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1.  Abnormal Activity-Dependent Brain Lactate and Glutamate+Glutamine Responses in Panic Disorder 
Biological psychiatry  2013;73(11):1111-1119.
Background
Prior evidence suggests panic disorder (PD) is characterized by neurometabolic abnormalities, including increased brain lactate responses to neural activation. Increased lactate responses could reflect a general upregulation of metabolic responses to neural activation. However, prior studies in PD have not measured activity-dependent changes in brain metabolites other than lactate. Here we examine activity-dependent changes in both lactate and glutamate plus glutamine (glx) in PD.
Methods
Twenty-one PD patients (13 remitted, 8 symptomatic) and 12 healthy volunteers were studied. A single-voxel, J-difference, magnetic resonance spectroscopy editing sequence was used to measure lactate and glx changes in visual cortex induced by visual stimulation.
Results
PD patients had significantly greater activity-dependent increases in brain lactate than healthy volunteers. The differences were significant for both remitted and symptomatic PD patients, who did not differ from each other. Activity-dependent changes in glx were significantly smaller in PD patients than in healthy volunteers. The temporal correlation between lactate and glx changes was significantly stronger in control subjects than in PD patients.
Conclusions
The novel demonstration that glx responses are diminished and temporally decoupled from lactate responses in PD contradicts the model of a general upregulation of activity-dependent brain metabolic responses in PD. The increase in activity-dependent brain lactate accumulation appears to be a trait feature of PD. Given the close relationship between lactate and pH in the brain, the findings are consistent with a model of brain metabolic and pH dysregulation associated with altered function of acid-sensitive fear circuits contributing to trait vulnerability in PD.
doi:10.1016/j.biopsych.2012.12.015
PMCID: PMC3636170  PMID: 23332354
agoraphobia; anxiety disorders; lactic acid; acid-sensing; glutamatergic; neuroenergetics; monocarboxylate transporters
2.  Behavioral regulation in methamphetamine abusers: An fMRI study 
Psychiatry research  2012;211(3):234-238.
Background
The goal of this study was to extend our previous findings of abnormal prefrontal function in methamphetamine (MA) abusers and controls and to link the imaging data to behavioral, demographic and drug use variables.
Methods
We employed a fast-event related fMRI design to examine trial to trial reaction time (RT) adjustments in 30 MA abusers and 30 controls. A variant of the Stroop task was employed to measure influence of response conflict on RT, including the level of trial-to-trial RT adjustments seen after conflict trials.
Results
Compared to control subjects, MA abusers exhibited reduced RT adjustments and reduced activation in the prefrontal cortex (PFC) after conflict trials. RT adjustment correlated negatively with PFC brain activity in the MA group, while a trend for a positive correlation was observed in controls. No correlations were observed between task performance or brain activity and age, education or drug use variables.
Conclusions
These data support our previous findings that the ability to adapt a behavioral response based on prior experience is compromised in MA abusers. Interestingly, these impairments do not appear to be linked to drug use patterns or to educational levels.
doi:10.1016/j.pscychresns.2012.10.003
PMCID: PMC3594424  PMID: 23149023
Methamphetamine; prefrontal; cognitive control; fMRI; imaging
3.  Subclinical Cerebral Edema in Children With Diabetic Ketoacidosis Randomized to 2 Different Rehydration Protocols 
Pediatrics  2013;131(1):e73-e80.
OBJECTIVE:
Previous studies show that vasogenic cerebral edema (CE) occurs during diabetic ketoacidosis (DKA) treatment in children, but the role of intravenous fluids in contributing to CE is unclear. We used magnetic resonance diffusion weighted imaging to quantify subclinical CE in children with DKA randomized to 2 intravenous fluid regimens.
