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1.  Glutamate Imaging (GluCEST) Lateralizes Epileptic Foci in Non-Lesional Temporal Lobe Epilepsy 
Science translational medicine  2015;7(309):309ra161.
When neuroimaging reveals a brain lesion, drug-resistant epilepsy patients show better outcomes after resective surgery than do the one-third of drug resistant epilepsy patients who have normal brain MRIs. We applied a glutamate imaging method, GluCEST (Glutamate Chemical Exchange Saturation Transfer), to patients with non-lesional temporal lobe epilepsy (TLE) based on conventional MRI. GluCEST correctly lateralized the temporal lobe seizure focus on visual and quantitative analysis in all patients. MR spectra, available in a subset of patients and controls, corroborated the GluCEST findings. Hippocampal volumes were not significantly different between hemispheres. GluCEST allowed for high-resolution functional imaging of brain glutamate and has potential to identify the epileptic focus in patients previously deemed non-lesional. This method may lead to improved clinical outcomes for temporal lobe epilepsy as well as other localization-related epilepsies.
doi:10.1126/scitranslmed.aaa7095
PMCID: PMC4710355  PMID: 26468323
2.  Decomposing cerebral blood flow MRI into functional and structural components: A non-local approach based on prediction 
NeuroImage  2014;105:156-170.
We present RIPMMARC (Rotation Invariant Patch-based Multi-Modality Analysis aRChitecture), a flexible and widely applicable method for extracting information unique to a given modality from a multi-modal data set. We use RIPMMARC to improve interpretation of arterial spin labeling (ASL) perfusion images by removing the component of perfusion that is predicted by the underlying anatomy. Using patch-based, rotation invariant descriptors derived from the anatomical image, we learn a predictive relationship between local neuroanatomical structure and the corresponding perfusion image. This relation allows us to produce an image of perfusion that would be predicted given only the underlying anatomy and a residual image that represents perfusion information that cannot be predicted by anatomical features. Our learned structural features are significantly better at predicting brain perfusion than tissue probability maps, which are the input to standard partial volume correction techniques. Studies in test-retest data show that both the anatomically predicted and residual perfusion signal are highly replicable for a given subject. In a pediatric population, both the raw perfusion and structurally predicted images are tightly linked to age throughout adolescence throughout the brain. Interestingly, the residual perfusion also shows a strong correlation with age in select regions including the hippocampi (corr= 0.38, p-value < 10−6), precuneus (corr= −0.44, p < 10−5), and combined default mode network regions (corr= −0.45, p < 10−8) that is independent of global anatomy-perfusion trends. This finding suggests that there is a regionally heterogeneous pattern of functional specialization that is distinct from that of cortical structural development.
doi:10.1016/j.neuroimage.2014.10.052
PMCID: PMC4356637  PMID: 25449745
3.  Recommended Implementation of Arterial Spin Labeled Perfusion MRI for Clinical Applications: A consensus of the ISMRM Perfusion Study Group and the European Consortium for ASL in Dementia 
Magnetic resonance in medicine  2014;73(1):102-116.
This article provides a summary statement of recommended implementations of arterial spin labeling (ASL) for clinical applications. It is a consensus of the ISMRM Perfusion Study Group and the European ‘ASL in Dementia’ consortium, both of whom met to reach this consensus in October 2012 in Amsterdam. Although ASL continues to undergo rapid technical development, we believe that current ASL methods are robust and ready to provide useful clinical information, and that a consensus statement on recommended implementations will help the clinical community to adopt a standardized approach. In this article we describe the major considerations and tradeoffs in implementing an ASL protocol, and provide specific recommendations for a standard approach. Our conclusions are that, as an optimal default implementation we recommend: pseudo-continuous labeling, background suppression, a segmented 3D readout without vascular crushing gradients, and calculation and presentation of both label/control difference images and cerebral blood flow in absolute units using a simplified model.
doi:10.1002/mrm.25197
PMCID: PMC4190138  PMID: 24715426
Arterial Spin Labeling; Perfusion; Cerebral Blood Flow
4.  In Vivo Measurement of Glutamate Loss is Associated with Synapse Loss in a Mouse Model of Tauopathy 
NeuroImage  2014;101:185-192.
Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodegenerative diseases such as Alzheimer’s disease (AD) and several other tauopathies. The current method for measuring glutamate in vivo is using proton magnetic resonance spectroscopy (1H MRS), although it has poor spatial resolution and weak sensitivity to glutamate changes. In this study, we sought to measure the effect of tau pathology on glutamate levels throughout the brain of a mouse model of tauopathy using a novel magnetic resonance imaging (MRI) technique. We employed glutamate chemical exchange saturation transfer (GluCEST) imaging, which has been previously validated as a complimentary method for measuring glutamate levels with several important advantages over conventional 1H MRS. We hypothesized that the regional changes in glutamate levels would correlate with histological measurements of pathology including pathological tau, synapse and neuron loss. Imaging and spectroscopy were carried out on tau transgenic mice with the P301S mutation (PS19, n=9) and their wild-type littermates (WT, n=8), followed by immunohistochemistry of their brain tissue. GluCEST imaging resolution allowed for sub-hippocampal analysis of glutamate. Glutamate was significantly decreased by 29% in the CA sub-region of the PS19 hippocampus, and by 15% in the thalamus, where synapse loss was also measured. Glutamate levels and synapse density remained high in the dentate gyrus sub-region of the hippocampus, where neurogenesis is known to occur. The further development of GluCEST imaging for preclinical applications will be valuable, as therapies are being tested in mouse models of tauopathy.
doi:10.1016/j.neuroimage.2014.06.067
PMCID: PMC4303593  PMID: 25003815
Glutamate; synapse loss; tauopathy; dentate gyrus; neurogenesis; chemical exchange saturation transfer
5.  Evaluation of Segmented 3D Acquisition Schemes for Whole-brain High-resolution Arterial Spin Labeling at 3T 
NMR in biomedicine  2014;27(11):1387-1396.
Recent technical developments have significantly increased the SNR of arterial spin labeled (ASL) perfusion MRI. Despite this, typical ASL acquisitions still employ large voxel sizes. The purpose of this work was to implement and evaluate two ASL sequences optimized for whole-brain high-resolution perfusion imaging, combining pseudo-continuous ASL (pCASL), background suppression (BS) and 3D segmented readouts, with different in-plane k-space trajectories.
Identical labeling and BS pulses were implemented for both sequences. Two segmented 3D readout schemes with different in-plane trajectories were compared: Cartesian (3D GRASE), and spiral (3D RARE Stack-Of-Spirals). High-resolution perfusion images (2×2×4 mm3) were acquired in fifteen young healthy volunteers with the two ASL sequences at 3T. The quality of the perfusion maps was evaluated in terms of SNR and gray-to-white matter contrast. Point-spread-function simulations were carried out to assess the impact of readout differences on the effective resolution.
The combination of pCASL, in-plane segmented 3D readouts and BS provided high-SNR high-resolution ASL perfusion images of the whole brain. Although both sequences produced excellent image quality, the 3D RARE Stack-Of-Spirals readout yielded higher temporal and spatial SNR than 3D GRASE (Spatial SNR = 8.5 ± 2.8 and 3.7 ± 1.4; Temporal SNR = 27.4 ± 12.5 and 15.6 ± 7.6, respectively) and decreased through-plane blurring due to its inherent oversampling of the central k-space region, its reduced effective TE and shorter total readout time, at the expense of a slight increase in the effective in-plane voxel size.
doi:10.1002/nbm.3201
PMCID: PMC4233410  PMID: 25263944
Perfusion imaging; arterial spin labeling; spiral imaging; high-resolution ASL; segmented readouts; cerebral blood flow
6.  Lifestyle Modification in Blood Pressure Study II (LIMBS): Study protocol of a randomized controlled trial assessing the efficacy of a 24 week structured yoga program versus lifestyle modification on blood pressure reduction 
Contemporary clinical trials  2013;36(1):32-40.
