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1.  Neural Substrates Associated with Weather-Induced Mood Variability: An Exploratory Study Using ASL Perfusion fMRI 
Journal of cognitive science  2011;12(2):195-210.
Daily variations in weather are known to be associated with variations in mood. However, little is known about the specific brain regions that instantiate weather-related mood changes. We used a data-driven approach and ASL perfusion fMRI to assess the neural substrates associated with weather-induced mood variability. The data-driven approach was conducted with mood ratings under various weather conditions (N = 464). Forward stepwise regression was conducted to develop a statistical model of mood as a function of weather conditions. The model results were used to calculate the mood-relevant weather index which served as the covariate in the regression analysis of the resting CBF (N = 42) measured by ASL perfusion fMRI under various weather conditions. The resting CBF activities in the left insula-prefrontal cortex and left superior parietal lobe were negatively correlated (corrected p<0.05) with the weather index, indicating that better mood-relevant weather conditions were associated with lower CBF in these regions within the brain’s emotional network. The present study represents a first step toward the investigation of the effect of natural environment on baseline human brain function, and suggests the feasibility of ASL perfusion fMRI for such study.
PMCID: PMC4018827  PMID: 24834022
ASL perfusion fMRI; cerebral blood flow; weather; mood; insula
2.  Comparison of 2D and 3D single-shot ASL perfusion fMRI sequences 
NeuroImage  2012;0:10.1016/j.neuroimage.2012.10.087.
Arterial Spin Labeling (ASL) can be implemented by combining different labeling schemes and readout sequences. In this study, the performance of 2D and 3D single-shot pulsed-continuous ASL (pCASL) sequences was assessed in a group of young healthy volunteers undergoing a baseline perfusion and a functional study with a sensory-motor activation paradigm. The evaluated sequences were 2D echo-planar imaging (2D EPI), 3D single-shot fast spin echo with in-plane spiral readout (3D FSE spiral), and 3D single-shot gradient-and-spin-echo (3D GRASE). The 3D sequences were implemented with and without the addition of an optimized background suppression (BS) scheme. Labeling efficiency, signal-to-noise ratio (SNR), and gray matter (GM) to white matter (WM) contrast ratio were assessed in baseline perfusion measurements. 3D acquisitions without BS yielded 2-fold increments in spatial SNR, but no change in temporal SNR. The addition of BS to the 3D sequences yielded a 3-fold temporal SNR increase compared to the unsuppressed sequences. 2D EPI provided better GM-to-WM contrast ratio than the 3D sequences. The analysis of functional data at the subject level showed a 3-fold increase in statistical power for the BS 3D sequences, although the improvement was attenuated at the group level. 3D without BS did not increase the maximum t-values, however, it yielded larger activation clusters than 2D. These results demonstrate that BS 3D single-shot imaging sequences improve the performance of pCASL in baseline and activation studies, particularly for individual subject analyses where the improvement in temporal SNR translates into markedly enhanced power for task activation detection.
PMCID: PMC3587033  PMID: 23142069
arterial spin labeling; readout sequence; background suppression; spiral imaging; 3D GRASE; EPI
3.  Interictal cortical hyperresponsiveness in migraine is directly related to the presence of aura 
The objective of this study was to compare the interictal cortical response to a visual stimulus between migraine with aura (MWA), migraine without aura (MwoA), and control subjects.
In a prospective case-control study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) was used to assess the response to a visual stimulus and arterial spin labeled perfusion MR to determine resting cerebral blood flow. A standardized questionnaire was used to assess interictal visual discomfort.
Seventy-five subjects (25 MWA, 25 MwoA, and 25 controls) were studied. BOLD fMRI response to visual stimulation within primary visual cortex was greater in MWA (3.09±0.15%) compared to MwoA (2.36±0.13%, p=0.0008) and control subjects (2.47±0.11%, p=0.002); responses were also greater in the lateral geniculate nuclei in MWA. No difference was found between MwoA and control groups. Whole brain analysis showed that increased activation in MWA was confined to the occipital pole. Regional resting cerebral blood flow did not differ between groups. MWA and MwoA subjects had significantly greater levels of interictal visual discomfort compared to controls (p=0.008 and p=0.005, respectively), but this did not correlate with BOLD response.
Despite similar interictal symptoms of visual discomfort, only MWA subjects have cortical hyperresponsiveness to visual stimulus, suggesting a direct connection between cortical hyperresponsiveness and aura itself.