METHODS:
Children with DKA were randomized to receive fluids at a more rapid rate (n = 8) or a slower rate (n = 10), with all other aspects of DKA treatment kept identical. Children underwent diffusion weighted imaging 3 to 6 hours and 9 to 12 hours after beginning DKA treatment and after recovery from DKA (≥72 hours after beginning treatment). We calculated brain apparent diffusion coefficient (ADC) values as the average of measurements in the basal ganglia, thalamus, frontal white matter, and hippocampus and determined the mean brain ADC value during DKA treatment by averaging data from the 3- to 6-hour and 9- to 12-hour measurements. The difference in mean brain ADC between DKA treatment and postrecovery was used as an index of the severity of CE during DKA treatment.
RESULTS:
Mean brain ADC values during DKA treatment were significantly higher than postrecovery values, consistent with vasogenic CE (842 ± 38 vs 800 ± 41×10–6 mm2/second, P = .002). We did not detect significant differences in ADC elevation in children treated with more rapid versus slower rehydration (β coefficient 0.11 for 1 SD change in ADC, 95% confidence interval: –0.91 to 1.13).
CONCLUSIONS:
ADC changes during DKA treatment (reflective of vasogenic CE) do not appear to be substantially affected by the rate of intravenous fluid administration.
doi:10.1542/peds.2012-1049
PMCID: PMC3529948  PMID: 23230065
diabetic ketoacidosis; MRI; diffusion weighted imaging; cerebral edema; cerebral injury
4.  Real-Time Magnetic Resonance Imaging (MRI) during Active Wrist Motion—Initial Observations 
PLoS ONE  2013;8(12):e84004.
Background
Non-invasive imaging techniques such as magnetic resonance imaging (MRI) provide the ability to evaluate the complex anatomy of bone and soft tissues of the wrist without the use of ionizing radiation. Dynamic instability of wrist – occurring during joint motion – is a complex condition that has assumed increased importance in musculoskeletal medicine. The objective of this study was to develop an MRI protocol for evaluating the wrist during continuous active motion, to show that dynamic imaging of the wrist is realizable, and to demonstrate that the resulting anatomical images enable the measurement of metrics commonly evaluated for dynamic wrist instability.
Methods
A 3-Tesla “active-MRI” protocol was developed using a bSSFP sequence with 475 ms temporal resolution for continuous imaging of the moving wrist. Fifteen wrists of 10 asymptomatic volunteers were scanned during active supination/pronation, radial/ulnar deviation, “clenched-fist”, and volarflexion/dorsiflexion maneuvers. Two physicians evaluated distal radioulnar joint (DRUJ) congruity, extensor carpi ulnaris (ECU) tendon translation, the scapholunate (SL) interval, and the SL, radiolunate (RL) and capitolunate (CL) angles from the resulting images.
Results
The mean DRUJ subluxation ratio was 0.04 in supination, 0.10 in neutral, and 0.14 in pronation. The ECU tendon was subluxated or translated out of its groove in 3 wrists in pronation, 9 wrists in neutral, and 11 wrists in supination. The mean SL interval was 1.43 mm for neutral, ulnar deviation, radial deviation positions, and increased to 1.64 mm during the clenched-fist maneuver. Measurement of SL, RL and CL angles in neutral and dorsiflexion was also accomplished.
Conclusion
This study demonstrates the initial performance of active-MRI, which may be useful in the investigation of dynamic wrist instability in vivo.
doi:10.1371/journal.pone.0084004
PMCID: PMC3877133  PMID: 24391865
5.  Associations between vascular risk factors, carotid atherosclerosis and cortical volume and thickness in older adults 
Background and Purpose
To investigate whether the Framingham Cardiovascular Risk Profile (FCRP) and carotid artery intima-media thickness (CIMT) are associated with cortical volume and thickness.
