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1.  APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer’s disease 
Psychiatry research  2013;214(3):10.1016/j.pscychresns.2013.09.006.
Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer’s disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer’s disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer’s disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer’s disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology.
PMCID: PMC3851589  PMID: 24080518
Entorhinal cortex; Hippocampus; Magnetic resonance imaging; Cortical unfolding; APOE-4 allele
2.  The Autism Brain Imaging Data Exchange: Towards Large-Scale Evaluation of the Intrinsic Brain Architecture in Autism 
Molecular psychiatry  2013;19(6):659-667.
Autism spectrum disorders (ASD) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, life-long nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. While the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE) – a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) datasets with corresponding structural MRI and phenotypic information from 539 individuals with ASD and 573 age-matched typical controls (TC; 7–64 years) ( Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 males with ASD and 403 male age-matched TC. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo and hyperconnectivity in the ASD literature; both were detected, though hypoconnectivity dominated, particularly for cortico-cortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASD (mid and posterior insula, posterior cingulate cortex), and highlighted less commonly explored regions such as thalamus. The survey of the ABIDE R-fMRI datasets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international datasets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.
PMCID: PMC4162310  PMID: 23774715
Resting state fMRI; Intrinsic functional connectivity; Data sharing; Large-scale networks; Default network; Interhemispheric connectivity; Thalamus
3.  Advancing understanding of affect labeling with dynamic causal modeling 
NeuroImage  2013;0:481-488.
Mechanistic understandings of forms of incidental emotion regulation have implications for basic and translational research in the affective sciences. In this study we applied Dynamic Causal Modeling (DCM) for fMRI to a common paradigm of labeling facial affect to elucidate prefrontal to subcortical influences. Four brain regions were used to model affect labeling, including right ventrolateral prefrontal cortex (vlPFC), amygdala and Broca’s area. 64 models were compared, for each of 45 healthy subjects. Family level inference split the model space to a likely driving input and Bayesian Model Selection within the winning family of 32 models revealed a strong pattern of endogenous network connectivity. Modulatory effects of labeling were most prominently observed following Bayesian Model Averaging, with the dampening influence on amygdala originating from Broca’s area but much more strongly from right vlPFC. These results solidify and extend previous correlation and regression-based estimations of negative corticolimbic coupling.
PMCID: PMC3759566  PMID: 23774393
affect labeling; incidental emotion regulation; effective connectivity; dynamic causal modeling
4.  Over-Reactive Brain Responses to Sensory Stimuli in Youth With Autism Spectrum Disorders RH: fMRI Response to Sensory Stimuli in ASD 
Sensory over-responsivity (SOR), defined as a negative response to or avoidance of sensory stimuli, is both highly prevalent and extremely impairing in youth with autism spectrum disorders (ASD), yet little is known about the neurological bases of SOR. This study aimed to examine the functional neural correlates of SOR by comparing brain responses to sensory stimuli in youth with and without ASD.
Twenty-five high-functioning youth with ASD and 25 age- and IQ-equivalent typically developing (TD) youth were presented with mildly aversive auditory and visual stimuli during a functional magnetic resonance imaging (fMRI) scan. Parents provided ratings of children's SOR and anxiety symptom severity.
Compared to TD participants, ASD participants displayed greater activation in primary sensory cortical areas as well as amygdala, hippocampus, and orbital-frontal cortex. In both groups, the level of activity in these areas was positively correlated with level of SOR severity as rated by parents, over and above behavioral ratings of anxiety.
This study demonstrates that youth with ASD show neural hyper-responsivity to sensory stimuli, and that behavioral symptoms of SOR may be related to both heightened responsivity in primary sensory regions as well as areas related to emotion processing, and regulation.
PMCID: PMC3820504  PMID: 24157390
amygdala; anxiety; autism spectrum disorders; functional magnetic resonance; imaging (fMRI); sensory over-responsivity
5.  Impaired automatization of a cognitive skill in first-degree relatives of patients with schizophrenia 
Psychiatry research  2013;215(2):294-299.