Hypertension is a major public health issue affecting 68 million adults in the United States. Lifestyle modifications including complementary therapies such as the movement based mind body practice of yoga have become increasingly popular in the United States and have been considered as a potential alternative to medication in blood pressure reduction. We completed a pilot study in 2009 which showed meaningful decreases in 24-hour ambulatory blood pressure readings after a 12 week period of yoga participation. Based on data from our pilot study we are now completing The Lifestyle Modification and Blood Pressure Study (LIMBS II) which is a phase 2 randomized controlled trial designed to determine the effects of yoga therapy and enhanced lifestyle modification on lowering blood pressure in pre-hypertensive and stage 1 hypertensive subjects. Using 24-hour ambulatory blood pressure monitoring, LIMBS II aims to compare the effects on blood pressure reduction in subjects randomized for 24 weeks to one of the three following groups: yoga therapy versus blood pressure education program (sodium restriction and walking program) versus a combination program that involves components of both groups. LIMBS II will also examine the impact that changes in blood pressure have on cerebral blood flow. If successful the LIMBS study will determine if yoga therapy combined with enhanced lifestyle modification will result in clinically meaningful decreases in blood pressure and thus can be implemented as an alternative to drug therapy for patients with prehypertension and stage 1 hypertension.
doi:10.1016/j.cct.2013.05.010
PMCID: PMC4593488  PMID: 23721984
hypertension; yoga; prehypertension; functional MRI; phase 2 clinical randomized trial
7.  Age-Related Differences in Working Memory Deficits During Nicotine Withdrawal 
Addiction biology  2013;19(5):907-917.
Nicotine withdrawal is associated with subtle working memory deficits that predict subsequent relapse. We examined the neural substrates underlying these processes in treatment-seeking smokers, and explored the moderating influence of age on abstinence-induced alterations in brain activity and performance. Sixty-three smokers participated in two blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) scans while performing a visual N-back task on two separate occasions: smoking as usual and after 24 hours of biochemically confirmed abstinence (order counterbalanced). Abstinence (versus smoking) led to reduced accuracy, slower median correct response time, and reduced BOLD signal change in the 3 a priori regions of interest (ROIs): medial frontal/cingulate gyrus and right and left dorsolateral prefrontal cortex. Significant age x session effects were found for BOLD signal change in all three regions, as well as for withdrawal and craving; for all measures, abstinence effects were attenuated in smokers aged >50 years compared to those < 50 years old. These results suggest that abstinence effects on neurocognitive function may be more pronounced for younger smokers, and may indicate a new avenue for research exploring mechanisms underlying age differences in smoking cessation success.
doi:10.1111/adb.12051
PMCID: PMC3701751  PMID: 23496760
Addiction; cognition; fMRI; nicotine; withdrawal; age
9.  Neural Correlates of Post-Conventional Moral Reasoning: A Voxel-Based Morphometry Study 
PLoS ONE  2015;10(6):e0122914.
Going back to Kohlberg, moral development research affirms that people progress through different stages of moral reasoning as cognitive abilities mature. Individuals at a lower level of moral reasoning judge moral issues mainly based on self-interest (personal interests schema) or based on adherence to laws and rules (maintaining norms schema), whereas individuals at the post-conventional level judge moral issues based on deeper principles and shared ideals. However, the extent to which moral development is reflected in structural brain architecture remains unknown. To investigate this question, we used voxel-based morphometry and examined the brain structure in a sample of 67 Master of Business Administration (MBA) students. Subjects completed the Defining Issues Test (DIT-2) which measures moral development in terms of cognitive schema preference. Results demonstrate that subjects at the post-conventional level of moral reasoning were characterized by increased gray matter volume in the ventromedial prefrontal cortex and subgenual anterior cingulate cortex, compared with subjects at a lower level of moral reasoning. Our findings support an important role for both cognitive and emotional processes in moral reasoning and provide first evidence for individual differences in brain structure according to the stages of moral reasoning first proposed by Kohlberg decades ago.