PMCID: PMC3658127  PMID: 23359872
Migraine with aura; cortical hyperresponsiveness; hyperexcitability; visual sensitivity
4.  Brain Entropy Mapping Using fMRI 
PLoS ONE  2014;9(3):e89948.
Entropy is an important trait for life as well as the human brain. Characterizing brain entropy (BEN) may provide an informative tool to assess brain states and brain functions. Yet little is known about the distribution and regional organization of BEN in normal brain. The purpose of this study was to examine the whole brain entropy patterns using a large cohort of normal subjects. A series of experiments were first performed to validate an approximate entropy measure regarding its sensitivity, specificity, and reliability using synthetic data and fMRI data. Resting state fMRI data from a large cohort of normal subjects (n = 1049) from multi-sites were then used to derive a 3-dimensional BEN map, showing a sharp low-high entropy contrast between the neocortex and the rest of brain. The spatial heterogeneity of resting BEN was further studied using a data-driven clustering method, and the entire brain was found to be organized into 7 hierarchical regional BEN networks that are consistent with known structural and functional brain parcellations. These findings suggest BEN mapping as a physiologically and functionally meaningful measure for studying brain functions.
PMCID: PMC3962327  PMID: 24657999
5.  Oral alprazolam acutely increases nucleus accumbens perfusion 
Molecular psychiatry  2012;18(9):960-961.
Benzodiazepines treat anxiety, but can also produce euphoric effects, contributing to abuse. Using perfusion magnetic resonance imaging, we provide the first direct evidence in humans that alprazolam (Xanax) acutely increases perfusion in the nucleus accumbens, a key reward-processing region linked to addiction.
PMCID: PMC3957329  PMID: 23070072
6.  Acute baclofen diminishes resting baseline blood flow to limbic structures: A perfusion fMRI study 
Drug and alcohol dependence  2012;125(0):60-66.
Preclinical and clinical evidence show that the GABA B agonist, baclofen is a promising treatment for addictive disorders; however, until recently its mechanism of action in the human brain was unknown. In previous work we utilized a laboratory model that included a medication versus placebo regimen to examine baclofen’s actions on brain circuitry. Perfusion fMRI [measure of cerebral blood flow (CBF)] data acquired ‘at rest’ before and on the last day of the 21-day medication regimen showed that baclofen diminished CBF bilaterally in the VS, insula and medial orbitofrontal cortex (mOFC). In the present study, we hypothesized that a single dose of baclofen would have effects similar to repeated dosing.
To test our hypothesis, in a crossover design, CBF data were acquired using pseudo continuous arterial spin labeled (pCASL) perfusion fMRI. Subjects were either un-medicated or were administered a 20 mg dose of baclofen approximately 110 min prior to scanning.
Acute baclofen diminished mOFC, amygdala, and ventral anterior insula CBF without causing sedation (family-wise error corrected at p = 0.001).
Results demonstrate that similar to repeated dosing, an acute dose of baclofen blunts the ‘limbic’ substrate that is hyper-responsive to drugs and drug cues. Smokers often manage their craving and can remain abstinent for extended periods after quitting, however the risk of eventual relapse approaches 90%. Given that chronic medication may not be a practical solution to the long-term risk of relapse, acute baclofen may be useful on an ‘as-needed’ basis to block craving during ‘at risk’ situations.
PMCID: PMC3770303  PMID: 22513380
Addiction; fMRI; GABA B agonist; Cerebral blood flow; Smoking cessation; Treatment; Baclofe
7.  Effects of Varenicline on Smoking Cue–Triggered Neural and Craving Responses 
Archives of general psychiatry  2011;68(5):516-526.
Varenicline, an effective smoking cessation medication, functions as an α4β2 nicotinic acetylcholine receptor partial agonist. It indirectly affects the dopaminergic reward system by reducing withdrawal symptoms during abstinence and by decreasing the reinforcement received from nicotine while smoking. We hypothesize that varenicline would have a third mechanism to blunt responses to smoking cues in the reward-related ventral striatum and medial orbitofrontal cortex and would be associated with a reduction in smoking cue–elicited craving.
A laboratory model of conditioned responding and arterial spin-labeled perfusion functional magnetic resonance imaging, a biomarker of regional brain activity, was used to test our hypothesis. Perfusion functional magnetic resonance imaging is quantitative and stable across time, facilitating the measurement of medication-induced neural modifications in the brain in response to a challenge (smoking cue exposure) and in the brain in the resting condition (without provocation). Smokers were imaged during rest and during smoking cue exposure before and after a 3-week randomized placebo-controlled medication regimen. Subjects were nonabstinent to explicitly examine the effects of varenicline on cue reactivity independent of withdrawal.