We studied healthy, first-degree relatives of patients with schizophrenia to test the hypothesis that deficits in cognitive skill learning are associated with genetic liability to schizophrenia. Using the Weather Prediction Task (WPT), 23 healthy controls and 10 adult first-degree Relatives Of Schizophrenia (ROS) patients were examined to determine the extent to which cognitive skill learning was automated using a dual-task paradigm to detect subtle impairments in skill learning. Automatization of a skill is the ability to execute a task without the demand for executive control and effortful behavior and is a skill in which schizophrenia patients possess a deficit. ROS patients did not differ from healthy controls in accuracy or reaction time on the WPT either during early or late training on the single-task trials. In contrast, the healthy control and ROS groups were differentially affected during the dual-task trials. Our results demonstrate that the ROS group did not automate the task as well as controls and continued to rely on controlled processing even after extensive practice. This suggests that adult ROS patients may engage in compensatory strategies to achieve normal levels of performance and support the hypothesis that impaired cognitive skill learning is associated with genetic risk for schizophrenia.
PMCID: PMC4191851  PMID: 24359887
Automatization; Schizophrenia; Skill learning; Genetic liability
6.  Locomotor Training Remodels fMRI Sensorimotor Cortical Activations in Children After Cerebral Hemispherectomy 
This study examined whether locomotor training, which included body weight–supported treadmill therapy, improved walking and induced cortical representational adaptations using functional magnetic resonance imaging in the remaining sensorimotor network after cerebral hemispherectomy.
Hemispherectomy patients (n = 12) under-went 2 weeks of gait training for at least 30 hours each. They were tested pre- and posttraining with the Fugl-Meyer Motor Assessment, unassisted single-limb stance time, and usual and fastest walking speeds. Three patients performed voluntary ankle movements as the functional magnetic resonance imaging activation task pre- and posttraining. Control subjects included 5 healthy children tested 2 weeks apart, 2 of whom trained on the treadmill, and 2 hemispherectomy patients who received upper extremity rehabilitation and no gait therapy.
Although patients reported improvements with gait training, behavioral outcomes did not significantly change. Training was associated with increased volume and intensity of cortical activation in the primary sensorimotor (S1M1), supplementary motor, motor cingulate, and secondary soma-tosensory cortex for the paretic foot, along with greater overlap in the representation for each moving foot in S1M1 and the supplementary motor area of the remaining hemisphere. Control subjects showed a decrease in activation in these cortical regions after training.
Locomotor training of hemispherectomy patients improved mobility subjectively in association with functional magnetic resonance imaging evidence of cortical remodeling with ankle dorsiflexion. These findings support the notion that hemispherectomy patients may respond to rehabilitation interventions through mechanisms of activity-dependent cortical plasticity. The authors hypothesize that developmentally persistent descending ipsilateral and contralateral corticospinal tracts may allow the remaining hemisphere to maintain bilateral lower extremity motor control after surgery.
PMCID: PMC4080925  PMID: 17369509
Gait; Epilepsy; Functional recovery; fMRI; Plasticity; Rehabilitation; Walking
7.  Frontostriatal neuroimaging findings differ in patients with bipolar disorder who have or do not have ADHD comorbidity 
Journal of affective disorders  2012;147(1-3):389-396.
The inferior frontal cortical (IFC)-striatal network plays an integral role in response inhibition and is compromised in patients with Bipolar Disorder (BP) or Attention-Deficit/Hyperactivity Disorder (ADHD). Prior BP functional neuroimaging studies have not accounted for ADHD comorbidity despite its high prevalence.
The authors conducted an fMRI study using a response inhibition task (Go-NoGo) in 32 euthymic adults with BP, half with comorbid ADHD (BP/ADHD); 16 adults with ADHD alone; and 30 healthy controls. Within- and between-group whole-brain analyses were performed to assess for significant neural function differences.
All groups activated frontal and striatal regions involved in response inhibition. ANOVA results demonstrated significant interaction effects of BP and ADHD in the anterior and posterior cingulate, left superior and middle frontal gyri and left inferior parietal lobule. Follow-up comparisons showed significant differences between BP subjects with and without ADHD. Other regions demonstrated main effects of BP (left inferior frontal gyrus, left middle frontal gyrus, right superior frontal gyrus and left insula) and ADHD (left inferior frontal gyrus, left precentral gyrus and right anterior cingulate).