doi:10.1371/journal.pone.0122914
PMCID: PMC4454660  PMID: 26039547
10.  Continuous Optical Monitoring of Cerebral Hemodynamics during Head-of-Bed Manipulation in Brain-Injured Adults 
Neurocritical care  2014;20(3):443-453.
Introduction
Head-of-bed manipulation is commonly performed in the neurocritical care unit to optimize cerebral blood flow (CBF), but its effects on CBF are rarely measured. This pilot study employs a novel, non-invasive instrument combining two techniques, diffuse correlation spectroscopy (DCS) for measurement of CBF and near-infrared spectroscopy (NIRS) for measurement of cerebral oxy- and deoxy-hemoglobin concentrations, to monitor patients during head-of-bed lowering.
Methods
Ten brain-injured patients and ten control subjects were monitored continuously with DCS and NIRS while the head-of-bed was positioned first at 30° and then at 0°. Relative CBF (rCBF) and concurrent changes in oxy- (ΔHbO2), deoxy- (ΔHb), and total-hemoglobin concentrations (ΔTHC) from left/right frontal cortices were monitored for 5 minutes at each position. Patient and control response differences were assessed.
Results
rCBF, ΔHbO2, and ΔTHC responses to head lowering differed significantly between brain-injured patients and healthy controls (P<0.02). For patients, rCBF changes were heterogeneous, with no net change observed in the group average (0.3% ± 28.2%, P=0.938). rCBF increased in controls (18.6% ± 9.4%, P<0.001). ΔHbO2, ΔHb, and ΔTHC increased with head lowering in both groups, but to a larger degree in brain-injured patients. rCBF correlated moderately with changes in cerebral perfusion pressure (R=0.40, P<0.001), but not intracranial pressure.
Conclusion
DCS/NIRS detected differences in CBF and oxygenation responses of brain-injured patients versus controls during head-of-bed manipulation. This pilot study supports the feasibility of continuous bedside measurement of cerebrovascular hemodynamics with DCS/NIRS and provides the rationale for further investigation in larger cohorts.
doi:10.1007/s12028-013-9849-7
PMCID: PMC3883971  PMID: 23653267
Diffuse correlation spectroscopy; Near-infrared spectroscopy; Diffuse optical spectroscopy; Head-of-bed; Cerebral blood flow; Neurocritical care; Cerebral hemodynamics
11.  Optical Bedside Monitoring of Cerebral Blood Flow in Acute Ischemic Stroke Patients during Head of Bed Manipulation 
Background and Purpose
A primary goal of acute ischemic stroke (AIS) management is to maximize perfusion in the affected region and surrounding ischemic penumbra. However, interventions to maximize perfusion, such as flat head-of-bed (HOB) positioning, are currently prescribed empirically. Bedside monitoring of cerebral blood flow (CBF) allows the effects of interventions such as flat HOB to be monitored, and may ultimately be used to guide clinical management.
Methods
Cerebral perfusion was measured during head of bed (HOB) manipulations in 17 patients with unilateral acute ischemic stroke affecting large cortical territories in the anterior circulation. Simultaneous measurements of frontal CBF and arterial flow velocity were performed with diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound, respectively. Results were analyzed in the context of available clinical data and a previous study.
