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1.  Altered memory-related functional connectivity of the anterior and posterior hippocampus in older adults at increased genetic risk for Alzheimer’s disease 
Human brain mapping  2015;37(1):366-380.
The hippocampal complex is affected early in Alzheimer’s disease (AD). Increasingly, altered functional connectivity of the hippocampus is recognized as an important feature of preclinical AD. Carriers of the APOEε4 allele are at an increased risk for AD, which could lead to altered hippocampal connectivity even in healthy older adults. To test this hypothesis, we used a paired-associates memory task to examine differences in task-dependent functional connectivity of the anterior and posterior hippocampus in non-demented APOEε4 carriers (n=34, 18F) and non-carriers (n=46, 31F). We examined anterior and posterior portions of the hippocampus separately to test the theory that APOEε4-mediated differences would be more pronounced in the anterior region, which is affected earlier in the AD course. This study is the first to use a psychophysiological interaction approach to query the context-dependent connectivity of subregions of the hippocampus during a memory task in adults at increased genetic risk for AD. During encoding, APOEε4 carriers had lower functional connectivity change compared to baseline between the anterior hippocampus and right precuneus, anterior insula and cingulate cortex. During retrieval, bilateral supramarginal gyrus and right precuneus showed lower functional connectivity change with anterior hippocampus in carriers. Also during retrieval, carriers showed lower connectivity change in the posterior hippocampus with auditory cortex. In each case, APOEε4 carriers showed strong negative connectivity changes compared to non-carriers where positive connectivity change was measured. These differences may represent prodromal functional changes mediated in part by APOEε4 and are consistent with the anterior-to-posterior theory of AD progression in the hippocampus.
PMCID: PMC4715627  PMID: 26503161
aging; APOE; connectivity; fMRI; preclinical Alzheimer’s disease; psychophysiological interaction
2.  Neuroimaging genetic risk for Alzheimer's disease in preclinical individuals: From candidate genes to polygenic approaches 
Better characterization of the preclinical phase of Alzheimer's disease (AD) is needed in order to develop effective interventions. Neuropathological changes in AD, including neuronal loss and the formation of proteinaceous deposits, begin up to 20 years before the onset of clinical symptoms. As such, the emergence of cognitive impairment should not be the sole basis used to diagnose AD nor to evaluate individuals for enrollment in clinical trials for preventative AD treatments. Instead, early preclinical biomarkers of disease and genetic risk should be used to determine most likely prognosis and enroll individuals in appropriate clinical trials. Neuroimaging-based biomarkers and genetic analysis together present a powerful system for classifying preclinical pathology in patients. Disease modifying interventions are more likely to produce positive outcomes when administered early in the course of AD. In this review, we examine the utility of the neuroimaging genetics field as it applies to AD and early detection during the preclinical phase. Neuroimaging studies focused on single genetic risk factors are summarized. However, we particularly focus on the recent increased interest in polygenic methods and discuss the benefits and disadvantages of these approaches. We discuss challenges in the neuroimaging genetics field, including limitations of statistical power arising from small effect sizes and the over-use of cross-sectional designs. Despite the limitations, neuroimaging genetics has already begun to influence clinical trial design and will play a major role in the prevention of AD.
PMCID: PMC4743051  PMID: 26858991
neuroimaging; genetics; Alzheimer's disease; polygenic risk score; preclinical; clinical trials
3.  An Alzheimer’s Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults 
eNeuro  2016;3(3):ENEURO.0098-16.2016.
Variants at 21 genetic loci have been associated with an increased risk for Alzheimer’s disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = −0.40; p = 0.003; WRS: r = −0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = −0.35; p = 0.009; WRS: r = −0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.
PMCID: PMC4945997  PMID: 27482534
clinical trials; normal aging; polygenic risk score; preclinical Alzheimer's disease; structural MRI
4.  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
5.  Neurobiology of Sensory Overresponsivity in Youth With Autism Spectrum Disorders 
JAMA psychiatry  2015;72(8):778-786.
More than half of youth with autism spectrum disorders (ASDs) have sensory overresponsivity (SOR), an extreme negative reaction to sensory stimuli. However, little is known about the neurobiological basis of SOR, and there are few effective treatments. Understanding whether SOR is due to an initial heightened sensory response or to deficits in regulating emotional reactions to stimuli has important implications for intervention.
