United States Department of Veterans Affairs
MIRECC Centers

VISN 19 MIRECC Specialties: Brain and Biology

 

Veteran's Integrated Service Network (VISN) 19 Mental Illness Research Education Clinical Center

Research, Education and Clinical Care Related to
Brain & Biology

 

Research Projects

Creatine Augmentation in Veterans with SSRI-Resistant Major Depression
Research Team: Douglas Kondo MD, Kristen Fiedler BS, Elliott Bueler
Based on the results of prior clinical trials, the research team is conducting a study to learn if the nutritional supplement CREATINE is an effective adjunctive (i.e. add-on) treatment for SSRI-resistant Major Depression.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Pilot Study to Determine the Forward Rate Constant for Creatine Kinase by Magnetization Transfer Magnetic Resonance Spectroscopy (MRS) in Healthy Human Brain and Bipolar Disorder
Research Team: Perry Renshaw MD PhD, Kristen Fiedler BS, Elliott Bueler
We propose to use a type of brain scan to allow us to measure the concentration of certain brain chemicals in individuals with bipolar disorder.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Recent Presentations Related to Brain & Biology

TBI and Aggression: Forensic Neuropsychiatric Evaluation
10/28/11
Hal S. Wortzel, MD 
Appleton CBOC
Keywords: Assessment, Brain & Biology, TBI
PowerPoint | PDF 
Neuroimaging For Forensic Psychologists
9/23/11
Hal S. Wortzel, MD 
Denver CARES
Keywords: Brain & Biology, Incarcerated Veterans
PowerPoint | PDF 
Disrobing Associated with Epileptic Seizures and Forensic Implications
7/6/11
Hal S. Wortzel, MD 
University of Colorado School of Medicine Behavioral Neurology & Neuropsychiatry Case Conference
Keywords: Brain & Biology, Incarcerated Veterans
PowerPoint | PDF 
Neurotoxin Exposure in Forensic Assessment: “Look what my meds made me do…” - A Case of Alleged Mefloquine-Induced Criminal Behavior
10/23/10
Hal S. Wortzel, MD
41st Annual Meeting of the American Academy of Psychiatry and the Law, Tucson, AZ
Keywords: Brain & Biology, Incarcerated Veterans
PowerPoint | PDF
Review of Clinical Neuroscience for Forensic Psychiatry: Forensic Neuropsychiatric Assessment of Cognition
10/22/10
Hal S. Wortzel, MD
41st Annual Meeting of the American Academy of Psychiatry and the Law, Tucson, AZ
Keywords: Brain & Biology, Incarcerated Veterans
PowerPoint | PDF
Forensic Applications of Diffusion Tensor Imaging in Mild Traumatic Brain Injury:  Current Status
10/21/10
Hal S. Wortzel, MD
41st Annual Meeting of the American Academy of Psychiatry and the Law, Tucson, AZ
Keywords: Brain & Biology, Incarcerated Veterans, TBI
PowerPoint | PDF

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Recent Publications (since 2009)

Agarawal, N., Port, J. D., Bazzocchi, M., & Renshaw, P. F. (2010). Update on the use of MR for assessment and diagnosis of psychiatric diseases. Radiology, 255(1), 23-41.
The lack of quantitative objective measures of psychiatric diseases such as anxiety and depression is one reason that the causative factors of psychiatric diseases remain obscure. The fact that human behavior is complex and cannot be easily tested in laboratories or reproduced in animal models further complicates our understanding of psychiatric diseases. During the past 3 decades, several magnetic resonance (MR)-based tools such as MR morphometry, diffusion-tensor imaging, functional MR imaging, and MR spectroscopy have yielded findings that provide tangible evidence of the neurobiologic manifestations of psychiatric diseases. In this article, we summarize major MR findings of schizophrenia, bipolar disorder, anxiety disorders, and attention deficit-hyperactivity disorder as examples to illustrate the promise that MR techniques hold for not only revealing the neurobiological underpinnings of psychiatric disorders but also enhancing our understanding of healthy human behavior. However, many radiologists remain skeptical about the diagnostic value of MR in psychiatric disease. Many inconsistent, noncomparable reports in the literature contribute to this skepticism. The aims of this article are to (a) illustrate the most reported MR findings of major psychiatric disorders such as schizophrenia, mood disorders, anxiety disorders, and attention deficit-hyperactivity disorder; (b) inform radiologists of the potential roles of MR imaging in psychiatric imaging research; and (c) discuss several confounding factors in the design and interpretation of MR imaging findings in psychiatry.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Agarawal, N., Sung, Y. H., Jensen, J. E., daCunha, G., Harper, D. Olson, D., & Renshaw, P. F. (2010). Short-term administration of uridine increases brain membrane phospholipid precursors in healthy adults: A 31-phosphorus magnetic resonance spectroscopy study at 4T. Bipolar Disorders, 12(8), 825-833.
OBJECTIVES: Altered metabolism of membrane phospholipids has been implicated in bipolar disorder. In humans, uridine is an important precursor of cytidine diphosphate (CDP)-choline, which plays a critical role in phospholipid synthesis and is currently being evaluated as a potential treatment for bipolar depression. METHODS: A total of 17 healthy males (mean age ± SD: 32.73 ± 7.2 years; range: 21.8-46.4 years) were enrolled in this study. Subjects underwent a 31-phosphorus magnetic resonance spectroscopy ((31) P-MRS) acquisition at baseline and then again after seven days of either 2 g of uridine or placebo administration. A two-dimensional chemical shift imaging (31) P-MRS acquisition collected spectral data from a 4 × 4 cluster of voxels acquired in the axial plane encompassing the subcortical structures as well as frontal-temporal cortical gray and white matter. The slab thickness was 3 cm and the approximate total volume of brain sampled was 432 cm(3) . The spectra obtained were analyzed using a fully automated in-house fitting algorithm. A population-averaged generalized estimating equation was used to evaluate changes both in phosphomonoesters (PME) [phosphocholine (PCho) and phosphoethanolamine (PEtn)] and phosphodiesters (PDE) [glycerophosphocholine (GPCho) and glycerophosphethanolamine (GPEtn)]. Metabolite ratios were reported with respect to the total integrated (31) P resonance area. RESULTS: The uridine group had significantly increased total PME and PEtn levels over the one-week period [6.32 and 7.17% for PME and PEtn, respectively (p<0.001)]. Other metabolite levels such as PCho, PDE, GPEtn and GPCho showed no significant changes following either uridine or placebo (all p>0.05). CONCLUSIONS: This is the first study to report a direct effect of uridine on membrane phospholipid precursors in healthy adults using (31) P-MRS. Sustained administration of uridine appears to increase PME in healthy subjects. Further investigation is required to clarify the effects of uridine in disorders with altered phospholipid metabolism such as bipolar disorder.
Keywords: Brain & Biology
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Anderson, J. S., Dhatt, H., Ferguson, M. A., Lopez-Larson, M., Schrock, L., House, P., Yurgelun-Todd, D. (2011). Functional connectivity targeting for deep brain stimulation in essential tremor. American Journal of Neuroradiology.