This study, as the first of its kind, requires replication using large sample sizes and controlling for potential effects of medication.
Euthymic bipolar adults with comorbid ADHD have significantly different neural activation patterns from BP patients without this comorbidity. If understanding of the neurobiology of bipolar disorder is to be achieved, it is critical to control for this potential confound, something not done by most prior fMRI studies of adults with BP.
PMCID: PMC3562405  PMID: 23057969
Bipolar disorder; euthymia; fMRI; ADHD; response inhibition; inferior frontal cortex
8.  DTI correlates of distinct cognitive impairments in Parkinson’s disease 
Human brain mapping  2013;35(4):1325-1333.
The spectrum of cognitive symptoms in Parkinson’s disease (PD) can span various domains, including executive function, language, attention, memory and visuospatial skills. These symptoms may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. The primary purpose of this study is to find microstructural correlates of impairments across these cognitive domains in PD using diffusion tensor imaging (DTI). Sixteen PD patients with comprehensive neuropsychological evaluation and DTI data were retrospectively studied. Fractional anisotropy (FA) and mean diffusivity (MD) values were calculated for 40 regions of interest (ROIs) and were regressed against neurocognitive scores in each domain. Executive function directly correlated with FA and inversely correlated with MD in mostly frontal white matter tracts, especially the anterior limb of the internal capsule and genu of the corpus callosum. Likewise, language and attentional performance demonstrated correlations with DTI parameters in the frontal regions, but the attention domain additionally recruited regions widespread throughout the brain, with the most significant correlation identified in cingulate gyrus (cingulum). Lastly, memory impairment mainly involved MD alterations within the fornix. No significant correlations were found between visuospatial skills and DTI measures. Despite some overlap, unique patterns of white matter diffusivity underlie impairments in distinct cognitive domains in patients with PD. DTI combined with neurocognitive tests may be a valuable biomarker for identifying cognitive impairments in PD.
PMCID: PMC3664116  PMID: 23417856
Cognition; Parkinson’s; connectivity; tractography; neurodegenerative; white matter; neuroimaging; brain
9.  Psychological Well-Being and Regional Brain Amyloid and Tau in Mild Cognitive Impairment 
To determine whether psychological well-being in people with mild cognitive impairment (MCI), a risk state for Alzheimer disease (AD), is associated with in vivo measures of brain pathology.
Cross-sectional clinical assessments and positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile (FDDNP), a molecule that binds to plaques and tangles, were performed on middle-aged and older adults at a university research institute. Volunteers were aged 40–85 years with MCI (N = 35) or normal cognition (N = 29) without depression or anxiety. Statistical analyses included general linear models, using regional FDDNP-PET binding values as dependent variables and the Vigor-Activity subscale of the Profile of Mood States (POMS) as the independent variable, covarying for age. The POMS is a self-rated inventory of 65 adjectives that describe positive and negative feelings.
Scores on the POMS Vigor-Activity subscale were inversely associated with degree of FDDNP binding in the posterior cingulate cortex (r = −0.35, p = 0.04) in the MCI group but not in the control group.
Psychological well-being, as indicated by self-reports of greater vigor and activity, is associated with lower FDDNP-PET binding in the posterior cingulate cortex, a region involved in emotional regulation, in individuals with MCI but not in those with normal cognition. These findings are consistent with previous work indicating that deposition of brain amyloid plaques and tau tangles may result in noncognitive and cognitive symptoms in persons at risk for AD.
PMCID: PMC3883933  PMID: 23567426
Aging; FDDNP; positron emission tomography; POMS; well-being
10.  Differences in resting corticolimbic functional connectivity in bipolar I euthymia 
Bipolar disorders  2013;15(2):156-166.
We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects.
Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low frequency fluctuations in blood oxygen level-dependent (BOLD) signal were correlated in the six connections between four anatomically-defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed-to-voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation.
The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC).
Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait-related and clinically-important imaging biomarker.
PMCID: PMC3582748  PMID: 23347587
amygdala; bipolar disorder; euthymia; functional connectivity; resting state; ventrolateral prefrontal cortex
11.  Atypical Neural Processing of Ironic and Sincere Remarks in Children and Adolescents with Autism Spectrum Disorders 
Metaphor and symbol  2012;27(1):70-92.
Individuals with ASD show consistent impairment in processing pragmatic language when attention to multiple social cues (e.g., facial expression, tone of voice) is often needed to navigate social interactions. Building upon prior fMRI work examining how facial affect and prosodic cues are used to infer a speaker's communicative intent, the authors examined whether children and adolescents with ASD differ from typically developing (TD) controls in their processing of sincere versus ironic remarks. At the behavioral level, children and adolescents with ASD and matched TD controls were able to determine whether a speaker's remark was sincere or ironic equally well, with both groups showing longer response times for ironic remarks. At the neural level, for both sincere and ironic scenarios, an extended cortical network—including canonical language areas in the left hemisphere and their right hemisphere counterparts—was activated in both groups, albeit to a lesser degree in the ASD sample. Despite overall similar patterns of activity observed for the two conditions in both groups, significant modulation of activity was detected when directly comparing sincere and ironic scenarios within and between groups. While both TD and ASD groups showed significantly greater activity in several nodes of this extended network when processing ironic versus sincere remarks, increased activity was largely confined to left language areas in TD controls, whereas the ASD sample showed a more bilateral activation profile which included both language and “theory of mind” areas (i.e., ventromedial prefrontal cortex). These findings suggest that, for high-functioning individuals with ASD, increased activity in right hemisphere homologues of language areas in the left hemisphere, as well as regions involved in social cognition, may reflect compensatory mechanisms supporting normative behavioral task performance.
PMCID: PMC3909704  PMID: 24497750
12.  Frontal-amygdala connectivity alterations during emotion down-regulation in bipolar I disorder 
Biological psychiatry  2012;73(2):127-135.
The symptoms of bipolar disorder suggest dysfunction of emotion regulatory networks. In healthy control populations, down-regulation of emotional responses activates the ventral lateral prefrontal cortex (vlPFC) and dampens amygdala activation. This study investigated frontal and limbic function and connectivity during emotion down-regulation in euthymic subjects with bipolar I disorder (BPI) and healthy control subjects.
30 BPI and 26 control subjects underwent fMRI scanning while performing an emotion processing task with passive viewing and emotion down-regulation conditions. Contrasts were made for each group comparing the down-regulation and passive viewing conditions and these were entered into a between-group random effects analysis to assess group differences in activation. Psychophysiological Interaction (PPI) analyses were conducted to test for significant group differences in functional connectivity between the amygdala and inhibitory frontal regions (i.e., vlPFC).
Control subjects showed the expected robust bilateral activation of frontal and limbic regions during passive viewing and emotion down-regulation tasks. Between-group analyses revealed similar activation of BP and control subjects during passive viewing but significantly decreased activation in bilateral vlPFC, bilateral anterior and posterior cingulate, medial frontal gyrus and bilateral dlPFC during emotion down-regulation in subjects with BP. Connectivity analysis demonstrated that control subjects had significantly greater negative functional connectivity between the left amygdala and bilateral vlPFC compared to subjects with BP.
This study provides evidence that dysfunction in the neural networks responsible for emotion regulation, including the prefrontal cortex, cingulate and subcortical structures, are present in BPI subjects even in euthymia.
PMCID: PMC3525751  PMID: 22858151
amygdala; vlPFC; functional connectivity; functional neuroimaging; bipolar disorder; emotion regulation
13.  Vascular Risk and FDDNP-PET Influence Cognitive Performance 
Journal of Alzheimer's disease : JAD  2013;35(1):10.3233/JAD-121903.