Results
Frontal CBF, averaged over the patient cohort, decreased by 17% (p=0.034) and 15% (p=0.011) in the ipsilesional and contralesional hemispheres, respectively, when HOB was changed from flat to 30°. Significant (cohort-averaged) changes in blood velocity were not observed. Individually, varying responses to HOB manipulation were observed, including paradoxical increases in CBF with increasing HOB angle. Clinical features, stroke volume, and distance to the optical probe could not explain this paradoxical response.
Conclusions
A lower HOB angle results in an increase in cortical CBF without a significant change in arterial flow velocity in AIS, but there is variability across patients in this response. Bedside CBF monitoring with DCS provides a potential means to individualize interventions designed to optimize CBF in AIS.
doi:10.1161/STROKEAHA.113.004116
PMCID: PMC4006296  PMID: 24652308
stroke; perfusion; near-infrared spectroscopy; cerebral hemodynamics; head-of-bed manipulation
12.  Design and methods of the NiCK study: neurocognitive assessment and magnetic resonance imaging analysis of children and young adults with chronic kidney disease 
BMC Nephrology  2015;16:66.
Background
Chronic kidney disease is strongly linked to neurocognitive deficits in adults and children, but the pathophysiologic processes leading to these deficits remain poorly understood. The NiCK study (Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease) seeks to address critical gaps in our understanding of the biological basis for neurologic abnormalities in chronic kidney disease. In this report, we describe the objectives, design, and methods of the NiCK study.
Design/methods
The NiCK Study is a cross-sectional cohort study in which neurocognitive and neuroimaging phenotyping is performed in children and young adults, aged 8 to 25 years, with chronic kidney disease compared to healthy controls. Assessments include (1) comprehensive neurocognitive testing (using traditional and computerized methods); (2) detailed clinical phenotyping; and (3) multimodal magnetic resonance imaging (MRI) to assess brain structure (using T1-weighted MRI, T2-weighted MRI, and diffusion tensor imaging), functional connectivity (using functional MRI), and blood flow (using arterial spin labeled MRI). Primary analyses will examine group differences in neurocognitive testing and neuroimaging between subjects with chronic kidney disease and healthy controls. Mechanisms responsible for neurocognitive dysfunction resulting from kidney disease will be explored by examining associations between neurocognitive testing and regional changes in brain structure, functional connectivity, or blood flow. In addition, the neurologic impact of kidney disease comorbidities such as anemia and hypertension will be explored. We highlight aspects of our analytical approach that illustrate the challenges and opportunities posed by data of this scope.
Discussion
The NiCK study provides a unique opportunity to address key questions about the biological basis of neurocognitive deficits in chronic kidney disease. Understanding these mechanisms could have great public health impact by guiding screening strategies, delivery of health information, and targeted treatment strategies for chronic kidney disease and its related comorbidities.
doi:10.1186/s12882-015-0061-1
PMCID: PMC4419485  PMID: 25924831
Neurocognition; Neuropsychological; Chronic kidney disease; Hypertension; Cerebrovascular disease; Cardiovascular disease; Neuroimaging; Magnetic resonance imaging; Children; Adolescents; Adults
13.  Altered salience network connectivity predicts macronutrient intake after sleep deprivation 
Scientific Reports  2015;5:8215.
Although insufficient sleep is a well-recognized risk factor for overeating and weight gain, the neural mechanisms underlying increased caloric (particularly fat) intake after sleep deprivation remain unclear. Here we used resting-state functional magnetic resonance imaging and examined brain connectivity changes associated with macronutrient intake after one night of total sleep deprivation (TSD). Compared to the day following baseline sleep, healthy adults consumed a greater percentage of calories from fat and a lower percentage of calories from carbohydrates during the day following TSD. Subjects also exhibited increased brain connectivity in the salience network from the dorsal anterior cingulate cortex (dACC) to bilateral putamen and bilateral anterior insula (aINS) after TSD. Moreover, dACC-putamen and dACC-aINS connectivity correlated with increased fat and decreased carbohydrate intake during the day following TSD, but not during the day following baseline sleep. These findings provide a potential neural mechanism by which sleep loss leads to increased fat intake.
doi:10.1038/srep08215
PMCID: PMC4314629  PMID: 25645575
14.  Direct Visualization of Short Transverse Relaxation Time Component (ViSTa) 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.06.047.