BACKGROUND AND PURPOSE: Deep brain stimulation of the thalamus has become a valuable treatment for medication-refractory essential tremor, but current targeting provides only a limited ability to account for individual anatomic variability. We examined whether functional connectivity measurements among the motor cortex, superior cerebellum, and thalamus would allow discrimination of precise targets useful for image guidance of neurostimulator placement. MATERIALS AND METHODS: Resting BOLD images (8 minutes) were obtained in 58 healthy adolescent and adult volunteers. Regions of interest were identified from an anatomic atlas and a finger movement task in each subject in the primary motor cortex and motor activation region of the bilateral superior cerebellum. Correlation was measured in the time series of each thalamic voxel with the 4 seeds. An analogous procedure was performed on a single subject imaged for 10 hours to constrain the time needed for single-subject optimization of thalamic targets. RESULTS: Mean connectivity images from 58 subjects showed precisely localized targets within the expected location of the ventral intermediate nucleus of the thalamus, within a single voxel of currently used deep brain stimulation anatomic targets. These targets could be mapped with single-voxel accuracy in a single subject with 3 hours of imaging time, though targets were reproduced in different locations for the individual than for the group averages. CONCLUSIONS: Interindividual variability likely exists in optimal placement for thalamic deep brain stimulation targeting of the cerebellar thalamus for essential tremor. Individualized thalamic targets can be precisely estimated for image guidance with sufficient imaging time.
Keywords: Brain & Biology
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Anderson, J. S., Druzgal, T. J., Lopez-Larson, M. P., Jeong, E. K., Desai, K., Yurgelun-Todd, D. (2011). Network anticorrelations, global regression, and phase-shifted soft tissue correction. Human Brain Mapping, 32(6), 919-934.
Synchronized low-frequency BOLD fluctuations are observed in dissociable large-scale, distributed networks with functional specialization. Two such networks, referred to as the task-positive network (TPN) and the task-negative network (TNN) because they tend to be active or inactive during cognitively demanding tasks, show reproducible anticorrelation of resting BOLD fluctuations after removal of the global brain signal. Because global signal regression mandates that anticorrelated regions to a given seed region must exist, it is unclear whether such anticorrelations are an artifact of global regression or an intrinsic property of neural activity. In this study, we demonstrate from simulated data that spurious anticorrelations are introduced during global regression for any two networks as a linear function of their size. Using actual resting state data, we also show that both the TPN and TNN become anticorrelated with the orbits when soft tissues are included in the global regression algorithm. Finally, we propose a technique using phase-shifted soft tissue regression (PSTCor) that allows improved correction of global physiological artifacts without global regression that shows improved anatomic specificity to global regression but does not show significant network anticorrelations. These results imply that observed anticorrelations between TNN and TPN may be largely or entirely artifactual in the resting state. These results also imply that differences in network anticorrelations attributed to pathophysiological or behavioral states may be due to differences in network size or recruitment rather than actual anticorrelations.
Keywords: Brain & Biology
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Anderson, J. S., Ferguson, M. A., Lopez-Larson, M., & Yurgelun-Todd, D. (2010). Topographic maps of multisensory attention. Proceedings of the National Academy of Science, 107(46), 20110-20114.
The intraparietal sulcus (IPS) region is uniquely situated at the intersection of visual, somatosensory, and auditory association cortices, ideally located for processing of multisensory attention. We examined the internal architecture of the IPS region and its connectivity to other regions in the dorsal attention and cinguloinsular networks using maximal connectivity clustering. We show with resting state fMRI data from 58 healthy adolescent and young adult volunteers that points of maximal connectivity between the IPS and other regions in the dorsal attention and cinguloinsular networks are topographically organized, with at least seven maps of the IPS region in each hemisphere. Distinct clusters of the IPS exhibited differential connectivity to auditory, visual, somatosensory, and default mode networks, suggesting local specialization within the IPS region for different sensory modalities. In an independent task activation paradigm with 16 subjects, attention to different sensory modalities showed similar functional specialization within the left intraparietal sulcus region. The default mode network, in contrast, did not show a topographical relationship between regions in the network, but rather maximal connectivity in each region to a single central cluster of the other regions. The topographical architecture of multisensory attention may represent a mechanism for specificity in top-down control of attention from dorsolateral prefrontal and lateral orbitofrontal cortex and may represent an organizational unit for multisensory representations in the brain.
Keywords: Brain & Biology
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Anderson, J. S., Ferguson, M. A., Lopez-Larson, M., & Yurgelun-Todd, D. (2011). Reproducibility of single-subject functional connectivity measurements. American Journal of Neuroradiology, 32(3), 548-555.
BACKGROUND AND PURPOSE: Measurements of resting-state functional connectivity have increasingly been used for characterization of neuropathologic and neurodevelopmental populations. We collected data to characterize how much imaging time is necessary to obtain reproducible quantitative functional connectivity measurements needed for a reliable single-subject diagnostic test. MATERIALS AND METHODS: We obtained 100 five-minute BOLD scans on a single subject, divided into 10 sessions of 10 scans each, with the subject at rest or while watching video clips of cartoons. These data were compared with resting-state BOLD scans from 36 healthy control subjects by evaluating the correlation between each pair of 64 small spheric regions of interest obtained from a published functional brain parcellation. RESULTS: Single-subject and group data converged to reliable estimates of individual and population connectivity values proportional to 1 / sqrt(n). Dramatic improvements in reliability were seen by using ≤25 minutes of imaging time, with smaller improvements for additional time. Functional connectivity "fingerprints" for the individual and population began diverging at approximately 15 minutes of imaging time, with increasing reliability even at 4 hours of imaging time. Twenty-five minutes of BOLD imaging time was required before any individual connections could reliably discriminate an individual from a group of healthy control subjects. A classifier discriminating scans during which our subject was resting or watching cartoons was 95% accurate at 10 minutes and 100% accurate at 15 minutes of imaging time. CONCLUSIONS: An individual subject and control population converged to reliable different functional connectivity profiles that were task-modulated and could be discriminated with sufficient imaging time.
Keywords: Brain & Biology
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Bracken, B. K., Jensen, J. E., Prescot, A. P., Cohen, B. M., Renshaw, P. F., & Ongur, D. (2011). Brain metabolite concentrations across cortical regions in healthy adults. Brain Research, 1369, 89-94.
Magnetic resonance spectroscopy (MRS) can provide in vivo information about metabolite levels across multiple brain regions. This study used MRS to examine concentrations of N-acetylaspartate (NAA), a marker of neuronal integrity and function, and choline (Cho), which is related to the amount of cell membrane per unit volume, in anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) in healthy individuals. Data were drawn from two experiments which examined glutamatergic and GABAergic signaling in schizophrenia and bipolar disorder. After controlling for gray matter percentages, NAA/creatine (Cr) was 18% higher in POC than in ACC (p<0.001); Cho/Cr was 46% lower in POC than in ACC (p<0.001). There was an effect of study (p<0.001 for both metabolites), but no region by study interaction (NAA p=0.101, Cho p=0.850). Since NAA is localized to the intracellular space, these data suggest that ACC neuronal compartment is reduced as compared with POC, or that there is a lower concentration of NAA per cell in the ACC than POC, or both. Since elevated Cho suggests more cell membrane per unit volume, reduced NAA in ACC appears to be coupled with increases in overall cell membrane compartment. These findings are consistent with a number of previous studies using proton MRS which found increasing NAA and decreasing Cho moving caudally, and with postmortem anatomical studies which found neurons in more widely spaced bundles in ACC when compared to parietal and occipital cortices. MRS may be a useful tool for studying physical properties of the living human brain.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Brenner LA. Neuropsychological and neuroimaging findings in traumatic brain injury and post-traumatic stress disorder. Dialogues Clin Neurosci. 2011;13(3):311-23. Review.
Advances in imaging technology, coupled with military personnel returning home from Iraq and Afghanistan with traumatic brain injury (TBI) and/or post-traumatic stress disorder (PTSD), have increased interest in the neuropsychology and neurobiology of these two conditions. There has been a particular focus on differential diagnosis. This paper provides an overviev of findings regarding the neuropsychological and neurobiological underpinnings of TBI and for PTSD. A specific focus is on assessment using neuropsychological measures and imaging techniques. Challenges associated with the assessment of individuals with one or both conditions are also discussed. Although use of neuropsychological and neuroimaging test results may assist with diagnosis and treatment planning, further work is needed to identify objective biomarkers for each condition. Such advances would be expected to facilitate differential diagnosis and implementation of best treatment practices.