To determine differences in brain responses, habituation, and connectivity during exposure to mildly aversive sensory stimuli in youth with ASDs and SOR compared with youth with ASDs without SOR and compared with typically developing control subjects.
Functional magnetic resonance imaging was used to examine brain responses and habituation to mildly aversive auditory and tactile stimuli in 19 high-functioning youths with ASDs and 19 age- and IQ-matched, typically developing youths (age range, 9-17 years). Brain activity was related to parents’ ratings of children's SOR symptoms. Functional connectivity between the amygdala and orbitofrontal cortex was compared between ASDs subgroups with and without SOR and typically developing controls without SOR. The study dates were March 2012 through February 2014.
Relative increases in blood oxygen level–dependent signal response across the whole brain and within the amygdala during exposure to sensory stimuli compared with fixation, as well as correlation between blood oxygen level–dependent signal change in the amygdala and orbitofrontal cortex.
The mean age in both groups was 14 years and the majority in both groups (16 of 19 each) were male. Compared with neurotypical control participants, participants with ASDs displayed stronger activation in primary sensory cortices and the amygdala (P < .05, corrected). This activity was positively correlated with SOR symptoms after controlling for anxiety. The ASDs with SOR subgroup had decreased neural habituation to stimuli in sensory cortices and the amygdala compared with groups without SOR. Youth with ASDs without SOR showed a pattern of amygdala downregulation, with negative connectivity between the amygdala and orbitofrontal cortex (thresholded at z > 1.70, P < .05).
Results demonstrate that youth with ASDs and SOR show sensorilimbic hyperresponsivity to mildly aversive tactile and auditory stimuli, particularly to multiple modalities presented simultaneously, and show that this hyperresponsivity is due to failure to habituate. In addition, findings suggest that a subset of youth with ASDs can regulate their responses through prefrontal downregulation of amygdala activity. Implications for intervention include minimizing exposure to multiple sensory modalities and building coping strategies for regulating emotional response to stimuli.
PMCID: PMC4861140  PMID: 26061819
6.  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
7.  Association between lesion location and language function in adult glioma using voxel-based lesion-symptom mapping 
NeuroImage : Clinical  2015;9:617-624.
Management of language difficulties is an important aspect of clinical care for glioma patients, and accurately identifying the possible language deficits in patients based on lesion location would be beneficial to clinicians. To that end, we examined the relationship between lesion presence and language performance on tests of receptive language and expressive language using a highly specific voxel-based lesion–symptom mapping (VLSM) approach in glioma patients.
98 adults with primary glioma, who were pre-surgical candidates, were administered seven neurocognitive tests within the domains of receptive language and expressive language. The association between language performance and lesion presence was examined using VLSM. Statistical parametric maps were created for each test, and composite maps for both receptive language and expressive language were created to display the significant voxels common to all tests within these language domains.
We identified clusters of voxels with a significant relationship between lesion presence and language performance. All tasks were associated with several white matter pathways. The receptive language tasks were additionally all associated with regions primarily within the lateral temporal lobe and medial temporal lobe. In contrast, the expressive language tasks shared little overlap, despite each task being independently associated with large anatomic areas.
Our findings identify the key anatomic structures involved in language functioning in adult glioma patients using an innovative lesion analysis technique and suggest that expressive language abilities may be more task-dependent and distributed than receptive language abilities.
•Examined the association between lesion location and language in glioma patients.•Utilized a highly specific voxel-based lesion–symptom mapping (VLSM) approach.•Receptive language tasks were all associated with temporal and subcortical regions.•Expressive language tasks showed little overlap across associated brain regions.•Findings suggest expressive language is a more task-dependent, distributed ability.
PMCID: PMC4644251  PMID: 26740915
Glioma; Neurocognitive functioning; Language; Lesion–symptom mapping; Language; MRI
8.  Altered Structural Brain Connectivity in Healthy Carriers of the Autism Risk Gene, CNTNAP2 
Brain connectivity  2011;1(6):447-459.