Methods
Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3T and 4T MRI at three sites. Freesurfer (v5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of FCRP and CIMT with cortical volume and thickness
Results
152 subjects (82 men) were aged 78 (±7) years old, 94 had a CDR of 0, 58 had a clinical dementia rating (CDR) of 0.5 and the mean mini-mental status examination (MMSE) was 28 ± 2. FCRP score was inversely associated with total gray matter (GM) volume, parietal and temporal GM volume (adjusted p<0.04). FCRP was inversely associated with parietal and total cerebral GM thickness (adjusted p<0.03). CIMT was inversely associated with thickness of parietal GM only (adjusted p=0.04). Including history of myocardial infarction or stroke and radiologic evidence of brain infarction, or apoE genotype did not alter relationships with FCRP or CIMT.
Conclusions
Increased cardiovascular risk was associated with reduced GM volume and thickness in regions also affected by Alzheimer’s disease (AD), independent of infarcts and apoE genotype. These results suggest a “double hit” toward developing dementia when someone with incipient AD also has high cardiovascular risk.
doi:10.1161/STROKEAHA.112.659722
PMCID: PMC3732460  PMID: 22984010
Framingham cardiovascular risk profile; carotid intima media thickness; gray matter; cortical volume; cortical thickness; atrophy
6.  Increased Rate of Amygdala Growth in Children Aged 2 to 4 Years With Autism Spectrum Disorders 
Archives of general psychiatry  2012;69(1):53-61.
Context
Precocious amygdala enlargement is commonly observed in young children with autism. However, the age at which abnormal amygdala enlargement begins and the relative growth trajectories of the amygdala and total brain remain unclear.
Objective
To determine whether the rate of amygdala growth is abnormal and disproportionate to total brain growth in very young children with autism spectrum disorders (ASDs).
Design
Longitudinal structural magnetic resonance imaging study.
Setting
Neuroimaging and diagnostic assessments were performed at an academic medical center. Participants were recruited from the community.
Participants
Baseline scans were acquired in 132 boys (85 with ASD and 47 control subjects with typical development [TD]; mean age, 37 months). Longitudinal magnetic resonance images were acquired in 70 participants (45 with ASD and 25 TD controls) 1 year later.
Main Outcome Measure
Amygdala volumes and total cerebral volumes (TCVs) were evaluated at both time points, and 1-year growth rates were calculated.
Results
The amygdala was larger in children with ASD at both time points, but the magnitude of enlargement was greater at time 2. The TCV was also enlarged in the children with ASD by the same magnitude at both time points. When we controlled for TCV, amygdala enlargement remained significant at both time points. The rate of amygdala growth during this 1-year interval was faster in children with ASD than in TD controls. The rate of TCV growth did not differ between groups. Post hoc exploratory analyses revealed 3 patterns of amygdala and TCV growth rates in the ASD group.
Conclusions
Disproportionate amygdala enlargement is present by 37 months of age in ASD. The amygdala continues to grow at an increased rate, but substantial heterogeneity exists in amygdala and TCV growth patterns. Future studies aimed at clinical characterization of different growth patterns could have implications for choice and outcomes of treatment and behavioral therapy.
doi:10.1001/archgenpsychiatry.2011.145
PMCID: PMC3632313  PMID: 22213789
7.  Comment Regarding Increased Striatal Glutamate in Schizophrenia 
Neuropsychopharmacology  2012;37(4):1067-1068.
doi:10.1038/npp.2011.180
PMCID: PMC3280647  PMID: 22327901
8.  Volumetric Correlates of Spatiotemporal Working and Recognition Memory Impairment in Aged Rhesus Monkeys 
Cerebral Cortex (New York, NY)  2010;21(7):1559-1573.
