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1.  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.
doi:10.1002/hbm.22256
PMCID: PMC3664116  PMID: 23417856
Cognition; Parkinson’s; connectivity; tractography; neurodegenerative; white matter; neuroimaging; brain
2.  Psychological Well-Being and Regional Brain Amyloid and Tau in Mild Cognitive Impairment 
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jagp.2012.09.002
PMCID: PMC3883933  PMID: 23567426
Aging; FDDNP; positron emission tomography; POMS; well-being
3.  Differences in resting corticolimbic functional connectivity in bipolar I euthymia 
Bipolar disorders  2013;15(2):156-166.
Objective
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1111/bdi.12047
PMCID: PMC3582748  PMID: 23347587
amygdala; bipolar disorder; euthymia; functional connectivity; resting state; ventrolateral prefrontal cortex
4.  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.
doi:10.1080/10926488.2012.638856
PMCID: PMC3909704  PMID: 24497750
5.  Frontal-amygdala connectivity alterations during emotion down-regulation in bipolar I disorder 
Biological psychiatry  2012;73(2):127-135.
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2012.06.030
PMCID: PMC3525751  PMID: 22858151
amygdala; vlPFC; functional connectivity; functional neuroimaging; bipolar disorder; emotion regulation
6.  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.
doi:10.3233/JAD-121903
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
7.  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.
doi:10.1002/hbm.22141
PMCID: PMC3812259  PMID: 22806961
early onset; functional magnetic resonance imaging; PSEN1; APP; mutation; hippocampus; medial temporal lobe; volume
8.  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.
doi:10.1016/j.pscychresns.2012.04.017
PMCID: PMC3634917  PMID: 23149028
methamphetamine; white matter; alcohol; diffusion imaging; teratogen; in utero
9.  Prediction of Cognitive Decline Based on Hemispheric Cortical Surface Maps of FDDNP PET 
NeuroImage  2012;61(4):10.1016/j.neuroimage.2012.02.056.
Objectives
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.
Methods
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.
Results
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.
Conclusion
FDDNP scans reflect progressive neuropathology accumulation and can potentially be used to predict the cognitive state of an individual.
doi:10.1016/j.neuroimage.2012.02.056
PMCID: PMC3839850  PMID: 22401755
cortical surface maps; MR; FDDNP PET; MMSE
10.  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.
doi:10.1007/s11065-012-9193-2
PMCID: PMC3797601  PMID: 22359096
Alzheimer’s disease; APOE Genotype; Family history; Genetic risk; Risk factors; Neuroimaging
11.  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.
doi:10.1017/S135561770808140X
PMCID: PMC3047502  PMID: 18954473
Functional MRI; Autism; Asperger’s; Face processing; Face inversion; Development
12.  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.
doi:10.1002/hbm.20823
PMCID: PMC2787760  PMID: 19507155
aging; medial temporal lobe; cingulate gyrus; cognition; frontal lobe; Alzheimer's disease
13.  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.
doi:10.1523/JNEUROSCI.3446-12.2013
PMCID: PMC3670947  PMID: 23467374
amygdala; prefrontal cortex; development; fMRI; functional connectivity; emotion regulation; anxiety; inhibition
14.  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.
Objective
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.
Method
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.
Results
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.
Conclusions
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.
doi:10.1176/appi.ajp.2012.11030349
PMCID: PMC3740182  PMID: 22773540
15.  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.
doi:10.1155/2013/946298
PMCID: PMC3736548  PMID: 23970941
16.  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.
doi:10.1038/nn1611
PMCID: PMC3713227  PMID: 16327784
17.  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.
doi:10.1093/cercor/bhr171
PMCID: PMC3328339  PMID: 21784971
amygdala; connectivity; default mode network; face processing; mirror neuron system
18.  Prediction of Cognitive Decline by Positron Emission Tomography of Brain Amyloid and Tau 
Archives of neurology  2012;69(2):215-222.
Objective
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.
Design
Two-year, longitudinal follow-up study.
Setting
A university research institute.
Participants
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.
Results
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.
Conclusions
[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.
doi:10.1001/archneurol.2011.559
PMCID: PMC3623972  PMID: 22332188
19.  Basal ganglia structures differentially contribute to verbal fluency: Evidence from Human Immunodeficiency Virus (HIV)-infected adults 
Neuropsychologia  2011;50(3):390-395.
Background
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.
Method
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.
Results
Performance on phonemic word generation significantly predicted caudate volume, whereas performance on phonemic switching predicted putamen volume.