Recently, carriers of a common variant in the autism risk gene, CNTNAP2, were found to have altered functional brain connectivity using functional MRI. Here we scanned 328 young adults with high-field (4-Tesla) diffusion imaging, to test the hypothesis that carriers of this gene variant would have altered structural brain connectivity. All participants (209 females, 119 males, age: 23.4 +/−2.17 SD years) were scanned with 105-gradient high angular diffusion imaging (HARDI) at 4 Tesla. After performing a whole-brain fiber tractography using the full angular resolution of the diffusion scans, 70 cortical surface-based regions of interest were created from each individual’s co-registered anatomical data to compute graph metrics for all pairs of cortical regions. In graph theory analyses, subjects homozygous for the risk allele (CC) had lower characteristic path length, greater small-worldness and global efficiency in whole brain analyses, as well as greater eccentricity (maximum path length) in 60 of 70 nodes in regional analyses. These results were not reducible to differences in more commonly studied traits such as fiber density or fractional anisotropy. This is the first study to link graph theory metrics of brain structural connectivity to a common genetic variant linked with autism and will help us understand the neurobiology of circuits implicated in risk for autism.
PMCID: PMC3420970  PMID: 22500773
structural connectivity; HARDI; autism; CNTNAP2; graph theory; twins
9.  High-resolution 7T fMRI of Human Hippocampal Subfields during Associative Learning 
Journal of cognitive neuroscience  2014;27(6):1194-1206.
Examining the function of individual human hippocampal subfields remains challenging due to their small sizes and convoluted structures. Previous human functional magnetic resonance (fMRI) studies at 3 Tesla (T) have successfully detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, 3 and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution functional magnetic resonance imaging (fMRI) scanning at 7T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning, and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases.
PMCID: PMC4417053  PMID: 25514656
Hippocampus; memory; fMRI; MRI; high-resolution imaging
10.  Cortical Cartography Reveals Political and Physical Maps 
Epilepsia  2014;55(5):633-637.
Advances in functional imaging have provided non-invasive techniques to probe brain organization of multiple constructs including language and memory. Because of high overall rates of agreements with older techniques, including Wada testing and cortical stimulation mapping (CSM), some have proposed that those approaches should be largely abandoned because of their invasiveness, and replaced with non-invasive functional imaging methods. High overall agreement, however, is based largely on concordant language lateralization in series dominated by cases of typical cerebral dominance. Advocating a universal switch from Wada testing and cortical stimulation mapping to fMRI or magnetoencephalography (MEG) ignores the differences in specific expertise across epilepsy centers, many of which often have greater skill with one approach rather than the other, and that Wada, CSM, fMRI, and MEG protocols vary across institutions resulting in different outcomes and reliability. Specific patient characteristics also affect whether Wada or CSM might influence surgical management, making it difficult to accept broad recommendations against currently useful clinical tools. Although the development of non-invasive techniques has diminished the frequency of more invasive approaches, advocating their use to replace Wada testing and CSM across all epilepsy surgery programs without consideration of the different skills, protocols, and expertise at any given center site is ill-advised.
PMCID: PMC4197796  PMID: 24815217
Wada testing; fMRI; MEG; cortical stimulation mapping
11.  Deficits in inferior frontal cortex activation in euthymic bipolar disorder patients during a response inhibition task 
Bipolar disorders  2012;14(4):442-450.
The inferior frontal cortical–striatal network plays an integral role in response inhibition in normal populations. While inferior frontal cortex (IFC) impairment has been reported in mania, this study explored whether this dysfunction persists in euthymia.
Functional magnetic resonance imaging (fMRI) activation was evaluated in 32 euthymic patients with bipolar I disorder and 30 healthy subjects while performing the Go/NoGo response inhibition task. Behavioral data were collected to evaluate accuracy and response time. Within-group and between-group comparisons of activation were conducted using wholebrain analyses to probe significant group differences in neural function.
Both groups activated bilateral IFC. However, between-group comparisons showed a significantly reduced activation in this brain region in euthymic patients with bipolar disorder compared to healthy subjects. Other frontal and basal ganglia regions involved in response inhibition were additionally significantly reduced in bipolar disorder patients, in both the medicated and the unmedicated subgroups. No areas of greater activation were observed in bipolar disorder patients versus healthy subjects.
Bipolar disorder patients, even during euthymia, have a persistent reduction in activation of brain regions involved in response inhibition, suggesting that reduced activation in orbitofrontal cortex and striatum is not solely related to the state of mania. These findings may represent underlying trait abnormalities in bipolar disorder.