Spatiotemporal and recognition memory are affected by aging in humans and macaque monkeys. To investigate whether these deficits are coupled with atrophy of memory-related brain regions, T1-weighted magnetic resonance images were acquired and volumes of the cerebrum, ventricles, prefrontal cortex (PFC), calcarine cortex, hippocampus, and striatum were quantified in young and aged rhesus monkeys. Subjects were tested on a spatiotemporal memory procedure (delayed response [DR]) that requires the integrity of the PFC and a medial temporal lobe-dependent recognition memory task (delayed nonmatching to sample [DNMS]). Region of interest analyses revealed that age inversely correlated with striatal, dorsolateral prefrontal cortex (dlPFC), and anterior cingulate cortex volumes. Hippocampal volume predicted acquisition of the DR task. Striatal volume correlated with DNMS acquisition, whereas total prefrontal gray matter, prefrontal white matter, and dlPFC volumes each predicted DNMS accuracy. A regional covariance analysis revealed that age-related volumetric changes could be captured in a distributed network that was coupled with declining performance across delays on the DNMS task. This volumetric analysis adds to growing evidence that cognitive aging in primates arises from region-specific morphometric alterations distributed across multiple memory-related brain systems, including subdivisions of the PFC.
doi:10.1093/cercor/bhq210
PMCID: PMC3116736  PMID: 21127015
age-related memory impairment; medial temporal lobe; MRI; prefrontal cortex; rhesus monkey
9.  Atypical Developmental Trajectory of Functionally Significant Cortical Areas in Children with Chromosome 22q11.2 Deletion Syndrome 
Human brain mapping  2011;33(1):213-223.
Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder associated with neurocognitive impairments. This article focuses on the cortical gyrification changes that are associated with the genetic disorder in 6–15-year-old children with 22q11.2DS, when compared with a group of age-matched typically developing (TD) children. Local gyrification index (lGI; Schaer et al. [2008]: IEEE Trans Med Imaging 27:161–170) was used to characterize the cortical gyrification at each vertex of the pial surface. Vertex-wise statistical analysis of lGI differences between the two groups revealed cortical areas of significant reduction in cortical gyrification in children with 22q11.2DS, which were mainly distributed along the medial aspect of each hemisphere. To gain further insight into the developmental trajectory of the cortical gyrification, we examined age as a factor in lGI changes over the 6–15 years of development, within and across the two groups of children. Our primary results pertaining to the developmental trajectory of cortical gyrification revealed cortical regions where the change in lGI over the 6–15 years of age was significantly modulated by diagnosis, implying an atypical development of cortical gyrification in children with 22q11.2DS, when compared with the TD children. Significantly, these cortical areas included parietal structures that are associated, in typical individuals, with visuospatial, attentional, and numerical cognition tasks in which children with 22q11.2DS show impairments.
doi:10.1002/hbm.21206
PMCID: PMC3212617  PMID: 21416559
22q11.2DS; development; cortex; gyrification; impairment
10.  Extended findings of Brain Metabolite Normalization in MA-Dependent Subjects Across Sustained Abstinence: A Proton MRS Study 
Drug and alcohol dependence  2010;113(2-3):133-138.
Objective
The goal of the present study was to extend our previous findings on long-term methamphetamine (MA) use and drug abstinence on brain metabolite levels in an expanded group of MA-dependent individuals.
Methods
Seventeen MA abusers with sustained drug abstinence (1 year to 5 years), 30 MA abusers with short-term drug abstinence (1 month to 6 months) and 24 non-substance using controls were studied using MR spectroscopy (MRS). MRS measures of NAA/Cr, Cho/Cr and Cho/NAA were obtained in the anterior cingulate cortex (ACC) and in the primary visual cortex (PVC).
Results
ACC-Cho/NAA values were abnormally high in the short-term abstinent group compared to controls [F(1,52)=18.76, p<0.0001]. No differences were observed between controls and the long-term abstinent group [F(1,39)=0.97, p=0.97]. New evidence of lower ACC-NAA/Cr levels were observed in the short-term abstinent MA abusers compared to controls [F(1,52)=23.05, p<0.0001] and long-term abstinent MA abusers [F(1,45)=7.06, p=0.01]. No differences were observed between long-term abstinent MA abusers and controls [F(1,39)=0.48, p=0.49].