The relationship of cerebrovascular risk and Alzheimer’s disease (AD) pathology to cognition in pre-dementia has been extensively investigated and is well-established. Cerebrovascular risk can be measured using a Framingham Stroke Risk Profile (FSRP) score, while positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl{ethylidene)malononitrile (FDDNP) measure AD neuropathology (i.e., amyloid-β plaques and tau tangles). Here we report results of 75 healthy non-demented subjects (mean age, 63 years) who underwent neuropsychological testing, physical assessments, and FDDNP-PET scans. Controlling for AD family history, education, and APOE4 status in a general linear model, higher FSRP risk and global FDDNP-PET binding were each associated with poorer cognitive functioning. The interaction of FSRP and global FDDNP-PET binding was not significant in the model, indicating that stroke risk and plaque and tangle burden each contributed to worse cognitive performance. Within our healthy volunteers, age, blood pressure, and antihypertensive medication use were vascular risks that contributed significantly to the above findings. These findings suggest that even mild cerebrovascular risk may influence the extent of cognitive dysfunction in pre-dementia, along with amyloid-β and tau burden.
PMCID: PMC3874398  PMID: 23380994
Aging; Alzheimer’s disease; amyloid-µ plaques; FDDNP; Framingham stroke risk profile; mild cognitive impairment; older adults; positron emission tomography; tau tangles
14.  Memory Performance and fMRI Signal in Presymptomatic Familial Alzheimer’s Disease 
Human brain mapping  2012;34(12):10.1002/hbm.22141.
Rare autosomal dominant mutations result in familial Alzheimer’s disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late-onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation-carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD-relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes.
PMCID: PMC3812259  PMID: 22806961
early onset; functional magnetic resonance imaging; PSEN1; APP; mutation; hippocampus; medial temporal lobe; volume
15.  White matter microstructural alterations in children with prenatal methamphetamine/polydrug exposure 
Psychiatry research  2012;204(0):140-148.
Little is known about the effects of prenatal methamphetamine exposure on white matter microstructure, and the impact of concomitant alcohol exposure. Diffusion tensor imaging and neurocognitive testing were performed on 21 children with prenatal methamphetamine exposure (age 9.8±1.8 years; 17 also exposed to alcohol), 19 children with prenatal alcohol but not methamphetamine exposure (age 10.8±2.3 years), and 27 typically-developing children (age 10.3±3.3 years). Whole-brain maps of fractional anisotropy (FA) were evaluated using tract-based spatial statistics. Relative to unexposed controls, children with prenatal methamphetamine exposure demonstrated higher FA mainly in left-sided regions, including the left anterior corona radiata (LCR) and corticospinal tract (P<0.05, corrected). Post-hoc analyses of these FA differences showed they likely result more from lower radial diffusivity (RD) than higher axial diffusivity (AD). Relative to the methamphetamine-exposed group, children with prenatal alcohol exposure showed lower FA in frontotemporal regions – particularly the right external capsule (P<0.05, corrected). We failed to find any group-performance interaction (on tests of executive functioning and visuomotor integration) in predicting FA; however, FA in the right external capsule was significantly associated with performance on a test of visuomotor integration across groups (P<0.05). This report demonstrates unique diffusion abnormalities in children with prenatal methamphetamine/polydrug exposure that are distinct from those associated with alcohol exposure alone, and illustrates that these abnormalities in brain microstructure are persistent into childhood and adolescence – long after the polydrug exposure in utero.
PMCID: PMC3634917  PMID: 23149028
methamphetamine; white matter; alcohol; diffusion imaging; teratogen; in utero
16.  Prediction of Cognitive Decline Based on Hemispheric Cortical Surface Maps of FDDNP PET 
NeuroImage  2012;61(4):10.1016/j.neuroimage.2012.02.056.
A cross-sectional study to establish whether a subject’s cognitive state can be predicted based on regional values obtained from brain cortical maps of FDDNP Distribution Volume Ratio (DVR), which shows the pattern of beta amyloid and neurofibrillary binding, along with those of early summed FDDNP PET images (reflecting the pattern of perfusion) was performed.