Center for the Study of Addictions, University of Pennsylvania, Philadelphia.
Subjects were nicotine-dependent smokers who responded to advertisements placed on local radio and Listservs to participate in a medication-related research study that specifically stated “this is not a Quit Smoking Study” and “smokers may be contemplating but not currently considering quitting.”
Prerandomization smoking cues vs nonsmoking cues activated the ventral striatum and medial orbitofrontal cortex (t=3.77) and elicited subjective reports of craving (P=.006). Craving reports correlated with increased activity in the posterior cingulate (t=4.11). Administration of varenicline diminished smoking cue– elicited ventral striatum and medial orbitofrontal cortex responses (t values from −3.75 to −5.63) and reduced self-reported smoking cue–elicited craving, whereas placebo-treated subjects exhibited responses similar to those observed prior to randomization. Varenicline-induced activation of lateral orbitofrontal cortex in the brain at rest (t=5.63) predicted blunting of smoking cue responses in the medial orbitofrontal cortex (r=−0.74).
Varenicline’s reciprocal actions in the reward-activated medial orbitofrontal cortex and in the reward-evaluating lateral orbitofrontal cortex underlie a diminished smoking cue response, revealing a distinctive new action that likely contributes to its clinical efficacy.
PMCID: PMC3743240  PMID: 21199958
8.  A VBM study demonstrating ‘apparent’ effects of a single dose of medication on T1-weighted MRIs 
Brain structure & function  2013;218(1):97-104.
Voxel-based morphometry (VBM) studies have interpreted longitudinal medication- or behaviorally-induced changes observed on T1-weighted magnetic resonance images (MRIs) as changes in neuronal structure. Although neurogenesis or atrophy certainly occurs, the use of T1-weighted scans to identify change in brain structure in vivo in humans has a vulnerability: the T1 relaxation time for arterial blood and gray matter are not clearly distinguishable and therefore, apparent reported structural findings might be at least partially related to changes in blood flow or other physiological signals. To examine the hypothesis that apparent structural modifications may reflect changes introduced by additional mechanisms irrespective of potential neuronal growth/atrophy, we acquired a high resolution T1-weighted structural scan and a 5-minute perfusion fMRI scan (a measurement of blood flow), prior to and after administration of an acute pharmacological manipulation, In a within subjects design, 15 subjects were either un-medicated or were administered a 20 mg dose of baclofen (an FDA-approved anti-spastic) approximately 110 minutes prior to acquiring a T1-weighted scan and a pseudo continuous arterial spin labeled (pCASL) perfusion fMRI scan. Using diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) within SPM7 we observed macroscopic, and therefore implausible, baclofen-induced decreases in VBM ‘gray matter’ signal in the dorsal rostral anterior cingulate [Family-wise error (FWE) corrected at p < 0.04, T= 6.54, extent: 1460 voxels] that overlapped with changes in blood flow. Given that gray matter reductions are unlikely following a single dose of medication these findings suggest that changes in blood flow are masquerading as reductions in gray matter on the T1-weighted scan irrespective of the temporal interval between baseline measures and longitudinal manipulations. These results underscore the crucial and immediate need to develop in vivo neuroimaging biomarkers for humans that can uniquely capture changes in neuronal structure dissociable from those related to blood flow or other physiological signals.
PMCID: PMC3743241  PMID: 22302433
voxel based morphometry; T1-weighted structural scan; perfusion fMRI; cerebral blood flow; gray matter; neurogenesis
9.  Migraine with Aura Is Associated with an Incomplete Circle of Willis: Results of a Prospective Observational Study 
PLoS ONE  2013;8(7):e71007.
To compare the prevalence of an incomplete circle of Willis in patients with migraine with aura, migraine without aura, and control subjects, and correlate circle of Willis variations with alterations in cerebral perfusion.
Migraine with aura, migraine without aura, and control subjects were prospectively enrolled in a 1∶1∶1 ratio. Magnetic resonance angiography was performed to examine circle of Willis anatomy and arterial spin labeled perfusion magnetic resonance imaging to measure cerebral blood flow. A standardized template rating system was used to categorize circle of Willis variants. The primary pre-specified outcome measure was the frequency of an incomplete circle of Willis. The association between circle of Willis variations and cerebral blood flow was also analyzed.