Conclusions
The new findings of relative NAA/Cr normalization across periods of abstinence suggest that adaptive changes following cessation of MA abuse may be broader than initially thought. These changes may contribute to some degree of normalization of neuronal function in the ACC.
doi:10.1016/j.drugalcdep.2010.07.015
PMCID: PMC3000435  PMID: 20739127
Methamphetamine; imaging; MRS; NAA; Cho; anterior cingulate cortex
11.  Sub-Regional Hippocampal Injury is Associated with Fornix Degeneration in Alzheimer’s Disease 
We examined in vivo evidence of axonal degeneration in association with neuronal pathology in Alzheimer’s disease (AD) through analysis of fornix microstructural integrity and measures of hippocampal subfield atrophy. Based on known anatomical topography, we hypothesized that the local thickness of subiculum and CA1 hippocampus fields would be associated with fornix integrity, reflecting an association between AD-related injury to hippocampal neurons and degeneration of associated axon fibers. To test this hypothesis, multi-modal imaging, combining measures of local hippocampal radii with diffusion tensor imaging (DTI), was applied to 44 individuals clinically diagnosed with AD, 44 individuals clinically diagnosed with mild cognitive impairment (MCI), and 96 cognitively normal individuals. Fornix microstructural degradation, as measured by reduced DTI-based fractional anisotropy (FA), was prominent in both MCI and AD, and was associated with reduced hippocampal volumes. Further, reduced fornix FA was associated with reduced anterior CA1 and antero-medial subiculum thickness. Finally, while both lesser fornix FA and lesser hippocampal volume were associated with lesser episodic memory, only the hippocampal measures were significant predictors of episodic memory in models including both hippocampal and fornix predictors. The region-specific association between fornix integrity and hippocampal neuronal death may provide in vivo evidence for degenerative white matter injury in AD: axonal pathology that is closely linked to neuronal injury.
doi:10.3389/fnagi.2012.00001
PMCID: PMC3323836  PMID: 22514534
hippocampus; fornix; fractional anisotropy; Alzheimer’s disease; mild cognitive impairment
12.  Integrating Conflict Detection and Attentional Control Mechanisms 
Journal of cognitive neuroscience  2010;23(9):2211-2221.
Human behavior involves monitoring and adjusting performance to meet established goals. Performance-monitoring systems that act by detecting conflict in stimulus and response processing have been hypothesized to influence cortical control systems to adjust and improve performance. Here we used fMRI to investigate the neural mechanisms of conflict monitoring and resolution during voluntary spatial attention. We tested the hypothesis that the ACC would be sensitive to conflict during attentional orienting and influence activity in the frontoparietal attentional control network that selectively modulates visual information processing. We found that activity in ACC increased monotonically with increasing attentional conflict. This increased conflict detection activity was correlated with both increased activity in the attentional control network and improved speed and accuracy from one trial to the next. These results establish a long hypothesized interaction between conflict detection systems and neural systems supporting voluntary control of visual attention.
doi:10.1162/jocn.2010.21595
PMCID: PMC3142580  PMID: 21126158
13.  Impaired Prefrontal Cortical Function and Disrupted Adaptive Cognitive Control in Methamphetamine Abusers: An fMRI Study 
Biological psychiatry  2009;65(8):706-709.
Background
Methamphetamine (MA) abuse is associated with neurotoxicity to frontostriatal brain regions with concomitant deleterious effects on cognitive processes. Deficits in behavioral control are thought to be one contributing factor to the sustainment of addictive behaviors in chronic MA abuse.
Methods
In order to examine patterns of behavioral control relevant to addiction, we employed a fast-event related fMRI design to examine trial to trial reaction time (RT) adjustments in 12 chronic MA abusers who met DSM-IV criteria for MA dependence and 16 non-substance abusing controls. A variant of the Stroop task was employed to contrast the groups on error rates, RT Stroop conflict effect and the level of trial-to-trial adjustments seen after incongruent trials.