Keywords: Brain & Biology, PTSD, Traumatic Brain Injury (TBI)
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Brenner, L. A., Ladley-O'Brien, S. E., Harwood, J. E. F., Filley, C. M., Kelly, J. P., Homaifar, B. Y., et al. (Adler, L. E.). (2009). An exploratory study of neuroimaging, neurological, and neuropsychological findings in traumatic brain injury and post traumatic stress disorder. Military Medicine, 174(4), 347-352.
Seventy-two veterans with traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), or both participated in assessment procedures to evaluate between group differences. Half the sample was randomly selected for magnetic resonance imaging (MRI). Neurologic examinations were conducted using the Neurologic Rating Scale (NRS). Neuropsychological measures included the Paced Auditory Serial Addition Test (PASAT), Rey Auditory Verbal Learning Test (RAVLT), Conners' Continuous Performance Test II (CPT II), and Halstead Impairment Index (HII) including the Booklet Category Test (BCT). Data were analyzed using linear regression. Participants with moderate/ severe TBI were significantly more likely to have trauma-related imaging findings, and more severe TBI predicted lower scores on the NRS. No significant between-group differences were identified on the HII, PASAT, RAVLT, or CPT II. TBI group performance was significantly better on the BCT. More severe TBI predicted abnormal imaging findings and lower NRS scores. Hypothesized between-group differences on neuropsychological measures were not supported.
Keywords: Brain & Biology, PTSD, Traumatic Brain Injury (TBI)
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Filley, C. M., Kozora, E., Brown, M. S., Miller, D. E., West, S. G., Arciniegas, D. B., et al. (2009). White matter microstructure and cognition in non-neuropsychiatric systemic lupus erythematosus. Cognitive and Behavioral Neurology, 22(1), 38-44.
OBJECTIVE: This study examined white matter (WM) structural and metabolic alterations in relation to cognition in patients with non-neuropsychiatric systemic lupus erythematosus (non-NPSLE). BACKGROUND: SLE can produce cognitive impairment even without overt neuropsychiatric features, but the pathogenesis of this dysfunction is not well understood. Our preliminary study of non-NPSLE found evidence correlating cognitive impairment with increased choline/creatine (Ch/Cr) in frontal lobe WM. METHODS: Subjects included 60 non-NPSLE patients and 24 controls. Magnetic resonance imaging and magnetic resonance spectroscopy were performed, and a battery of neuropsychologic tests was administered. Structural and metabolic measures were analyzed and correlated with neuropsychologic data. RESULTS: No significant differences were found in total brain, gray matter, and WM volumes, or in frontal WM N-acetylaspartate/Cr, but the non-NPSLE group had significantly increased Ch/Cr in frontal WM. A WM cognitive score (WMCS) that included the Paced Auditory Serial Addition Task, Letter Fluency, and Animal Naming was found to correlate with total WM volume, and lower WMCS correlated with higher left frontal WM Ch/Cr. CONCLUSIONS: Non-NPSLE patients had frontal WM metabolic changes that correlated with cognitive impairment, whereas no cerebral atrophy or WM axonal damage was evident. These data confirm and extend our previous observations supporting the role of microstructural WM changes in the cognitive impairment of non-NPSLE patients. The data also suggest that the WMCS may be sensitive to cognitive dysfunction from myelin damage that develops before axonal injury.
Keywords: Brain & Biology
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Forester, B. P., Berlow, Y. A., Harper, D. G., Jensen, J. E., Lange, N., Froimowitz, M. P., et al. (Renshaw, P. F.) (2010). Age-related changes in brain energetics and phospholipid metabolism. NMR in Biomedicine, 23(3),242-250.
Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus ((31)P) MRS. (31)P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21-84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (-0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using (31)P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non-demented and psychiatrically stable older adults and specifically analyzed gray-white matter differences in brain metabolism.
Keywords: Brain & Biology
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Forester, B.P., Harper, D.G., Jensen, J.E., Ravichandran, C., Jordan, B., Renshaw, P.F., & Cohen, B.M. (2009). 31Phosphorus magnetic resonance spectroscopy study of tissue specific changes in high energy phosphates before and after sertraline treatment of geriatric depression. Int J Geriatr Psychiatry, 24 (8): 788-797.
INTRODUCTION: We investigated tissue specific differences in markers of energy metabolism, including high energy phosphate compounds (beta and total NTP, PCr) and pH, in older adults with depression compared with healthy controls, before and after a 12-week treatment trial of sertraline. METHODS: Thirteen older adults, age > or =55, with Major Depressive Disorder (HAMD(17) score of > or =18) were recruited along with ten age-matched controls. The depression subjects had a pre- and post-treatment 4T (31)P-MRS scan using a three-dimensional chemical shift imaging sequence. The extracted brain images were segmented into white matter (WM), gray matter (GM) and CSF. A linear mixed effects model analyzed the effects of pre-treatment and post-treatment depression on phosphorus metabolite concentration estimates (including calculated pH and Mg(++)). RESULTS: Total tissue beta-NTP (-8%, t(18.66) = 3.50; p = 0.0024) and total tissue total NTP (-6%, t(17.41) = 2.68; p = 0.0156) were lower in subjects with geriatric depression compared with healthy controls. Total tissue levels of total-NTP changed significantly with treatment (-2%, t(14.84) = -2.47; p = 0.0259). Total NTP was reduced in the WM, but not the GM, in the pre-treatment depression group (t(51.65) = 4.02; p = 0.0002). Intracellular pH was higher in the GM of subjects with pre-treatment depression (t(1133.84) = -2.10; p = 0.0353) and decreased to approximate control levels after treatment (t(648.86) = -2.53; p = 0.0115). DISCUSSION: These findings demonstrate bioenergetic changes including tissue specific differences in (31)P-MRS metabolites in geriatric depression. Decreased white matter total NTP may reflect alterations in white matter function.
Keywords: Brain & Biology
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Forester, B. P., Streeter, C. C., Berlow, Y. A., Tian, H., Wardrop, M., Finn, C. T., et al. (Renshaw, P. F.) (2009). Brain lithium levels and effects on cognition and mood in geriatric bipolar disorder: A lithium-7 magnetic resonance spectroscopy study. American Journal of Geriatric Psychiatry, 17(1), 13-23.
OBJECTIVES: The authors investigated the relationship between brain lithium, serum lithium and age in adult subjects treated with lithium. In addition, the authors investigated the association between brain lithium and serum lithium with frontal lobe functioning and mood in a subgroup of older subjects. DESIGN: Cross-sectional assessment. SETTING: McLean Hospital's Geriatric Psychiatry Research Program and Brain Imaging Center; The Division of Psychiatry, Boston University School of Medicine. PARTICIPANTS: Twenty-six subjects, 20 to 85 years, with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-TR bipolar disorder (BD), currently treated with lithium. MEASUREMENTS: All subjects had measurements of mood (Hamilton Depression Rating Scale [HDRS] and Young Mania Rating Scale) and serum and brain lithium levels. Brain lithium levels were assessed using lithium Magnetic Resonance Spectroscopy. Ten subjects older than 50 years also had assessments of frontal lobe functioning (Stroop, Trails A and B, Wis. Card Sorting Task). RESULTS: Brain lithium levels correlated with serum lithium levels for the group as a whole. However, this relationship was not present for the group of subjects older than 50. For these older subjects elevations in brain (but not serum) lithium levels were associated with frontal lobe dysfunction and higher HDRS scores. The higher HDRS were associated with increased somatic symptoms. CONCLUSION: Frontal lobe dysfunction and elevated depression symptoms correlating with higher brain lithium levels supports conservative dosing recommendations in bipolar older adults. The absence of a predictable relationship between serum and brain lithium makes specific individual predictions about the "ideal" lithium serum level in an older adult with BD difficult.