170 subjects were enrolled (56 migraine with aura, 61 migraine without aura, 53 controls). An incomplete circle of Willis was significantly more common in the migraine with aura compared to control group (73% vs. 51%, p = 0.02), with a similar trend for the migraine without aura group (67% vs. 51%, p = 0.08). Using a quantitative score of the burden of circle of Willis variants, migraine with aura subjects had a higher burden of variants than controls (p = 0.02). Compared to those with a complete circle, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow (p = 0.05). Specific posterior cerebral artery variants were associated with greater asymmetries of blood flow in the posterior cerebral artery territory.
An incomplete circle of Willis is more common in migraine with aura subjects than controls, and is associated with alterations in cerebral blood flow.
PMCID: PMC3724801  PMID: 23923042
10.  Methylphenidate modulates sustained attention and cortical activation in survivors of traumatic brain injury: A perfusion fMRI study 
Psychopharmacology  2011;222(1):47-57.
Methylphenidate (MPH), the most widely prescribed psychostimulant to treat many neuropsychiatric conditions, is reported to improve attention and speed of processing in survivors of traumatic brain injury (TBI). The neural correlate of this efficacy, however, remains unclear.
Using perfusion fMRI as a biomarker of regional neural activity, the current study aimed to examine the neural correlates of single-dose (0.3 mg/kg) MPH administration in a randomized double-blind placebo-controlled cross-over study design.
Twenty-three individuals with moderate to severe TBI were tested on two occasions approximately one week apart. Perfusion fMRI scanning was carried out at rest and while participants performed cognitive tasks requiring sustained attention and working memory.
Behaviorally, MPH significantly improved both accuracy and reaction time (RT) in the sustained attention task, but only RT in the working memory task. A trend of global reduction of cerebral blood flow by MPH was observed in all task conditions including resting. Voxel-wise whole-brain analysis revealed an interaction effect of drug by condition (MPH-placebo X task-rest) for the sustained attention task in the left posterior superior parietal cortex and parieto-occipital junction (BA 7/19). The magnitude of drug-related deactivation of this area during task performance was correlated with improvement in RT.
Suppression of activity in this area during task performance may reflect a compensatory mechanism by which MPH ameliorates attention impairments in TBI.
PMCID: PMC3369011  PMID: 22203319
methylphenidate; traumatic brain injury; CBF; fMRI; sustained attention; working memory
11.  Influence of probe pressure on the diffuse correlation spectroscopy blood flow signal: extra-cerebral contributions 
Biomedical Optics Express  2013;4(7):978-994.
A pilot study explores relative contributions of extra-cerebral (scalp/skull) versus brain (cerebral) tissues to the blood flow index determined by diffuse correlation spectroscopy (DCS). Microvascular DCS flow measurements were made on the head during baseline and breath-holding/hyperventilation tasks, both with and without pressure. Baseline (resting) data enabled estimation of extra-cerebral flow signals and their pressure dependencies. A simple two-component model was used to derive baseline and activated cerebral blood flow (CBF) signals, and the DCS flow indices were also cross-correlated with concurrent Transcranial Doppler Ultrasound (TCD) blood velocity measurements. The study suggests new pressure-dependent experimental paradigms for elucidation of blood flow contributions from extra-cerebral and cerebral tissues.
PMCID: PMC3704102  PMID: 23847725
(170.3880) Medical and biological imaging; (170.2655) Functional monitoring and imaging; (170.3660) Light propagation in tissues; (170.6480) Spectroscopy, speckle
13.  Applications of Arterial Spin Labeled MRI in the Brain 
Perfusion provides oxygen and nutrients to tissues and is closely tied to tissue function, and disorders of perfusion are major sources of medical morbidity and mortality. It has been almost two decades since the use of arterial spin labeling (ASL) for noninvasive perfusion imaging was first reported. While initial ASL MRI studies focused primarily on technological development and validation, a number of robust ASL implementations have emerged, and ASL MRI is now also available commercially on several platforms. As a result, basic science and clinical applications of ASL MRI have begun to proliferate. Although ASL MRI can be carried out in any organ, most studies to date have focused on the brain. This review covers selected research and clinical applications of ASL MRI in the brain to illustrate is potential in both neuroscience research and clinical care.
PMCID: PMC3326188  PMID: 22246782
arterial spin labeling; cerebral blood flow; brain function; cognitive neuroscience; clinical neuroscience; magnetic resonance imaging
14.  Arterial spin labeled MRI in prodromal Alzheimer's disease: A multi-site study☆ 
NeuroImage : Clinical  2013;2:630-636.