Results
The MA abusers exhibited reduced RT adjustments along with reduced activation in the right prefrontal cortex compared to controls on conditions that measured the ability to use exposure to conflict situations (i.e., conflict trials) to regulate behavior. MA abusers did not differ from controls on accuracy rates or within-trial Stroop conflict effects.
Conclusions
The observed deficits in trial to trial RT adjustments suggest that the ability to adapt a behavioral response based on prior experience may be compromised in MA abusers. Such adjustments are critical to everyday functioning and deficits in modifying behavior based on prior events may reflect a key deficit that contributes to maladaptive drug seeking behavior.
doi:10.1016/j.biopsych.2008.11.026
PMCID: PMC2678684  PMID: 19136097
Methamphetamine; prefrontal; attention; fMRI; imaging
15.  Cognitive Control and White Matter Callosal Microstructure in Methamphetamine Dependent Subjects: A DTI Study 
Biological psychiatry  2008;65(2):122-128.
Background
Methamphetamine (MA) abuse causes damage to structures within the human cerebrum, with particular susceptibility to white matter (WM). Abnormalities have been reported in anterior regions with less evidence of changes in posterior regions. MA abusers have also shown deficits on attention tests that measure response conflict and cognitive control.
Methods
We examined cognitive control using a computerized measure of the Stroop selective attention task and indices of WM microstructure obtained from diffusion tensor imaging (DTI) in the callosal genu and splenium of 37 currently abstinent MA abusers and 17 non-substance abusing controls. Measurements of Fractional Anisotropy (FA), apparent diffusion coefficient (ADC) of callosal fibers and diffusion tensor eigenvalues were obtained in all subjects.
Results
The MA abusers exhibited greater Stroop reaction time interference (i.e., reduced cognitive control) [p=.04] compared to controls. After correcting for multiple comparisons, FA within the genu correlated significantly with measures of cognitive control in the MA abusers [p=.04, bonferroni corrected] but not in controls [p=.26]. Group differences in genu, but not splenium, FA were trend significant [p=.09].
Conclusions
MA abuse appears to alter anterior callosal WM microstructure with less evidence of change within posterior callosal WM microstructure. DTI indices within the genu, but not splenium, correlated with measures of cognitive control in chronic MA abusers.
doi:10.1016/j.biopsych.2008.08.004
PMCID: PMC2633131  PMID: 18814867
methamphetamine; diffusion tensor imaging; corpus callosum; cognitive control; Stroop; substance abuse
16.  Brain lactate responses during visual stimulation in fasting and hyperglycemic subjects: A 1.5 Tesla 1H-MRS study 
Psychiatry research  2006;148(1):47-54.
Proton magnetic resonance spectroscopy (1H-MRS) studies showing increased lactate during neural activation support a broader role for lactate in brain energy metabolism than was traditionally recognized. 1H-MRS measures of brain lactate responses have been used to study regional brain metabolism in clinical populations. This study examined whether variations in blood glucose influence the lactate response to visual stimulation in the visual cortex. Six subjects were scanned twice, receiving either saline or 21% glucose intravenously. Using 1H-MRS at 1.5 Tesla with a long echo time (TE=288 msec), the lactate doublet was visible at 1.32 ppm in the visual cortex of all subjects. Lactate increased significantly from resting to visual stimulation. Hyperglycemia had no effect on this increase. The order of the slice-selective gradients for defining the spectroscopy voxel had a pronounced effect on the extent of contamination by signal originating outside the voxel. The results of this preliminary study demonstrate a method for observing a consistent activity-stimulated increase in brain lactate at 1.5 Tesla and show that variations in blood glucose across the normal range have little effect on this response.
doi:10.1016/j.pscychresns.2006.02.004
PMCID: PMC1851693  PMID: 17020804
lactic acid; glycolysis; glycolytic; aerobic; PRESS

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