Keywords: Brain & Biology
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Gruber, S.A., Rogowska, J., & Yurgelun-Todd, D.A. (2009) Altered affective response in marijuana smokers: and fMRI study. Drug and Alcohol Dependence, 105(1-2):139-53.
More than 94 million Americans have tried marijuana, and it remains the most widely used illicit drug in the nation. Investigations of the cognitive effects of marijuana report alterations in brain function during tasks requiring executive control, including inhibition and decision-making. Endogenous cannabinoids regulate a variety of emotional responses, including anxiety, mood control, and aggression; nevertheless, little is known about smokers' responses to affective stimuli. The anterior cingulate and amygdala play key roles in the inhibition of impulsive behavior and affective regulation, and studies using PET and fMRI have demonstrated changes within these regions in marijuana smokers. Given alterations in mood and perception often observed in smokers, we hypothesized altered fMRI patterns of response in 15 chronic heavy marijuana smokers relative to 15 non-marijuana smoking control subjects during the viewing of masked happy and fearful faces. Despite no between-group differences on clinical or demographic measures, smokers demonstrated a relative decrease in both anterior cingulate and amygdalar activity during masked affective stimuli compared to controls, who showed relative increases in activation within these regions during the viewing of masked faces. Findings indicate that chronic heavy marijuana smokers demonstrate altered activation of frontal and limbic systems while viewing masked faces, consistent with autoradiographic studies reporting high CB-1 receptor density in these regions. These data suggest differences in affective processing in chronic smokers, even when stimuli are presented below the level of conscious processing, and underscore the likelihood that marijuana smokers process emotional information differently from those who do not smoke, which may result in negative consequences.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Gruber SA, Silveri MM, Dahlgren MK, Yurgelun-Todd D. Why so impulsive? White matter alterations are associated with impulsivity in chronic marijuana smokers. Exp Clin Psychopharmacol. 2011 Jun;19(3):231-42.
Difficulty monitoring and inhibiting impulsive behaviors has been reported in marijuana (MJ) smokers; neuroimaging studies, which examined frontal systems in chronic MJ smokers, have reported alterations during inhibitory tasks. Diffusion tensor imaging (DTI) provides a quantitative estimate of white matter integrity at the microstructural level. We applied DTI, clinical ratings, and impulsivity measures to explore the hypotheses that chronic, heavy MJ smokers would demonstrate alterations in white matter microstructure and a different association between white matter measures and impulsivity relative to nonsmoking control subjects (NS). Fractional anisotropy (FA), a measure of directional coherence, and trace, a measure of overall diffusivity, were calculated for 6 locations including bilateral frontal regions in 15 chronic MJ smokers and 15 NS. Subjects completed clinical rating scales, including the Barratt Impulsivity Scale (BIS). Analyses revealed significant reductions in left frontal FA in MJ smokers relative to NS and significantly higher levels of trace in the right genu. MJ smokers also had significantly higher BIS total and motor subscale scores relative to NS, which were positively correlated with left frontal FA values. Finally, age of onset of MJ use was positively correlated with frontal FA values and inversely related to trace. These data represent the first report of significant alterations in frontal white matter tracts associated with measures of impulsivity in chronic MJ smokers. Early MJ use may result in reduced FA and increased diffusivity, which may be associated with increased impulsivity, and ultimately contribute to the initiation of MJ use or the inability to discontinue use.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Hallahan, B., Newell, J., Soares, J. C., Brambilla, P. Strakowski, S. M., Fleck, D. E., Kieseppa, T., Altshuler, L. L., Fornito, A., Malhi, G. S., McIntosh, A. M., Yurgelun-Todd, D. A., Labar, K. S., Sharma, V., MacQueen, G. M., Murray, R. M., & McDonald, C. (2011). Structural magnetic resonance imaging in bipolar disorder: An international collaborative mega-analysis of individual adult patient data. Biological Psychiatry, 69(4), 326-335.
BACKGROUND: There is substantial inconsistency in results of brain structural magnetic resonance imaging studies in adult bipolar disorder. This is likely consequent upon limited statistical power of studies together with their clinical and methodological heterogeneity. The current study was undertaken to perform an international collaborative mega-analysis of regional volumetric measurements of individual patient and healthy subject data, to optimize statistical power, detect case-control differences, assess the association of psychotropic medication usage with brain structural variation, and detect other possible sources of heterogeneity. METHODS: Eleven international research groups contributed published and unpublished data on 321 individuals with bipolar disorder I and 442 healthy subjects. We used linear mixed effects regression models to evaluate differences in brain structure between patient groups. RESULTS: Individuals with bipolar disorder had increased right lateral ventricular, left temporal lobe, and right putamen volumes. Bipolar patients taking lithium displayed significantly increased hippocampal and amygdala volume compared with patients not treated with lithium and healthy comparison subjects. Cerebral volume reduction was significantly associated with illness duration in bipolar individuals. CONCLUSIONS: The application of mega-analysis to bipolar disorder imaging identified lithium use and illness duration as substantial and consistent sources of heterogeneity, with lithium use associated with regionally specific increased brain volume.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Han DH, Renshaw PF. Bupropion in the treatment of problematic online game play in patients with major depressive disorder. J Psychopharmacol. 2011 Mar 29. [Epub ahead of print]
As one of the problematic behaviors in patients with major depressive disorder (MDD), excessive online game play (EOP) has been reported in a number of recent studies. Bupropion has been evaluated as a potential treatment for MDD and substance dependence. We hypothesized that bupropion treatment would reduce the severity of EOP as well as depressive symptoms. Fifty male subjects with comorbid EOP and MDD were randomly assigned to bupropion + education for internet use (EDU) or placebo + EDU groups. The current study consisted in a 12-week, prospective, randomized, double-blind clinical trial, including an eight-week active treatment phase and a four-week post treatment follow-up period. During the active treatment period, Young Internet Addiction Scale (YIAS) scores and the mean time of online game playing in the bupropion group were greatly reduced compared with those of the placebo group. The Beck Depression Inventory (BDI) scores in the bupropion group were also greatly reduced compared with those of the placebo group. During the four-week post-treatment follow-up period, bupropion-associated reductions in online game play persisted, while depressive symptoms recurred. Conclusively, bupropion may improve depressive mood as well as reduce the severity of EOP in patients with comorbid MDD and online game addiction.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Han, D. H., Bolo, N., Daniels, M. A., Arenella, L., Lyoo, I. K., & Renshaw, P. F. (2011). Brain activity and desire for internet video game play. Comprehesive Psychiatry, 52(1), 88-95.
OBJECTIVE: Recent studies have suggested that the brain circuitry mediating cue-induced desire for video games is similar to that elicited by cues related to drugs and alcohol. We hypothesized that desire for Internet video games during cue presentation would activate similar brain regions to those that have been linked with craving for drugs or pathologic gambling. METHODS: This study involved the acquisition of diagnostic magnetic resonance imaging and functional magnetic resonance imaging data from 19 healthy male adults (age, 18-23 years) following training and a standardized 10-day period of game play with a specified novel Internet video game, "War Rock" (K2 Network, Irvine, CA). Using segments of videotape consisting of 5 contiguous 90-second segments of alternating resting, matched control, and video game-related scenes, desire to play the game was assessed using a 7-point visual analogue scale before and after presentation of the videotape. RESULTS: In responding to Internet video game stimuli, compared with neutral control stimuli, significantly greater activity was identified in left inferior frontal gyrus, left parahippocampal gyrus, right and left parietal lobe, right and left thalamus, and right cerebellum (false discovery rate <0.05, P < .009243). Self-reported desire was positively correlated with the β values of left inferior frontal gyrus, left parahippocampal gyrus, and right and left thalamus. Compared with the general players, subjects who played more Internet video game showed significantly greater activity in right medial frontal lobe, right and left frontal precentral gyrus, right parietal postcentral gyrus, right parahippocampal gyrus, and left parietal precuneus gyrus. Controlling for total game time, reported desire for the Internet video game in the subjects who played more Internet video game was positively correlated with activation in right medial frontal lobe and right parahippocampal gyrus. DISCUSSION: The present findings suggest that cue-induced activation to Internet video game stimuli may be similar to that observed during cue presentation in persons with substance dependence or pathologic gambling. In particular, cues appear to commonly elicit activity in the dorsolateral prefrontal, orbitofrontal cortex, parahippocampal gyrus, and thalamus.