PMCID: PMC4412746  PMID: 22631623
bipolar disorder; fMRI; orbitofrontal cortex; response inhibition; striatum
12.  Frontal contributions to face processing differences in autism: Evidence from fMRI of inverted face processing 
Functional neuroimaging studies of face processing deficits in autism have typically focused on visual processing regions, such as the fusiform face area (FFA), which have shown reduced activity in autism spectrum disorders (ASD), though inconsistently. We recently reported reduced activity in the inferior frontal region in ASD, implicating impaired mirror-neuron systems during face processing. In the present study, we used fMRI during a face processing task in which subjects had to match faces presented in the upright versus inverted position. Typically developing (TD) children showed a classic behavioral inversion effect, increased reaction time for inverted faces, while this effect was significantly reduced in ASD subjects. The fMRI data showed similar responses in the fusiform face area for ASD and TD children, with both groups demonstrating increased activation for inverted faces. However, the groups did differ in several brain regions implicated in social cognition, particularly prefrontal cortex and amygdala. These data suggest that the behavioral differences in processing upright versus inverted faces for TD children are related not to visual information processing but to the social significance of the stimuli. Our results are consistent with other recent studies implicating frontal and limbic dysfunction during face processing in autism.
PMCID: PMC3047502  PMID: 18954473
Functional MRI; Autism; Asperger’s; Face processing; Face inversion; Development
13.  Abnormal brain activation during working memory in children with prenatal exposure to drugs of abuse: the effects of methamphetamine, alcohol, and polydrug exposure 
NeuroImage  2010;54(4):3067-3075.
Structural and metabolic abnormalities in fronto-striatal structures have been reported in children with prenatal methamphetamine (MA) exposure. The current study was designed to quantify functional alterations to the fronto-striatal circuit in children with prenatal MA exposure using functional magnetic resonance imaging (fMRI). Because many women who use MA during pregnancy also use alcohol, a known teratogen, we examined 50 children (age range 7–15), 19 with prenatal MA exposure, 15 of whom had concomitant prenatal alcohol exposure (the MAA group), 13 with heavy prenatal alcohol but no MA exposure (ALC group), and 18 unexposed controls (CON group). We hypothesized that MA exposed children would demonstrate abnormal brain activation during a visuospatial working memory (WM) “N-Back” task. As predicted, the MAA group showed less activation than the CON group in many brain areas, including the striatum and frontal lobe in the left hemisphere. The ALC group showed less activation than the MAA group in several regions, including the right striatum. We found an inverse correlation between performance and activity in the striatum in both the CON and MAA groups. However, this relationship was significant in the caudate of the CON group but not the MAA group, and in the putamen of the MAA group but not the CON group. These findings suggest that structural damage in the fronto-striatal circuit after prenatal MA exposure leads to decreased recruitment of this circuit during a WM challenge, and raise the possibility that a rewiring of cortico-striatal networks may occur in children with prenatal MA exposure.
PMCID: PMC4405109  PMID: 21040792
14.  Entorhinal cortex structure and functional MRI response during an associative verbal memory task 
Human brain mapping  2009;30(12):3981-3992.
Entorhinal cortex (ERC) volume in adults with mild cognitive impairment has been shown to predict prodromal Alzheimer's disease (AD). Likewise, neuronal loss in ERC has been associated with AD, but not with normal aging. Because ERC is part of a major pathway modulating input to the hippocampus, structural changes there may result in changes to cognitive performance and functional brain activity during memory tasks. In 32 cognitively intact older adults, we examined the relationship between left ERC thickness and functional magnetic resonance imaging (fMRI) activity during an associative verbal memory task. This task has been shown previously to activate regions that are sensitive to aging and AD risk. ERC was manually defined on native space, high resolution, oblique coronal MRI scans. Subjects having thicker left ERC showed greater activation in anterior cingulate and medial frontal regions during memory retrieval, but not encoding. This result was independent of hippocampal volume. Anterior cingulate cortex is directly connected to ERC, and is, along with medial frontal cortex, implicated in error detection, which is impaired in AD. Our results suggest that in healthy older adults, processes that engage frontal regions during memory retrieval are related to ERC structure.
PMCID: PMC2787760  PMID: 19507155
aging; medial temporal lobe; cingulate gyrus; cognition; frontal lobe; Alzheimer's disease
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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