Dynamic FDDNP PET studies were performed in a group of 23 subjects (8 control (NL), 8 Mild Cognitive Impairment (MCI) and 7 Alzheimer’s Disease (AD) subjects). FDDNP DVR images were mapped to the MR derived hemispheric cortical surface map warped into a common space. A set of Regions of Interest (ROI) values of FDDNP DVR and early summed FDDNP PET (0-6 min post tracer injection), were thus calculated for each subject which along with the MMSE score were used to construct a linear mathematical model relating ROI values to MMSE. After the MMSE prediction models were developed, the models’ predictive ability was tested in a non-overlapping set of 8 additional individuals, whose cognitive status was unknown to the investigators who constructed the predictive models.
Among all possible subsets of ROIs, we found that the standard deviation of the predicted MMSE was 1.8 by using only DVR values from medial and lateral temporal and prefrontal regions plus the early summed FDDNP value in the posterior cingulate gyrus. The root mean square prediction error for the eight new subjects was 1.6.
FDDNP scans reflect progressive neuropathology accumulation and can potentially be used to predict the cognitive state of an individual.
PMCID: PMC3839850  PMID: 22401755
cortical surface maps; MR; FDDNP PET; MMSE
17.  Influence of Alzheimer Disease Family History and Genetic Risk on Cognitive Performance in Healthy Middle-Aged and Older People 
Identification of risk factors for Alzheimer disease (AD) is critical for establishing effective diagnostic and therapeutic strategies. Carrying the ε4 allele of the apolipoprotein E gene (APOE4) and having a family history of the disease are two such factors, with family history risk reflecting additional yet unknown or rarely studied genetic and perhaps nongenetic risks. Our aim was to determine the influence of APOE genotype and family history status on cognitive performance in healthy individuals.
Longitudinal study.
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Seventy-two cognitively healthy middle-aged and older people (mean age ± SD: 62 ± 9 years).
Neuropsychological examinations at baseline and after 2 years.
Subjects with a family history of AD had lower baseline scores in processing speed, executive functioning, memory encoding, and delayed memory when compared with those without a family history. The family history risk factor did not influence degree of cognitive decline over time. By contrast, baseline cognitive performance did not vary according to APOE4 carrier status. Non-APOE4 carriers showed improved cognitive performance in the memory domains at follow-up, while performance of APOE4 carriers did not change.
Our data highlight the unique contributions of each risk factor to cognitive performance in healthy people. Both factors should be modeled in neuropsychological assessments of people at risk for AD.
PMCID: PMC3816758  PMID: 21849821
Alzheimer disease; family history; APOE genotype
18.  Family History and APOE-4 Genetic Risk in Alzheimer’s Disease 
Neuropsychology review  2012;22(3):298-309.
Identifying risk factors for Alzheimer’s disease, such as carrying the APOE-4 allele, and understanding their contributions to disease pathophysiology or clinical presentation is critical for establishing and improving diagnostic and therapeutic strategies. A first-degree family history of Alzheimer’s disease represents a composite risk factor, which reflects the influence of known and unknown susceptibility genes and perhaps non-genetic risks. There is emerging evidence that investigating family history risk associated effects may contribute to advances in Alzheimer’s disease research and ultimately clinical practice.
PMCID: PMC3797601  PMID: 22359096
Alzheimer’s disease; APOE Genotype; Family history; Genetic risk; Risk factors; Neuroimaging
19.  A Developmental Shift from Positive to Negative Connectivity in Human Amygdala-Prefrontal Circuitry 
Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. While tracing studies have suggested changes in amygdala-cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala-prefrontal circuitry across the ages of 4 to 22 years using task-based functional magnetic resonance imaging (fMRI). Results suggest positive amygdala-prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala-mPFC functional connectivity was significantly positive (greater than zero) among participants younger than ten, whereas functional connectivity was significantly negative (less than zero) among participants ten years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections.
PMCID: PMC3670947  PMID: 23467374
amygdala; prefrontal cortex; development; fMRI; functional connectivity; emotion regulation; anxiety; inhibition
20.  Regional fMRI Hypoactivation and Altered Functional Connectivity During Emotion Processing in Nonmedicated Depressed Patients With Bipolar II Disorder 
The American journal of psychiatry  2012;169(8):831-840.