Keywords: Brain & Biology
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Han, D. H., Hwang, J. W., & Renshaw, P. F. (2010) Bupropion sustained release treatment decreases craving for video games and cue-induced brain activity in patients with Internet video game addiction. Experimental Clinical Psychopharmacology,18(4), 297-304.
Bupropion has been used in the treatment of patients with substance dependence based on its weak inhibition of dopamine and norepinephrine reuptake. We hypothesized that 6 weeks of bupropion sustained release (SR) treatment would decrease craving for Internet game play as well as video game cue-induced brain activity in patients with Internet video game addiction (IAG). Eleven subjects who met criteria for IAG, playing StarCraft (>30 hr/week), and eight healthy comparison subjects (HC) who had experience playing StarCraft (<3 days/week and <1 hr/day). At baseline and at the end of 6 weeks of bupropion SR treatment, brain activity in response to StarCraft cue presentation was assessed using 1.5 Tesla functional MRI. In addition, symptoms of depression, craving for playing the game, and the severity of Internet addiction were evaluated by Beck Depression Inventory, self-report of craving on a 7-point visual analogue scale, and Young's Internet Addiction Scale, respectively. In response to game cues, IAG showed higher brain activation in left occipital lobe cuneus, left dorsolateral prefrontal cortex, and left parahippocampal gyrus than HC. After a 6 week period of bupropion SR, craving for Internet video game play, total game play time, and cue-induced brain activity in dorsolateral prefrontal cortex were decreased in the IAG. We suggest that bupropion SR may change craving and brain activity in ways that are similar to those observed in individuals with substance abuse or dependence.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Han, D. H., Kim, Y. S., Lee, Y. S., Min, K. J., & Renshaw, P. F. (2010). Changes in cue-induced, prefrontal cortex activity with video-game play. Cyberpsychology, Behavior and Social Networking, 13(6), 655-661.
Brain responses, particularly within the orbitofrontal and cingulate cortices, to Internet video-game cues in college students are similar to those observed in patients with substance dependence in response to the substance-related cues. In this study, we report changes in brain activity between baseline and following 6 weeks of Internet video-game play. We hypothesized that subjects with high levels of self-reported craving for Internet video-game play would be associated with increased activity in the prefrontal cortex, particularly the orbitofrontal and anterior cingulate cortex. Twenty-one healthy university students were recruited. At baseline and after a 6-week period of Internet video-game play, brain activity during presentation of video-game cues was assessed using 3T blood oxygen level dependent functional magnetic resonance imaging. Craving for Internet video-game play was assessed by self-report on a 7-point visual analogue scale following cue presentation. During a standardized 6-week video-game play period, brain activity in the anterior cingulate and orbitofrontal cortex of the excessive Internet game-playing group (EIGP) increased in response to Internet video-game cues. In contrast, activity observed in the general player group (GP) was not changed or decreased. In addition, the change of craving for Internet video games was positively correlated with the change in activity of the anterior cingulate in all subjects. These changes in frontal-lobe activity with extended video-game play may be similar to those observed during the early stages of addiction.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Han, D.H., Lee, Y.S., Na, C., Ahn, J.Y., Chung, U.S., Daniels, M.A., Haws, C.A., & Renshaw, P.F. (2009). The effect of methylphenidate on internet video game play in children with attention-deficit/hyperactivity disorder. Compr Psychiatry, 50(3): 251-256.
OBJECTIVE: A number of studies about attention-deficit/hyperactivity disorder (ADHD) and Internet video game play have examined the prefrontal cortex and dopaminergic system. Stimulants such as methylphenidate (MPH), given to treat ADHD, and video game play have been found to increase synaptic dopamine. We hypothesized that MPH treatment would reduce Internet use in subjects with co-occurring ADHD and Internet video game addictions. METHODS: Sixty-two children (52 males and 10 females), drug-naive, diagnosed with ADHD, and Internet video game players, participated in this study. At the beginning of the study and after 8 weeks of treatment with Concerta (OROS methylphenidate HCl, Seoul, Korea), participants were assessed with Young's Internet Addiction Scale, Korean version (YIAS-K), Korean DuPaul's ADHD Rating Scale, and the Visual Continuous Performance Test. Their Internet usage time was also recorded. RESULTS: After 8 weeks of treatment, the YIAS-K scores and Internet usage times were significantly reduced. The changes in the YIAS-K scores between the baseline and 8-week assessments were positively correlated with the changes in total and inattention scores from the Korean DuPaul's ADHD Rating Scale, as well as omission errors from the Visual Continuous Performance Test. There was also a significant difference in the number of omission errors among non-Internet-addicted, mildly Internet addicted, and severely Internet addicted participants. DISCUSSION: We suggest that Internet video game playing might be a means of self-medication for children with ADHD. In addition, we cautiously suggest that MPH might be evaluated as a potential treatment of Internet addiction.
Keywords: Brain & Biology
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Henry, M. E., Jensen, J. E., Licata, S. C., Ravichandran, C., Butman, M. L., Shanahan, M., Lauriat, T. L., Renshaw, P. F. (2010). The acute and late CNS glutamine response to benzodiazepine challenge: a pilot pharmacokinetic study using proton magnetic resonance spectroscopy. Psychiatry Research, 184(3), 171-176.
Benzodiazepines (BZs), which are typically used as anxiolytics, act by modulating inhibitory signaling through gamma-aminobutyric acid A (GABA)(A) receptors. Functionally, the inhibitory effects of GABA may be counterbalanced by the excitatory effects of glutamate (Glu) as the two neurotransmitter systems are metabolically linked through their synthetic intermediate glutamine (Gln). The primary aim of this study was to determine whether the effects of different BZs on the GABA and Glu/Gln systems would vary according to the pharmacokinetics of the different drugs. Proton magnetic resonance spectroscopy ((1)H MRS) was used to measure GABA, Glu, and Gln levels in six healthy adult volunteers 1h and 10 h following immediate release alprazolam, extended release alprazolam, clonazepam, or placebo. Although there were no differences between 1 and 10 h when the drugs were examined individually, there was a trend level difference between the 1- and 10-h effects of BZs on Gln when the BZs were combined. In post-hoc comparisons, the difference in the Gln to creatine (Cr) ratio was 0.04 for the BZs versus placebo at 1h and 0.01 at 10h following the administration of drug (t(11)=2.49, P=0.03 1 h; t(10)=0.65, P=0.53 10 h; no correction for multiple comparisons). An increase in Gln/Cr at 1 h post-BZ is consistent with a functionally synergistic relationship between Glu/Gln and GABA in the brain. It also suggests that MRS may have sufficient sensitivity to detect acute drug effects.
Keywords: Brain & Biology
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Henry, M. E., Lauriat, T. L., Shanahan, M., Renshaw, P. F., Lyoo, I. K., Kim, J. E. (2011). Accuracy and stability of measuring GABA, glutamate, and glutamine by proton magnetic resonance spectroscopy: A phantom study at 4 Tesla. Journal of Magnetic Resonance, 208(2), 210-218.