We examined differences in cerebral blood flow (CBF) measured by Arterial Spin Labeled perfusion MRI (ASL MRI) across the continuum from cognitively normal (CN) older adults to mild Alzheimer's Disease (AD) using data from the multi-site Alzheimer's Disease Neuroimaging Initiative (ADNI). Measures of CBF, in a predetermined set of regions (meta-ROI), and hippocampal volume were compared between CN (n = 47), patients with early and late Mild Cognitive Impairment [EMCI (n = 32), LMCI (n = 35)], and AD (n = 15). Associations between these measures and disease severity, assessed by Clinical Dementia Rating scale sum of boxes (CDR SB), were also assessed. Mean meta-ROI CBF was associated with group status and significant hypoperfusion was observed in LMCI and AD relative to CN. Hippocampal volume was associated with group status, but only AD patients had significantly smaller volumes than the CN. When examining the relationship between these measures and disease severity, both were significantly associated with CDR SB and appeared to provide independent prediction of status. In light of the tight link between CBF and metabolism, ASL MRI represents a promising functional biomarker for early diagnosis and disease tracking in AD and this study is the first to demonstrate the feasibility in a multi-site context in this population. Combining functional and structural measures, which can be acquired in the same scanning session, appears to provide additional information about disease severity relative to either measure alone.
•Arterial Spin Labeled (ASL) MRI is a promising AD biomarker. No prior multi-site study of this modality in AD.•We measured cerebral blood flow (CBF) in a FDG PET defined region.•Reduced CBF was associated with MCI and AD and correlated with disease severity.•Hippocampal volume and ASL provide complementary information.•ASL MRI can be applied to this population in a multi-site context.
PMCID: PMC3777751  PMID: 24179814
15.  Direct Comparison of FDG-PET and ASL-MRI in Alzheimer’s Disease 
The utility flourodeoxyglucose PET (FDG-PET) imaging in Alzheimer’s Disease (AD) diagnosis is well established. Recently, measurement of cerebral blood flow using arterial spin labeling MRI (ASL-MRI) has shown diagnostic potential in AD, though it has never been directly compared to FDG-PET.
We employed a novel imaging protocol to obtain FDG-PET and ASL-MRI images concurrently in 17 AD patients and 19 age-matched controls. Paired FDG-PET and ASL-MRI images from 19 controls and 15 AD patients were included for qualitative analysis, while paired images 18 controls and 13 AD patients were suitable for quantitative analyses.
The combined imaging protocol was well tolerated. Both modalities revealed very similar regional abnormalities in AD, as well as comparable sensitivity and specificity for the detection of AD following visual review by two expert readers. Interobserver agreement was better for FDG-PET (kappa 0.75, SE 0.12) than ASL-MRI (kappa 0.51, SE 0.15), intermodality agreement was moderate to strong (kappa 0.45-0.61), and readers were more confident of FDG-PET reads. Simple quantitative analysis of global cerebral FDG uptake (FDG-PET) or whole brain cerebral blood flow (ASL-MRI) showed excellent diagnostic accuracy for both modalities, with area under ROC curves of 0.90 for FDG-PET (95% CI 0.79-0.99) and 0.91 for ASL-MRI (95% CI 0.80-1.00).
Our results demonstrate that FDG-PET and ASL-MRI identify similar regional abnormalities and have comparable diagnostic accuracy in a small population of AD patients, and support the further study of ASL-MRI in dementia diagnosis.
PMCID: PMC3264701  PMID: 22018493
ASL; FDG; PET; MRI; Alzheimer’s disease; spin label; fluorodeoxyglucose; dementia
16.  Serotonin transporter genotype modulates functional connectivity between amygdala and PCC/PCu during mood recovery 
The short (S) allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been associated with increased susceptibility to depression. Previous neuroimaging studies have consistently showed increased amygdala activity during the presentation of negative stimuli or regulation of negative emotion in the homozygous short allele carriers, suggesting the key role of amygdala response in mediating increased risk for depression. The brain default mode network (DMN) has also been shown to modulate amygdala activity. However, it remains unclear whether 5-HTTLPR genetic variation modulates functional connectivity (FC) between the amygdala and regions of DMN. In this study, we re-analyzed our previous imaging dataset and examined the effects of 5-HTTLPR genetic variation on amygdala connectivity. A total of 15 homozygous short (S/S) and 15 homozygous long individuals (L/L) were scanned in functional magnetic resonance imaging (fMRI) during four blocks: baseline, sad mood, mood recovery, and return to baseline. The S/S and L/L groups showed a similar pattern of FC and no differences were found between the two groups during baseline and sad mood scans. However, during mood recovery, the S/S group showed significantly reduced anti-correlation between amygdala and posterior cingulate cortex/precuneus (PCC/PCu) compared to the L/L group. Moreover, PCC/PCu-amygdala connectivity correlated with amygdala activity in the S/S group but not the L/L group. These results suggest that 5-HTTLPR genetic variation modulates amygdala connectivity which subsequently affects its activity during mood regulation, providing an additional mechanism by which the S allele confers depression risk.