Although the amygdala and ventrolateral prefrontal cortex have been implicated in the pathophysiology of bipolar I disorder, the neural mechanisms underlying bipolar II disorder remain unknown. The authors examined neural activity in response to negative emotional faces during an emotion perception task that reliably activates emotion regulatory regions.
Twenty-one nonmedicated depressed bipolar II patients and 21 healthy comparison subjects underwent functional MRI (fMRI) while performing an emotional face-matching task. Within- and between-group whole-brain fMRI activation and seed-based connectivity analyses were conducted.
In depressed bipolar II patients, random-effects between-group fMRI analyses revealed a significant reduction in activation in several regions, including the left and right ventrolateral prefrontal cortices (Brodmann's area [BA] 47) and the right amygdala, a priori regions of interest. Additionally, bipolar patients exhibited significantly reduced negative functional connectivity between the right amygdala and the right orbitofrontal cortex (BA 10) as well as the right dorsolateral prefrontal cortex (BA 46) relative to healthy comparison subjects.
These findings suggest that bipolar II depression is characterized by reduced regional orbitofrontal and limbic activation and altered connectivity in a fron-to-temporal circuit implicated in working memory and emotional learning. While the amygdala hypoactivation observed in bipolar II depression is opposite to the direction seen in bipolar I mania and may therefore be state dependent, the observed orbitofrontal cortex hypoactivation is consistent with findings in bipolar I depression, mania, and euthymia, suggesting a physiologic trait marker of the disorder.
PMCID: PMC3740182  PMID: 22773540
21.  Pomegranate Juice Augments Memory and fMRI Activity in Middle-Aged and Older Adults with Mild Memory Complaints 
Despite increasing emphasis on the potential of dietary antioxidants in preventing memory loss and on diet as a precursor of neurological health, rigorous studies investigating the cognitive effects of foods and their components are rare. Recent animal studies have reported memory and other cognitive benefits of polyphenols, found abundantly in pomegranate juice. We performed a preliminary, placebo-controlled randomized trial of pomegranate juice in older subjects with age-associated memory complaints using memory testing and functional brain activation (fMRI) as outcome measures. Thirty-two subjects (28 completers) were randomly assigned to drink 8 ounces of either pomegranate juice or a flavor-matched placebo drink for 4 weeks. Subjects received memory testing, fMRI scans during cognitive tasks, and blood draws for peripheral biomarkers before and after the intervention. Investigators and subjects were all blind to group membership. After 4 weeks, only the pomegranate group showed a significant improvement in the Buschke selective reminding test of verbal memory and a significant increase in plasma trolox-equivalent antioxidant capacity (TEAC) and urolithin A-glucuronide. Furthermore, compared to the placebo group, the pomegranate group had increased fMRI activity during verbal and visual memory tasks. While preliminary, these results suggest a role for pomegranate juice in augmenting memory function through task-related increases in functional brain activity.
PMCID: PMC3736548  PMID: 23970941
22.  Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders 
Nature neuroscience  2005;9(1):28-30.
To examine mirror neuron abnormalities in autism, high-functioning children with autism and matched controls underwent fMRI while imitating and observing emotional expressions. Although both groups performed the tasks equally well, children with autism showed no mirror neuron activity in the inferior frontal gyrus (pars opercularis). Notably, activity in this area was inversely related to symptom severity in the social domain, suggesting that a dysfunctional ‘mirror neuron system’ may underlie the social deficits observed in autism.
PMCID: PMC3713227  PMID: 16327784
23.  Reduced Functional Integration and Segregation of Distributed Neural Systems Underlying Social and Emotional Information Processing in Autism Spectrum Disorders 
Cerebral Cortex (New York, NY)  2011;22(5):1025-1037.