Proton magnetic resonance spectroscopy has the potential to provide valuable information about alterations in gamma-aminobutyric acid (GABA), glutamate (Glu), and glutamine (Gln) in psychiatric and neurological disorders. In order to use this technique effectively, it is important to establish the accuracy and reproducibility of the methodology. In this study, phantoms with known metabolite concentrations were used to compare the accuracy of 2D J-resolved MRS, single-echo 30 ms PRESS, and GABA-edited MEGA-PRESS for measuring all three aforementioned neurochemicals simultaneously. The phantoms included metabolite concentrations above and below the physiological range and scans were performed at baseline, 1 week, and 1 month time-points. For GABA measurement, MEGA-PRESS proved optimal with a measured-to-target correlation of R(2)=0.999, with J-resolved providing R(2)=0.973 for GABA. All three methods proved effective in measuring Glu with R(2)=0.987 (30 ms PRESS), R(2)=0.996 (J-resolved) and R(2)=0.910 (MEGA-PRESS). J-resolved and MEGA-PRESS yielded good results for Gln measures with respective R(2)=0.855 (J-resolved) and R(2)=0.815 (MEGA-PRESS). The 30 ms PRESS method proved ineffective in measuring GABA and Gln. When measurement stability at in vivo concentration was assessed as a function of varying spectral quality, J-resolved proved the most stable and immune to signal-to-noise and linewidth fluctuation compared to MEGA-PRESS and 30 ms PRESS.
Keywords: Brain & Biology
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Hooley, J.M., Gruber, S.A., Parker, H.A., Guillamot, J., Rogowska, J., & Yurgelun-Todd, D.A. (2010). Neural Processing of Emotional Overinvolvement in Borderline Personality Disorder. The Journal of Clinical Psychiatry.
OBJECTIVE: Patients with borderline personality disorder (BPD) fare better clinically if their families are rated as being high in emotional overinvolvement, which is characterized by marked emotionality, anxious concern, and protective behavior. This is not true of patients with disorders such as schizophrenia or major depression. We used functional magnetic resonance imaging methods to explore the link between emotional overinvolvement (EOI) and better clinical outcome in BPD. Specifically, we tested the hypothesis that, unlike healthy controls or people with other psychiatric problems, people with BPD process EOI as an approach-related stimulus. METHOD: Participants with BPD (n = 13) and dysthymia (n = 10) (DSM-IV criteria for both) and healthy controls (n = 11) were imaged using a high field strength (3T) scanner while they listened to a standardized auditory stimulus consisting of either 4 neutral or 4 EOI comments. Participants also rated their mood before and after exposure to the comments. RESULTS: All participants reported increased negative mood after hearing EOI and rated the EOI comments as negative stimuli. However, after subtracting activation to neutral comments, participants with BPD showed higher activation in left prefrontal regions during EOI compared to the other groups. Increased left prefrontal activation during EOI was also correlated with clinical measures indicative of borderline pathology. Participants with dysthymia showed increased amygdala activation during EOI. This was not true for the healthy controls or participants with BPD. CONCLUSIONS: For people with BPD, EOI may be activating neural circuitry implicated in the processing of approach-related stimuli. Increased left prefrontal activation to EOI may be a vulnerability marker for BPD. These findings may also help explain why BPD patients do better clinically in high EOI family environments.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Jensen, J.E., Licata, S.C., Ongur, D., Friedman, S.D., Prescot, A.P., Henry, M.E., & Renshaw, P.F. (2009). Quantification of J-resolved proton spectra in two-dimensions with LCModel using GAMMA-simulated basis sets at 4 Tesla. NMR Biomed, 22(7): 762-769.
A two-dimensional, J-resolved magnetic resonance spectroscopic extraction approach was developed employing GAMMA-simulated, LCModel basis-sets. In this approach, a two-dimensional J-resolved (2D-JPRESS) dataset was resolved into a series of one-dimensional spectra where each spectrum was modeled and fitted with its theoretically customized LCModel template. Metabolite levels were derived from the total integral across the J-series of spectra for each metabolite. Phantoms containing physiologic concentrations of the major brain chemicals were used for validation. Varying concentrations of glutamate and glutamine were evaluated at and around their accepted in vivo concentrations in order to compare the accuracy and precision of our method with 30 ms PRESS. We also assessed 2D-JPRESS and 30 ms PRESS in vivo, in a single voxel within the parieto-occipital cortex by scanning ten healthy volunteers once and a single healthy volunteer over nine repeated measures. Phantom studies demonstrated that serial fitting of 2D-JPRESS spectra with simulated LCModel basis sets provided accurate concentration estimates for common metabolites including glutamate and glutamine. Our in vivo results using 2D-JPRESS suggested superior reproducibility in measuring glutamine and glutamate relative to 30 ms PRESS. These novel methods have clear implications for clinical and research studies seeking to understand neurochemical dysfunction. 2009 John Wiley & Sons, Ltd.
Keywords: Brain & Biology
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Jeong EK, Sung YH, Kim SE, Zuo C, Shi X, Mellon EA, Renshaw PF. Measurement of creatine kinase reaction rate in human brain using magnetization transfer image-selected in vivo spectroscopy (MT-ISIS) and a volume (31)P/(1)H radiofrequency coil in a clinical 3-T MRI system. NMR Biomed. 2010 Dec 29. [Epub ahead of print]
High-energy phosphate metabolism, which allows the synthesis and regeneration of adenosine triphosphate (ATP), is a vital process for neuronal survival and activity. In particular, creatine kinase (CK) serves as an energy reservoir for the rapid buffering of ATP levels. Altered CK enzyme activity, reflecting compromised high-energy phosphate metabolism or mitochondrial dysfunction in the brain, can be assessed using magnetization transfer (MT) MRS. MT (31)P MRS has been used to measure the forward CK reaction rate in animal and human brain, employing a surface radiofrequency coil. However, long acquisition times and excessive radiofrequency irradiation prevent these methods from being used routinely for clinical evaluations. In this article, a new MT (31)P MRS method is presented, which can be practically used to measure the CK forward reaction rate constant in a clinical MRI system employing a volume head (31)P coil for spatial localization, without contamination from the scalp muscle, and an acquisition time of 30min. Other advantages associated with the method include radiofrequency homogeneity within the regions of interest of the brain using a volume coil with image-selected in vivo spectroscopy localization, and reduction of the specific absorption rate using nonadiabatic radiofrequency pulses for MT saturation. The mean value of k(f) was measured as 0.320±0.075s(-1) from 10 healthy volunteers with an age range of 18-40 years. These values are consistent with those obtained using earlier methods, and the technique may be used routinely to evaluate energetic processes in the brain on a clinical MRI system.
Keywords: Brain & Biology
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Kaufman, M.J., Prescot, A.P., Ongur, D., Evins, A.E., Barros, T.L., Medeiros, C.L., Covell, J., Wang, L., Fava, M., & Renshaw P.F. (2009). Oral glycine administration increases brain glycine/creatine ratios in men: A proton magnetic resonance spectroscopy study. Psychiatry Res, 173(2): 143-149.