PMCID: PMC3813895  PMID: 24198772
5-HTTLPR; amygdala; PCC/PCu; functional connectivity
17.  Absence of changes in cortical thickness in patients with migraine 
Previous studies have reported gray matter alterations in patients with migraine, particularly thinning of the cingulate gyrus, and thickening of the somatosensory cortex (SSC) and visual motion processing areas (V3A/MT+). We attempted to replicate these findings in a larger patient population.
Brain anatomy was collected with 3T MRI. Surface-based morphometry was used to segment each brain volume, reconstruct and inflate the cortical sheet, and estimate gray matter thickness.
Eighty-four age and sex-matched participants (28 migraine with aura, 28 migraine without aura, and 28 controls) were studied. No significant differences in somatosensory, cingulate gyrus, or V3A/MT+ cortical thickness were found between the groups, including analysis of specific subregions previously reported to be affected. Whole brain analysis found no regions of differential gray matter thickness between groups. A highly significant inverse correlation between age and whole brain and regional cortical thickness was identified. Power analyses indicate that even a small difference (~0.07 to 0.14 mm) in cortical thickness could have been detected between groups given the sample size.
Using highly sensitive surface-based morphometry, no differences in cortical thickness between patients with migraine and controls could be identified.
PMCID: PMC3512201  PMID: 21911412
Migraine; morphometry; cortical thickness; brain structure
18.  Heterogeneity of Functional Activation During Memory Encoding Across Hippocampal Subfields in Temporal Lobe Epilepsy 
Neuroimage  2011;58(4):1121-1130.
Pathology studies have shown that the anatomical subregions of the hippocampal formation are differentially affected in various neurological disorders, including temporal lobe epilepsy (TLE). Analysis of structure and function within these subregions using magnetic resonance imaging (MRI) has the potential to generate insights on disease associations as well as normative brain function. In this study, an atlas-based normalization method (Yushkevich et al., 2009) was used to label hippocampal subregions, making it possible to examine subfield-level functional activation during an episodic memory task in two different cohorts of healthy controls and subjects diagnosed with intractable unilateral TLE. We report, for the first time, functional activation patterns within hippocampal subfields in TLE. We detected group differences in subfield activation between patients and controls as well as inter-hemispheric activation asymmetry within subfields in patients, with dentate gyrus (DG) and the anterior hippocampus region showing the greatest effects. DG was also found to be more active than CA1 in controls, but not in patients’ epileptogenic side. These preliminary results will encourage further research on the utility of subfield-based biomarkers in TLE.
PMCID: PMC3285462  PMID: 21763431
hippocampus; shape-based normalization; postmortem atlas; fMRI; interhemispheric asymmetry; subfields; temporal lobe epilepsy
19.  Serotonin transporter genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults 
Psychiatry research  2011;193(3):161-167.
Recent attempts to understand the biological bases of depression vulnerability have revealed that both the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) and activity in the amygdala are associated with depression. Other studies have reported amygdala hyperactivity associated with the 5-HTTLPR short allele, linking the genetic and neuroimaging lines of research and suggesting a mechanism whereby the short allele confers depression risk. However, fewer investigations have examined the associations between depression, 5-HTTLPR variability, and amygdala activation in a single study. The current study thus investigated whether 5-HTTLPR genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults. Regional cerebral blood flow was measured with perfusion fMRI during a task-free scan. We hypothesized differential associations between depressive symptoms and amygdala activity among individuals homozygous for the short allele and individuals homozygous for the long allele. Both whole brain analyses and region-of-interest analyses confirmed this prediction, revealing a significant negative association among the long allele group and a trend of positive association among the short allele group. These results complement existing reports of short allele related amygdala hyperactivity and suggest an additional neurobiological mechanism whereby the 5-HTTLPR is associated with psychiatric outcomes.
PMCID: PMC3156965  PMID: 21764567
depression; mood; 5-HTTLPR; serotonin transporter; amygdala
20.  Relations between BOLD fMRI-Derived Resting Brain Activity and Cerebral Blood Flow 
PLoS ONE  2012;7(9):e44556.