White matter of the brain has been demonstrated to have multiple relaxation components. Among them, the short transverse relaxation time component (T2 < 40 ms; T2* < 25 ms at 3T) has been suggested to originate from myelin water whereas long transverse relaxation time components have been associated with axonal and/or interstitial water. In myelin water imaging, T2 or T2* signal decay is measured to estimate myelin water fraction based on T2 or T2* differences among the water components. This method has been demonstrated to be sensitive to demyelination in the brain but suffers from low SNR and image artifacts originating from ill-conditioned multi-exponential fitting. In this study, a novel approach that selectively acquires short transverse relaxation time signal is proposed. The method utilizes a double inversion RF pair to suppress a range of long T1 signal. This suppression leaves short T2* signal, which has been suggested to have short T1, as the primary source of the image. The experimental results confirms that after suppression of long T1 signals, the image is dominated by short T2* in the range of myelin water, allowing us to directly visualize the short transverse relaxation time component in the brain. Compared to conventional myelin water imaging, this new method of direct visualization of short relaxation time component (ViSTa) provides high quality images. When applied to multiple sclerosis patients, chronic lesions show significantly reduced signal intensity in ViSTa images suggesting sensitivity to demyelination.
doi:10.1016/j.neuroimage.2013.06.047
PMCID: PMC3815972  PMID: 23796545
background suppression; multiple water components in white matter; myelin water imaging; T1 of myelin water; T1 filter
15.  Prefrontal Transcranial Direct Current Stimulation Alters Activation and Connectivity in Cortical and Subcortical Reward Systems: A tDCS-fMRI Study 
Human brain mapping  2014;35(8):3673-3686.
Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique used both experimentally and therapeutically to modulate regional brain function. However, few studies have directly measured the aftereffects of tDCS on brain activity or examined changes in task-related brain activity consequent to prefrontal tDCS. To investigate the neural effects of tDCS, we collected fMRI data from 22 human subjects, both at rest and while performing the Balloon Analog Risk Task (BART), before and after true or sham transcranial direct current stimulation. TDCS decreased resting blood perfusion in orbitofrontal cortex and the right caudate and increased task-related activity in the right dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in response to losses but not wins or increasing risk. Network analysis showed that whole-brain connectivity of the right ACC correlated positively with the number of pumps subjects were willing to make on the BART, and that tDCS reduced connectivity between the right ACC and the rest of the brain. Whole-brain connectivity of the right DLPFC also correlated negatively with pumps on the BART, as prior literature would suggest. Our results suggest that tDCS can alter activation and connectivity in regions distal to the electrodes.
doi:10.1002/hbm.22429
PMCID: PMC4107089  PMID: 24453107
Balloon Analog Risk Task; fMRI; network analysis; resting-state connectivity; tDCS
16.  Reproducibility of functional network metrics and network structure: A comparison of task-related BOLD, resting ASL with BOLD contrast, and resting cerebral blood flow 
Network analysis is an emerging approach to functional connectivity in which the brain is construed as a graph, and its connectivity and information processing estimated by mathematical characterizations of graphs. There has been little to no work examining the reproducibility of network metrics derived from different types of functional magnetic resonance imaging data (e.g., resting versus task-related, or pulse sequences other than standard BOLD), or of measures of network structure at levels other than summary statistics. Here we take up these questions, comparing the reproducibility of graphs derived from resting arterial spin-labeling (ASL) perfusion fMRI to those derived from BOLD scans collected while the participant was performing a task. We also examine the reproducibility of the anatomical connectivity implied by the graph by investigating test-retest consistency of the graphs’ edges. We compare two measures of graph-edge consistency both within versus between subjects and across data types. We find a dissociation in the reproducibility of network metrics, with metrics from resting data most reproducible at lower frequencies and metrics from task-related data most reproducible at higher frequencies; that same dissociation is not recapitulated, however, in network structure, for which the task-related data is most consistent at all frequencies. Implications for the practice of network analysis are discussed.
doi:10.3758/s13415-013-0181-7
PMCID: PMC3778152  PMID: 23813017
17.  High Resolution Mapping of Modafinil Induced Changes in Glutamate Level in Rat Brain 
PLoS ONE  2014;9(7):e103154.