Oral high-dose glycine administration has been used as an adjuvant treatment for schizophrenia to enhance glutamate neurotransmission and mitigate glutamate system hypofunction thought to contribute to the disorder. Prior studies in schizophrenia subjects documented clinical improvements after 2 weeks of oral glycine administration, suggesting that brain glycine levels are sufficiently elevated to evoke a clinical response within that time frame. However, no human study has reported on brain glycine changes induced by its administration. We utilized a noninvasive proton magnetic resonance spectroscopy ((1)H-MRS) technique termed echo time-averaged (TEAV) (1)H-MRS, which permits noninvasive quantification of brain glycine in vivo, to determine whether 2 weeks of oral glycine administration (peak dose of 0.8 g/kg/day) increased brain glycine/creatine (Gly/Cr) ratios in 11 healthy adult men. In scans obtained 17 h after the last glycine dose, brain (Gly/Cr) ratios were significantly increased. The data indicate that it is possible to measure brain glycine changes with proton spectroscopy. Developing a more comprehensive understanding of human brain glycine dynamics may lead to optimized use of glycine site agonists and glycine transporter inhibitors to treat schizophrenia, and possibly to treat other disorders associated with glutamate system dysfunction.
Keywords: Brain & Biology
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Kaufman, R. E., Ostacher, M. J., Marks, E. H., Simon, N. M., Sachs, G. S., Jensen, J.E., et al. (Renshaw, P.F.) (2009). Brain GABA levels in patients with bipolar disorder. Progress in Neuro-psychopharmacology and Biological Psychiatry, 33, 427-434.
PURPOSE: A growing body of research supports an important role for GABA in the pathophysiology of bipolar and other mood disorders. The purpose of the current study was to directly examine brain GABA levels in a clinical sample of bipolar patients. GENERAL METHODS: We used magnetic resonance spectroscopy (MRS) to examine whole brain and regional GABA, glutamate and glutamine in 13 patients with bipolar disorder compared to a matched group of 11 healthy controls. FINDINGS: There were no significant differences in GABA, glutamate or glutamine between patients and controls. CONCLUSIONS: Further research is needed to better characterize the GABAergic and glutamatergic effects of pharmacotherapy, anxiety comorbidity and clinical state in bipolar disorder
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Killgore, W. D. S., & Yurgelun-Todd, D.A. (2010). Sex differences in cerebral responses to images of high versus low-calorie food. Neuroreport, 21, 354-358.
Men and women differ in cerebral organization and prevalence rates of eating disorders. However, no studies have yet examined sex differences in cerebral responses to the caloric content of food images. Sixteen healthy adults (eight men; eight women) underwent functional magnetic resonance imaging while viewing images of high-calorie and low-calorie foods. Compared with men, women showed significantly greater activation to calorie-rich foods within dorsolateral, ventrolateral, and ventromedial prefrontal cortex, middle/posterior cingulate, and insula. Men failed to show greater activation in any cortical region compared with women, although amygdala responses were greater in men at a more liberal threshold. When viewing high-calorie food images, women seem more responsive than men within cortical regions involved in behavioral control and self-referential cognition.
Keywords: Brain & Biology
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Killgore, W. D. S., & Yurgelun-Todd, D.A. (2009). Cerebral correlates of amygdala responses during non-conscious perception of facial affect in adolescent and pre-adolescent children. Journal of Cognitive Neuroscience, iFirst, 1-11.
During nonconscious perception of facial affect, healthy adults commonly activate a right-lateralized pathway comprising the superior colliculus, pulvinar, and amygdala. Whether this system is fully developed prior to adulthood is unknown. Twenty-three healthy adolescents underwent functional magnetic resonance imaging (fMRI) while viewing fearful, angry, and happy faces, backward masked by neutral faces. Left amygdala activation differed among the three affects, showing reductions to masked anger and increases to masked fear and happy faces. During masked fear, left amygdala activation correlated positively with extrastriate cortex and temporal poles and negatively with precuneus and middle cingulate gyrus. Responses of the left amygdala to masked anger correlated positively with right parahippocampal gyrus and negatively with dorsal anterior cingulate. Amygdala responses to masked happy faces were uncorrelated with other brain regions. Contrary to the right-lateralized pathway seen in adults, adolescents show evidence of a predominantly left-lateralized extrastriate pathway during masked presentations of facial affect.
Keywords: Brain & Biology
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Killgore, W. D. S., Ross, A. J., Kamiya, T., Kawada, Y., Renshaw, P.F., & Yurgelun-Todd, D. A. (2010). Citicoline affects appetite and cortico-limbic responses to images of high calorie foods. International Journal of Eating Disorders, 43, 6-13.
OBJECTIVE: Cytidine-5'-diphosphocholine (citicoline) has a variety of cognitive enhancing, neuroprotective, and neuroregenerative properties. In cocaine-addicted individuals, citicoline has been shown to increase brain dopamine levels and reduce cravings. The effects of this compound on appetite, food cravings, and brain responses to food are unknown. METHOD:: We compared the effects of treatment with Cognizin(R) citicoline (500 mg/day versus 2,000 mg/day) for 6 weeks on changes in appetite ratings, weight, and cortico-limbic responses to images of high-calorie foods using functional magnetic resonance imaging (fMRI). RESULTS:: After 6 weeks, there was no significant change in weight status, although significant declines in appetite ratings were observed for the 2,000 mg/day group. The higher dose group also showed significant increases in functional brain responses to food stimuli within the amygdala, insula, and lateral orbitofrontal cortex. Increased activation in these regions correlated with declines in appetite ratings. DISCUSSION:: These preliminary findings suggest a potential usefulness of citicoline in modulating appetite, but further research is warranted. (c) 2009 by Wiley Periodicals, Inc. Int J Eat Disord 2009.
Keywords: Brain & Biology
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Killgore, W. D., Rosso, I. M., Gruber, S. A., & Yurgelun-Todd, D.A. (2009). Amygdala volume and verbal memory performance in schizophrenia and bipolar disorder. Cognitive and Behavioral Neurology, 22, 28-37.
OBJECTIVE: To clarify the relationship between amygdala-hippocampal volume and cognitive performance in schizophrenia and bipolar disorder. BACKGROUND: Abnormalities of the amygdala-hippocampal complex and memory deficits have been reported in both schizophrenia and bipolar illness. METHOD: We examined memory performance and its relationship to the volumes of the whole brain, lateral ventricles, hippocampus, and amygdala using morphometric magnetic resonance imaging in 19 patients with schizophrenia, 11 bipolar patients, and 20 healthy controls. RESULTS: Schizophrenia patients performed more poorly than bipolar patients and controls on indices of memory functioning, whereas patients with bipolar disorder showed milder impairments relative to controls. The schizophrenia group showed reduced total cerebral volume and enlarged ventricles relative to controls, but no group differences were found for amygdala or hippocampal volume. Left amygdala volume was predictive of memory performance in both groups, correlating positively with better immediate and delayed verbal memory for bipolar patients and negatively with immediate and delayed verbal recall for schizophrenia patients. Amygdala volume was unrelated to memory performance in healthy subjects. CONCLUSIONS: Schizophrenia and bipolar disorder both seem to be associated with anomalous and differential limbic volume-function relationships, such that the amygdala may facilitate hippocampal-dependent memory processes in bipolar disorder but impair these same processes in schizophrenia
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Kim, J. E., Lyoo, I. K., Estes, A. M., Renshaw, P.F., Shaw, D. W., Friedman, S. D., et al. (2010). Laterobasal amygdalar enlargement in 6- to 7-year-old children with autism spectrum disorder. Archives of General Psychiatry, 67(11), 1187-97.