A growing body of evidence suggests that autism spectrum disorders (ASDs) are related to altered communication between brain regions. Here, we present findings showing that ASD is characterized by a pattern of reduced functional integration as well as reduced segregation of large-scale brain networks. Twenty-three children with ASD and 25 typically developing matched controls underwent functional magnetic resonance imaging while passively viewing emotional face expressions. We examined whole-brain functional connectivity of two brain structures previously implicated in emotional face processing in autism: the amygdala bilaterally and the right pars opercularis of the inferior frontal gyrus (rIFGpo). In the ASD group, we observed reduced functional integration (i.e., less long-range connectivity) between amygdala and secondary visual areas, as well as reduced segregation between amygdala and dorsolateral prefrontal cortex. For the rIFGpo seed, we observed reduced functional integration with parietal cortex and increased integration with right frontal cortex as well as right nucleus accumbens. Finally, we observed reduced segregation between rIFGpo and the ventromedial prefrontal cortex. We propose that a systems-level approach—whereby the integration and segregation of large-scale brain networks in ASD is examined in relation to typical development—may provide a more detailed characterization of the neural basis of ASD.
PMCID: PMC3328339  PMID: 21784971
amygdala; connectivity; default mode network; face processing; mirror neuron system
24.  Prediction of Cognitive Decline by Positron Emission Tomography of Brain Amyloid and Tau 
Archives of neurology  2012;69(2):215-222.
To determine whether 2-(1-{6-[(2-fluorine18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) brain regional values in individuals without dementia predict and correlate with future cognitive change.
Two-year, longitudinal follow-up study.
A university research institute.
Volunteer sample of 43 middle-aged and older persons (median age, 64 years), including 21 with mild cognitive impairment (MCI) and 22 with normal aging.
Main Outcome Measures
Longitudinal [18F]FDDNP positron emission tomography (PET) binding values in the medial and lateral temporal, posterior cingulate, parietal, frontal, and global (mean) regions of interest; neuropsychological test battery measuring 5 cognitive domains, including memory, language, attention (and information-processing speed), executive functioning, and visuospatial ability.
For the entire study group (MCI and normal aging), increases in frontal, posterior cingulate, and global binding at follow-up correlated with progression of memory decline (r=−0.32 to −0.37, P=.03 to .01) after 2 years. Moreover, higher baseline [18F]FDDNP binding was associated with future decline in most cognitive domains, including language, attention, executive, and visuospatial abilities (r=−0.31 to −0.56, P=.05 to .002). For the MCI group, frontal and parietal [18F]FDDNP binding yielded the greatest diagnostic accuracy in identifying converters to Alzheimer disease vs nonconverters after 2 years, with an area under the receiver operating characteristic curve of 0.88 (95% CI, 0.72–1.00) compared with 0.68 (95% CI, 0.45–0.91) for medial temporal binding.
[18F]FDDNP PET regional binding patterns are consistent with known neuropathologic patterns of plaque and tangle brain accumulation, spreading from the medial temporal to other neocortical regions as disease progresses. Because binding patterns predict future cognitive decline and increase over time along with clinical decline, [18F]FDDNP PET scanning may have practical utility in identifying people at risk for future cognitive decline and in tracking the effectiveness of novel interventions designed to prevent or delay neurodegeneration and cognitive decline.
PMCID: PMC3623972  PMID: 22332188
25.  Basal ganglia structures differentially contribute to verbal fluency: Evidence from Human Immunodeficiency Virus (HIV)-infected adults 
Neuropsychologia  2011;50(3):390-395.
The basal ganglia (BG) are involved in executive language functions (i.e., verbal fluency) through their connections with cortical structures. The caudate and putamen receive separate inputs from prefrontal and premotor cortices, and may differentially contribute to verbal fluency performance. We examined BG integrity in relation to lexicosemantic verbal fluency performance among older HIV infected adults.
20 older (50+ years) HIV+ adults underwent MRI and were administered measures of semantic and phonemic fluency. BG (caudate, putamen) regions of interest were extracted.
Performance on phonemic word generation significantly predicted caudate volume, whereas performance on phonemic switching predicted putamen volume.
These findings suggest a double dissociation of BG involvement in verbal fluency tasks with the caudate subserving word generation and the putamen associated with switching. As such, verbal fluency tasks appear to be selective to BG function.
PMCID: PMC3608185  PMID: 22223078
Basal ganglia; Verbal fluency; Magnetic resonance imaging; Human Immunodeficiency Virus; Neuropsychology; Aging

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