Consistent resting brain activity patterns have been repeatedly demonstrated using measures derived from resting BOLD fMRI data. While those metrics are presumed to reflect underlying spontaneous brain activity (SBA), it is challenging to prove that association because resting BOLD fMRI metrics are purely model-free and scale-free variables. Cerebral blood flow (CBF) is typically closely coupled to brain metabolism and is used as a surrogate marker for quantifying regional brain function, including resting function. Assessing the correlations between resting BOLD fMRI measures and CBF correlation should provide a means of linking of those measures to the underlying SBA, and a means to quantify those scale-free measures. The purpose of this paper was to examine the CBF correlations of 3 widely used neuroimaging-based SBA measures, including seed-region based functional connectivity (FC), regional homogeneity (ReHo), and amplitude of low frequency fluctuation (ALFF). Test-retest data were acquired to check the stability of potential correlations across time. Reproducible posterior cingulate cortex (PCC) FC vs regional CBF correlations were found in much of the default mode network and visual cortex. Dorsal anterior cingulate cortex (ACC) FC vs CBF correlations were consistently found in bilateral prefrontal cortex. Both ReHo and ALFF were found to be reliably correlated with CBF in most of brain cortex. None of the assessed SBA measures was correlated with whole brain mean CBF. These findings suggest that resting BOLD fMRI-derived measures are coupled with regional CBF and are therefore linked to regional SBA.
PMCID: PMC3448607  PMID: 23028560
21.  Magnetic Resonance Imaging of Glutamate 
Nature Medicine  2012;18(2):302-306.
Glutamate (Glu) exhibits a pH and concentration dependent chemical exchange saturation transfer effect (CEST) between its -amine group and bulk water, here termed GluCEST. GluCEST asymmetry is observed at ~3 parts per million downfield from bulk water. Following middle cerebral artery occlusion in the rat brain, an approximately 100% elevation of GluCEST in the ipsilateral side compared to the contralateral side was observed, and is predominantly due to pH changes. In a rat brain tumor model with blood brain barrier disruption, intravenous Glu injection resulted in a clear elevation of GluCEST and a comparable increase in the proton magnetic resonance spectroscopy signal of Glu. GluCEST maps from healthy human brain at 7T were also obtained. These results demonstrate the feasibility and potential of GluCEST for mapping relative changes in Glu concentration as well as pH in vivo. Potential contributions from other brain metabolites to the GluCEST effect are also discussed.
PMCID: PMC3274604  PMID: 22270722
22.  Modulation of resting brain cerebral blood flow by the GABA B agonist, baclofen: A longitudinal perfusion fMRI study 
Drug and Alcohol Dependence  2011;117(2-3):176-183.
Preclinical studies confirm that the GABA B agonist, baclofen blocks dopamine release in the reward-responsive ventral striatum (VS) and medial prefrontal cortex, and consequently, blocks drug motivated behavior. Its mechanism in humans is unknown. Here, we used continuous arterial spin labeled (CASL) perfusion fMRI to examine baclofen’s effects on blood flow in the human brain.
Twenty-one subjects (all smokers, 12 females) were randomized to receive either baclofen (80 mg/day; N = 10) or placebo (N = 11). A five minute quantitative perfusion fMRI resting baseline (RB) scan was acquired at two time points; prior to the dosing regimen (Time 1) and on the last day of 21 days of drug administration (Time 2). SPM2 was employed to compare changes in RB from Time 1 to 2.
Baclofen diminished cerebral blood flow (CBF) in the VS and mOFC and increased it in the lateral OFC, a region involved in suppressing previously rewarded behavior. CBF in bilateral insula was also blunted by baclofen (T values ranged from −11.29 to 15.3 at p = 0.001, 20 contiguous voxels). CBF at Time 2 was unchanged in placebo subjects. There were no differences between groups in side effects or cigarettes smoked per day (at either time point).
Baclofen’s modulatory actions on regions involved in motivated behavior in humans are reflected in the resting state and provide insight into the underlying mechanism behind its potential to block drug-motivated behavior, in preclinical studies, and its putative effectiveness as an anti-craving/anti-relapse agent in humans.
PMCID: PMC3348615  PMID: 21333466
Baclofen; GABA B agonist; Resting baseline perfusion fMRI; Addiction; Limbic circuitry; Cerebral blood flow
23.  Dopamine transporter genotype modulation of neural responses to smoking cues: confirmation in a new cohort 
Addiction Biology  2011;16(2):308-322.
Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9-repeat allele (9-repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10-repeat allele (10/10-repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N = 26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t = 3.77). Contrasts between allelic groups revealed that 9-repeat carriers had a greater response to SCs in the VS (t = 3.12) and mOFC (t = 3.19). In separate groups, 9-repeat carriers showed increased activity in the VS (t = 5.47) and mOFC (T = 4.96), while no increases were observed in 10-repeats. Subjective reports of craving correlated with increased activity in reward-related structures including the extended amygdala, insula and post-central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT-genotype dependent (r = 0.63–0.96). In secondary analyses, we found that The Fagerström Test for Nicotine Dependence scores correlated with enhanced SC-induced perfusion in 10/10-repeats in the insula, mOFC, medial temporal and superior frontal gyri (r = 0.50–0.82), while correlations were absent in 9-repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs.
PMCID: PMC3348624  PMID: 21299752
Addiction; dopamine transporter; genetic variability; neuroimaging; relapse vulnerability; smoking cues
24.  DAT Genotype Modulates Brain and Behavioral Responses Elicited by Cigarette Cues 
Neuropsychopharmacology  2008;34(3):717-728.
We previously demonstrated differential activation of the mesocorticolimbic reward circuitry in response to cigarette cues independent of withdrawal. Despite robust effects, we noted considerable individual variability in brain and subjective responses. As dopamine (DA) is critical for reward and its predictive signals, genetically driven variation in DA transmission may account for the observed differences. Evidence suggests that a variable number of tandem repeats (VNTRs) polymorphism in the DA transporter (DAT) SLC6A3 gene may influence DA transport. Brain and behavioral responses may be enhanced in probands carrying the 9-repeat allele. To test this hypothesis, perfusion fMR images were acquired during cue exposure in 19 smokers genotyped for the 40 bp VNTR polymorphism in the SLC6A3 gene. Contrasts between groups revealed that 9-repeat (9-repeats) had a greater response to smoking (vs nonsmoking) cues than smokers homozygous for the 10-repeat allele (10/10-repeats) bilaterally in the interconnected ventral striatal/pallidal/orbitofrontal cortex regions (VS/VP/OFC). Activity was increased in 9-repeats and decreased in 10/10-repeats in the VS/VP/OFC (p<0.001 for all analyses). Brain activity and craving was strongly correlated in 10/10-repeats in these regions and others (anterior cingulate, parahippocampal gyrus, and insula; r2 = 0.79–0.86, p<0.001 in all regions). Alternatively, there were no significant correlations between brain and behavior in 9-repeats. There were no differences in cigarette dependence, demographics, or resting baseline neural activity between groups. These results provide evidence that genetic variation in the DAT gene contributes to the neural and behavioral responses elicited by smoking cues.
PMCID: PMC3348625  PMID: 18704100
fMRI; dopamine transporter; gene; smoking; reward; cue
25.  Test-Retest Reliability of Arterial Spin Labeling with Common Labeling Strategies 
To compare the test-retest reproducibility of pseudo-continuous arterial spin labeling (ASL) with pulsed (PASL) and continuous (CASL) ASL.
Materials and methods
Twelve healthy subjects were scanned on a 3.0T scanner with PASL, CASL and pCASL. Scans were repeated within-session, after 1 hour and after 1 week to assess reproducibility at different scan intervals.
Comparison of within-subject coefficients of variation (wsCV) demonstrated high within-session reproducibility (i.e. low wsCV) for CASL-based methods (gray matter (GM) wsCV for pCASL: 3.5% ± 0.02%, CASL: 4.1% ± 0.07%) compared to PASL (wsCV: 7.5% ± 0.06%), due to the higher signal-to-noise ratio (SNR) associated with continuous labeling, evident in the 20% gain in temporal SNR and 58% gain in raw SNR for pCASL relative to PASL. At the one week scan interval, comparable reproducibility between PASL (GM wsCV 9.2% ± 0.12%) and pCASL (GM wsCV 8.5% ± 0.14%) was observed, indicating the dominance of physiological fluctuations.
Although all three approaches are capable of measuring cerebral blood flow within a few minutes of scanning, the high precision and SNR of pCASL, with its insensitivity to vessel geometry, make it an appealing method for future ASL application studies.
PMCID: PMC3069716  PMID: 21448961
magnetic resonance imaging; cerebral blood flow; arterial spin labeling; reproducibility; repeatability; pCASL

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