2.49 ± 0.13 and 2.97 ± 0.13, respectively, p = .0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analog Scale (minocycline: 5.26 cm ± 0.46 cm, placebo: 4.05 cm ± 0.46 cm; p = .0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding, and preliminary efficacy analysis results known to investigators. Conclusions: Minocycline treatment for 3 months in children with FXS resulted in greater global improvement than placebo. Treatment for 3 months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline.

Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS)

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Methods: Volumetric MRI studies, clinical staging, cognitive testing, and molecular analysis were conducted in 15 female premutation carriers affected by FXTAS (age 59.5 ± 10.3 years), 20 unaffected female carriers (43.3 ± 11.2 years), 11 genetically normal female controls (51.0 ± 10.3 years), 36 affected male carriers (65.0 ± 5.6 years), 25 unaffected male carriers (53.5 ± 12.5 years), and 39 male controls (58.0 ± 15.0 years). Female and male carriers with FXTAS were matched on duration of disease. Results: We found less pronounced reductions of cerebellar volume and a lower incidence of involvement (symmetric high T2 signal) of the middle cerebellar peduncles (MCP sign) in females affected by FXTAS (13%) compared with affected males (58%). We found reduced brain volumes and increased white matter disease associated with the presence of FXTAS in females compared with female controls. We also observed significant associations between reduced cerebellar volume and both increased severity of FXTAS symptoms and increased length of the CGG repeat expansion in male premutation carriers, but not in females. Conclusions: Females affected by fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrated milder brain changes than affected males, although they showed a similar pattern of radiologic findings consistent with brain atrophy and white matter disease. FXTAS should be considered (by ordering fragile X DNA testing) in females who present with late-onset ataxia, action tremor, or neuropathy, particularly in those with a family history of mental retardation, autism, or premature ovarian failure.

Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome.

Objectives: To assess changes in regional brain volumes associated with the fragile X–associated tremor/ataxia syndrome (FXTAS) and the molecular correlates of these changes. Methods: We administered molecular, MRI, and neurocognitive tests to 36 male premutation carriers (ages 51 to 79), 25 affected and 11 unaffected with FXTAS, and to 21 control subjects of similar age and education. Results: We found differences among the three groups in whole brain, cerebrum, cerebellum, ventricular volume, and whole-brain white matter hyperintensity, with the affected group showing significantly more pathology than the control and unaffected groups. Brainstem volume was significantly smaller in the unaffected group vs controls but did not differ from the affected group. Within the premutation sample, CGG repeat length correlated with reductions in IQ and cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity. Conclusions: The current findings, coupled with recent evidence linking the degree of neuropathology (numbers of intranuclear inclusions) to the size of the premutation allele, provide evidence that the neurodegenerative phenotype in the fragile X–associated tremor/ataxia syndrome is a consequence of the CGG repeat expansion.

Functional brain activation during arithmetic processing in females with fragile X syndrome is related to FMR1 protein expression

Arithmetic processing deficits in persons with fragile X Syndrome (fraX), the most common heritable cause of mental retardation, are well known. In this study, we characterize the neural underpinnings of these performance deficits using functional MRI. Given that a single gene defect (FMR1) is known to be responsible for this disorder, we also assess whether brain activation in arithmetic processing areas is related to amount of FMR1 protein expression (FMRP). Subjects included 16 females with fraX, and 16 female age‐matched controls. Subjects viewed arithmetic equations with two (1 + 3 = 4) or three (2 + 3 − 1 = 5) operands, and were asked to judge whether the results were correct or not. Subjects with fraX showed significant impairment in behavioral performance on the 3‐operand but not the 2‐operand arithmetic equations. Significant brain activation was observed bilaterally in the prefrontal and parietal cortices for unaffected subjects, and bilateral prefrontal and left angular gyrus for subjects with fraX, for both trial types. Subjects with fraX exhibited less overall activation than did unaffected subjects in both types of trials; and, unlike the unaffected group, did not show increased extent of activation in association with greater task difficulty. During the 3‐operand trials, activation in bilateral prefrontal and motor/premotor, and left supramarginal and angular gyri were positively correlated with FMRP, suggesting that decreased FMR1 protein expression underlies deficits in math performance in persons with fraX. More broadly, this investigation demonstrates a unique bridging of cognitive and molecular neuroscience and represents a useful approach for the study of brain development and function. Hum. Brain Mapping 16:206–218, 2002.

The psychophysics of visual motion and global form processing in autism

Several groups have recently reported that people with autism may suffer from a deficit in visual motion processing and proposed that these deficits may be related to a general dorsal stream dysfunction. In order to test the dorsal stream deficit hypothesis, we investigated coherent and biological motion perception as well as coherent form perception in a group of adolescents with autism and a group of age-matched typically developing controls. If the dorsal stream hypothesis were true, we would expect to document deficits in both coherent and biological motion processing in this group but find no deficit in coherent form perception. Using the method of constant stimuli and standard psychophysical analysis techniques, we measured thresholds for coherent motion, biological motion and coherent form. We found that adolescents with autism showed reduced sensitivity to both coherent and biological motion but performed as well as age-matched controls during coherent form perception. Correlations between intelligence quotient and task performance, however, appear to drive much of the group difference in coherent motion perception. Differences between groups on coherent motion perception did not remain significant when intelligence quotient was controlled for, but group differences in biological motion perception were more robust, remaining significant even when intelligence quotient differences were accounted for. Additionally, aspects of task performance on the biological motion perception task were related to autism symptomatology. These results do not support a general dorsal stream dysfunction in adolescents with autism but provide evidence of a more complex impairment in higher-level dynamic attentional processes.

Functional optimization of arithmetic processing in perfect performers.

Lesion and imaging studies to date have not clarified which sub-regions of the parietal lobe are specialized for arithmetic processing, and which perform supporting functions. We used functional magnetic resonance imaging to investigate parietal lobe function during arithmetic processing. Functional optimization was examined by analyzing regional differences in brain activation between perfect (100% accuracy) and imperfect performers. Perfect performers had significantly less activation only in the left angular gyrus, a finding that may be associated with skill mastery and long-term practice effects. The present results provide the first direct evidence of localized functional optimization for arithmetic processing in the human brain.