Conclusions
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.
doi:10.1016/j.neuropsychologia.2011.12.010
PMCID: PMC3608185  PMID: 22223078
Basal ganglia; Verbal fluency; Magnetic resonance imaging; Human Immunodeficiency Virus; Neuropsychology; Aging
20.  Mapping White Matter Integrity and Neurobehavioral Correlates in Children with Fetal Alcohol Spectrum Disorders 
Brain structural abnormalities and neurocognitive dysfunction have been observed in individuals with fetal alcohol spectrum disorders (FASDs). Little is known about how white matter integrity is related to these functional and morphological deficits. We used a combination of diffusion tensor and T1-weighted magnetic resonance imaging to evaluate white matter integrity in individuals with FASDs and related these findings to neurocognitive deficits. Seventeen children and adolescents with FASDs were compared with 19 typically developing age-and gender-matched controls. Lower fractional anisotropy (FA) was observed in individuals with FASDs relative to controls in the right lateral temporal lobe and bilaterally in the lateral aspects of the splenium of the corpus callosum. White matter density was also lower in some, but not all regions in which FA was lower. FA abnormalities were confirmed to be in areas of white matter in post hoc region of interest analyses, further supporting that less myelin or disorganized fiber tracts are associated with heavy prenatal alcohol exposure. Significant correlations between performance on a test of visuomotor integration and FA in bilateral splenium, but not temporal regions were observed within the FASD group. Correlations between the visuomotor task and FA within the splenium were not significant with in the control group, and were not significant for measures of reading ability. This suggests that this region of white matter is particularly susceptible to damage from prenatal alcohol exposure and that disruption of splenial fibers in this group is associated with poorer visuomotor integration.
doi:10.1523/JNEUROSCI.5067-07.2008
PMCID: PMC3567846  PMID: 18256251
FAS; FASDs; DTI; VBM; corpus callosum; visuomotor integration
21.  Increased fMRI signal with age in familial Alzheimer’s disease mutation carriers 
Neurobiology of aging  2010;33(2):424.e11-424.e21.
Although many Alzheimer’s disease (AD) patients have a family history of the disease, it is rarely inherited in a predictable way. Functional magnetic resonance imaging (fMRI) studies of non-demented adults carrying familial AD mutations provide an opportunity to prospectively identify brain differences associated with early AD-related changes. We compared fMRI activity of 18 non-demented autosomal dominant AD mutation carriers with fMRI activity in 8 of their non-carrier relatives as they performed a novelty encoding task in which they viewed novel and repeated images. Because age of disease onset is relatively consistent within families, we also correlated fMRI activity with subjects’ distance from the median age of diagnosis for their family. Mutation carriers did not show significantly different voxelwise fMRI activity from non-carriers as a group. However, as they approached their family age of disease diagnosis, only mutation carriers showed increased fMRI activity in the fusiform and middle temporal gyri. This suggests that during novelty encoding, increased fMRI activity in the temporal lobe may relate to incipient AD processes.
doi:10.1016/j.neurobiolaging.2010.09.028
PMCID: PMC3097258  PMID: 21129823
PSEN1; APP; fMRI; familial Alzheimer’s disease
22.  Normal amygdala activation but deficient ventrolateral prefrontal activation in adults with bipolar disorder during euthymia 
NeuroImage  2011;59(1):738-744.
Functional neuroimaging studies have implicated the involvement of the amygdala and ventrolateral prefrontal cortex (vlPFC) in the pathophysiology of bipolar disorder. Hyperactivity in the amygdala and hypoactivity in the vlPFC have been reported in manic bipolar patients scanned during the performance of an affective faces task. Whether this pattern of dysfunction persists during euthymia is unclear. Using functional magnetic resonance imaging (fMRI), 24 euthymic bipolar and 26 demographically matched healthy control subjects were scanned while performing an affective task paradigm involving the matching and labeling of emotional facial expressions. Neuroimaging results showed that, while amygdala activation did not differ significantly between groups, euthymic patients showed a significant decrease in activation of the right vlPFC (BA47) compared to healthy controls during emotion labeling. Additionally, significant decreases in activation of the right insula, putamen, thalamus and lingual gyrus were observed in euthymic bipolar relative to healthy control subjects during the emotion labeling condition. These data, taken in context with prior studies of bipolar mania using the same emotion recognition task, could suggest that amygdala dysfunction may be a state-related abnormality in bipolar disorder, whereas vlPFC dysfunction may represent a trait-related abnormality of the illness. Characterizing these patterns of activation is likely to help in understanding the neural changes related to the different mood states in bipolar disorder, as well as changes that represent more sustained abnormalities. Future studies that assess mood-state related changes in brain activation in longitudinal bipolar samples would be of interest.
doi:10.1016/j.neuroimage.2011.07.054
PMCID: PMC3216485  PMID: 21854858
bipolar disorder; amygdala; prefrontal cortex; fmri; emotion
23.  Gray matter loss correlates with mesial temporal lobe neuronal hyperexcitability inside the human seizure onset zone 
Epilepsia  2011;53(1):25-34.