Modafinil is marketed in the United States for the treatment of narcolepsy and daytime somnolence due to shift-work or sleep apnea. Investigations of this drug in the treatment of cocaine and nicotine dependence in addition to disorders of executive function are also underway. Modafinil has been known to increase glutamate levels in rat brain models. Proton magnetic resonance spectroscopy (1HMRS) has been commonly used to detect the glutamate (Glu) changes in vivo. In this study, we used a recently described glutamate chemical exchange saturation transfer (GluCEST) imaging technique to measure Modafinil induced regional Glu changes in rat brain and compared the results with Glu concentration measured by single voxel 1HMRS. No increases in either GluCEST maps or 1HMRS were observed after Modafinil injection over a period of 5 hours. However, a significant increase in GluCEST (19±4.4%) was observed 24 hours post Modafinil administration, which is consistent with results from previous biochemical studies. This change was not consistently seen with 1HMRS. GluCEST mapping allows regional cerebral Glu changes to be measured and may provide a useful clinical biomarker of Modafinil effects for the management of patients with sleep disorders and addiction.
doi:10.1371/journal.pone.0103154
PMCID: PMC4113382  PMID: 25068408
18.  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
19.  Comparison of 2D and 3D single-shot ASL perfusion fMRI sequences 
NeuroImage  2012;0:662-671.
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.
doi:10.1016/j.neuroimage.2012.10.087
PMCID: PMC3587033  PMID: 23142069
arterial spin labeling; readout sequence; background suppression; spiral imaging; 3D GRASE; EPI
20.  Interictal cortical hyperresponsiveness in migraine is directly related to the presence of aura 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1177/0333102412474503
PMCID: PMC3658127  PMID: 23359872
Migraine with aura; cortical hyperresponsiveness; hyperexcitability; visual sensitivity
21.  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.
doi:10.1371/journal.pone.0089948
PMCID: PMC3962327  PMID: 24657999
22.  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.
doi:10.1038/mp.2012.139
PMCID: PMC3957329  PMID: 23070072
23.  Acute baclofen diminishes resting baseline blood flow to limbic structures: A perfusion fMRI study 
Drug and alcohol dependence  2012;125(0):60-66.
Background
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.
Methods
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.
Results
Acute baclofen diminished mOFC, amygdala, and ventral anterior insula CBF without causing sedation (family-wise error corrected at p = 0.001).
Conclusions
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.
doi:10.1016/j.drugalcdep.2012.03.016
PMCID: PMC3770303  PMID: 22513380
Addiction; fMRI; GABA B agonist; Cerebral blood flow; Smoking cessation; Treatment; Baclofe
24.  Effects of Varenicline on Smoking Cue–Triggered Neural and Craving Responses 
Archives of general psychiatry  2011;68(5):516-526.
Context
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.
Design
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.
Setting
Center for the Study of Addictions, University of Pennsylvania, Philadelphia.
Subjects
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.”
Results
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).
Conclusions
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.
doi:10.1001/archgenpsychiatry.2010.190
PMCID: PMC3743240  PMID: 21199958
25.  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.
doi:10.1007/s00429-012-0385-6
PMCID: PMC3743241  PMID: 22302433
voxel based morphometry; T1-weighted structural scan; perfusion fMRI; cerebral blood flow; gray matter; neurogenesis

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