Summary
Purpose
Patient studies have not provided consistent evidence for interictal neuronal hyperexcitability inside the seizure onset zone (SOZ). We hypothesized that gray matter (GM) loss could have important effects on neuronal firing, and quantifying these effects would reveal significant differences in neuronal firing inside versus outside the SOZ.
Methods
MRI and computational unfolding of mesial temporal lobe (MTL) subregions was used to construct anatomical maps to compute GM loss in presurgical patients with medically intractable focal seizures in relation to control subjects. In patients, these same maps were used to locate the position of microelectrodes that recorded interictal neuronal activity. Single neuron firing and burst rates were evaluated in relation to GM loss and MTL subregions inside and outside the SOZ.
Key findings
MTL GM thickness was reduced inside and outside the SOZ in patients with respect to control subjects, yet GM loss was associated more strongly with firing and burst rates in several MTL subregions inside the SOZ. Adjusting single neuron firing and burst rates for the effects of GM loss revealed significantly higher firing rates in the subregion consisting of dentate gyrus and CA2 and CA3 (CA23DG), as well as CA1 and entorhinal cortex (EC) inside versus outside the SOZ where normalized MRI GM loss was ≥1.40 mm. Firing rates were higher in subicular cortex inside the SOZ at GM loss ≥1.97 mm, while burst rates were higher in CA23DG, CA1, and EC inside than outside the SOZ at similar levels of GM loss.
Significance
The correlation between GM loss and increased firing and burst rates suggests GM structural alterations in MTL subregions are associated with interictal neuronal hyperexcitability inside the SOZ. Significant differences in firing rates and bursting in areas with GM loss inside compared to outside the SOZ indicate that synaptic reorganization following cell loss could be associated with varying degrees of epileptogenicity in patients with intractable focal seizures.
doi:10.1111/j.1528-1167.2011.03333.x
PMCID: PMC3253228  PMID: 22126325
epilepsy; atrophy; interictal; hippocampus; MRI; microelectrode; single neuron
24.  Altered Structural Brain Connectivity in Healthy Carriers of the Autism Risk Gene, CNTNAP2 
Brain Connectivity  2011;1(6):447-459.
Abstract
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 women, 119 men, age: 23.4±2.17 SD years) were scanned with 105-gradient high-angular-resolution 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, and lower eccentricity (maximum path length) in 60 of the 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 that links graph theory metrics of brain structural connectivity to a common genetic variant linked with autism and will help us understand the neurobiology of the circuits implicated in the risk for autism.
doi:10.1089/brain.2011.0064
PMCID: PMC3420970  PMID: 22500773
autism; CNTNAP2; graph theory; HARDI; structural connectivity; twins
25.  Altered integration of speech and gesture in children with autism spectrum disorders 
Brain and Behavior  2012;2(5):606-619.
The presence of gesture during speech has been shown to impact perception, comprehension, learning, and memory in normal adults and typically developing children. In neurotypical individuals, the impact of viewing co-speech gestures representing an object and/or action (i.e., iconic gesture) or speech rhythm (i.e., beat gesture) has also been observed at the neural level. Yet, despite growing evidence of delayed gesture development in children with autism spectrum disorders (ASD), few studies have examined how the brain processes multimodal communicative cues occurring during everyday communication in individuals with ASD. Here, we used a previously validated functional magnetic resonance imaging (fMRI) paradigm to examine the neural processing of co-speech beat gesture in children with ASD and matched controls. Consistent with prior observations in adults, typically developing children showed increased responses in right superior temporal gyrus and sulcus while listening to speech accompanied by beat gesture. Children with ASD, however, exhibited no significant modulatory effects in secondary auditory cortices for the presence of co-speech beat gesture. Rather, relative to their typically developing counterparts, children with ASD showed significantly greater activity in visual cortex while listening to speech accompanied by beat gesture. Importantly, the severity of their socio-communicative impairments correlated with activity in this region, such that the more impaired children demonstrated the greatest activity in visual areas while viewing co-speech beat gesture. These findings suggest that although the typically developing brain recognizes beat gesture as communicative and successfully integrates it with co-occurring speech, information from multiple sensory modalities is not effectively integrated during social communication in the autistic brain.
doi:10.1002/brb3.81
PMCID: PMC3489813  PMID: 23139906
Autism spectrum disorders; fMRI; gesture; language; superior temporal gyrus

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