CONTEXT: There is substantial imaging evidence for volumetric abnormalities of the amygdala in younger children with autism spectrum disorder (ASD). The amygdala can be divided into functionally distinct laterobasal, superficial, and centromedial subregions. To date, we are not aware of any in vivo reports specifically assessing subregional amygdalar abnormalities in individuals with ASD. OBJECTIVES: To evaluate alterations in subregional amygdalar morphology in children with ASD compared with typically developing (TD) children and to examine the relationships with ASD symptom severity. DESIGN: A cross-sectional study encompassing a narrow age range of children with ASD and age-matched TD children that evaluated magnetic resonance imaging-defined subregional morphology of the amygdala using a novel subregional analytic method. SETTING: Participants were recruited and clinically evaluated through the University of Washington Autism Center and imaged at the Diagnostic Imaging Sciences Center at the University of Washington. Imaging data were analyzed through the Brain Imaging Laboratory at the Seoul National University. PARTICIPANTS: Fifty-one children 6 to 7 years of age (ASD, n = 31 and TD, n = 20) were assessed using magnetic resonance imaging and behavioral measures. MAIN OUTCOME MEASURES: Volume and subregional measures of the amygdala and measures of social and communication functioning. RESULTS: The ASD group exhibited larger right and left amygdalae, by 12.7% and 11.0%, respectively, relative to the TD group. Subregional analysis revealed that the ASD group had enlarged laterobasal amygdalar subregions, relative to the TD group, after adjusting for age, sex, and hemispheric cerebral volume (P < .05, false discovery rate corrected and with clustered surface points >15). Exploratory analyses revealed that there were linear trends comparing a strictly defined subgroup of children with autistic disorder, who exhibited the greatest extent of laterobasal enlargement, followed by a subgroup of children with pervasive developmental disorder not otherwise specified and then the group of TD children (P for linear trend <.001). There were linear trends between enlargement of laterobasal subregions and lower levels of social and communication functioning (P < .001, P < .001, and P = .001 for 3 areas in the right laterobasal subregion; P < .001 for 1 area in the left laterobasal subregion). CONCLUSION: The current study demonstrates bilateral enlargement of laterobasal subregions of the amygdala in 6- to 7-year-old children with ASD and that subregional alterations are associated with deficits in social and communicative behavior.
Keywords: Brain & Biology
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Kim, N., Kim, H. J., Hwang, J., Yoon, S. J., Cho, H. B., Renshaw, P.F., Lyco, I. K., & Kim, J. E. (2011). Amygdalar shape analysis method using surface contour aligning, spherical mapping, and probabilistic subregional segmentation. Neuroscience Letter, 488(1), 65-69.
The objective of this study was to develop a reliable method for the shape analysis of the amygdala, a structure that is important in gaining a better understanding of the limbic system in the human brain. The goal of this study was threefold; to develop (1) a robust method for aligning the contour of the amygdala; (2) a reproducible method for extracting surface parameters of the amygdala using a spherical mapping technique; and (3) a standardized approach for statistical assessment and visualization of shape alterations by applying the probabilistic maps of amygdalar subregions. This technique was validated by conducting an artificial phantom study and by assessing sex-related amygdalar shape differences using T1-weighted images from healthy volunteers. In the phantom study, the region with atrophy was detected successfully through the shape analysis process. In the human study, the average radii of the centromedial (CM) subregion in the left amygdala and laterobasal (LB), superficial (SF) and CM subregions in the right amygdala were different between sexes (t-tests, p=0.02, 0.04, 0.04, and 0.002, respectively). In addition, focal regions with larger radii in amygdalae of men than those of women were found predominantly on the surfaces of bilateral SF and bilateral CM subregions, after the volumes of the amygdala had been scaled to the unit volume (1000mm(3)) (Mann-Whitney U-test, false discovery rate corrected p<0.05, clustered vertex points>25). Regions with smaller radii in amygdalae of men were found predominantly on the anterior surfaces of the right LB and SF subregions (Mann-Whitney U-test, false discovery rate corrected p<0.05, clustered vertex points>25). This is generally in agreement with previous findings from animal studies. The current method may be used for measuring subtle local shape changes of the amygdala in various psychiatric or neurologic disorders.
Keywords: Brain & Biology
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Kondo, D. G., Hellem, T. L., Sung, Y. H., Kim, N., Jeong, E. K., Delmastro, K. K., Shi, X., & Renshaw, P.F. (2011). Review: Magnetic resonance spectroscopy studies of pediatric major depressive disorder. Depression Research & Treatment, Epub 2010 Oct 4.
Introduction. This paper focuses on the application of Magnetic Resonance Spectroscopy (MRS) to the study of Major Depressive Disorder (MDD) in children and adolescents. Method. A literature search using the National Institutes of Health's PubMed database was conducted to identify indexed peer-reviewed MRS studies in pediatric patients with MDD. Results. The literature search yielded 18 articles reporting original MRS data in pediatric MDD. Neurochemical alterations in Choline, Glutamate, and N-Acetyl Aspartate are associated with pediatric MDD, suggesting pathophysiologic continuity with adult MDD. Conclusions. The MRS literature in pediatric MDD is modest but growing. In studies that are methodologically comparable, the results have been consistent. Because it offers a noninvasive and repeatable measurement of relevant in vivo brain chemistry, MRS has the potential to provide insights into the pathophysiology of MDD as well as the mediators and moderators of treatment response.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Kondo, D. G., Sung, Y. H., Hellem, T. L., Delmastro, K. K., Jeong, E. K., Kim, N., Shi, X. & Renshaw, P.F. (2011). Open-label uridine for treatment of depressed adolescents with bipolar disorder. Journal of Child and Adolescent Psychopharmacology, 21(2), 171-175.
This report is an open-label case series of seven depressed adolescents with bipolar disorder treated with uridine for 6 weeks. Treatment response was measured with the Children's Depression Rating Scale-Revised and the Clinical Global Impressions scale. Uridine was associated with decreased depressive symptoms, and was well tolerated by study participants. Further systematic studies of uridine are warranted.
Keywords: Brain & Biology
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Lee, J.N., Hsu, E.W., Rashkin, E., Thatcher, J.W., Kreitschitz, S., Gale, P., Healy, L., & Marchand, W.R. (2010). Reliability of fMRI motor tasks in structures of the corticostriatal circuitry: implications for future studies and circuit function. Neuroimage.
The corticostriatal circuits are important information processing networks. There is evidence that these circuits may be dysfunctional in a variety of neuropsychiatric conditions ranging from Parkinson's disease to bipolar disorder. Cross-sectional fMRI studies may clarify normal circuit function, and longitudinal studies may provide information on changes related to age in control subjects, as well as illness progression and treatment response in patient groups. In this paper, we report a comprehensive analysis of the utility of several motor tasks as cross-sectional and longitudinal probes of corticostriatal function in terms of their activation strength and reliability. Our findings suggest that the motor tasks studied can be useful probes of corticostriatal function for studies utilizing group comparisons. However, longitudinal clinical studies in which individual results are important will need to take into account wide variation in individual activation and reliability. For example, measures of activation strength and reliability based on percent signal change display a dichotomy between simple motor tasks, which have high reliability and low activation, and complex tasks, which have lower reliability and higher activation. Size and overlap ratios calculated from activation maps produced a different view of reliability than intraclass correlation coefficients (ICC) based on percent signal change. Finally, these results suggest that the corticostriatal circuitry exhibit individualized responses to motor adaptation.
Keywords: Brain & Biology
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Lee, S. H., Han, D. H., Oh, S., Lyoo, I. K., Lee, Y. S., Renshaw, P.F., et al. (2009). Quantitative electroencephalographic (qEEG) correlates of craving during virtual reality therapy in alcohol-dependent patients. Pharmacology, Biochemistry & Behavior, 91(3), 393-397.
Virtual reality (VR) is an evolving technology that is being applied to treat a wide range of medical and psychiatric diseases. A virtual reality therapy (VRT) with multisensory stimulation has been applied to patients with alcohol dependence (ADP). We hypothesized that the VRTP for alcohol dependence would reduce the craving for alcohol and increase alpha wave activity in frontal areas of individuals with ADP. Twenty ADP and eighteen ADP were exposed to a series of 10 VRTP sessions (VRTP-ADP) and cognitive behavioral therapy (nVRTP-ADP), respectively. Fifteen healthy controls were exposed to VRTP for comparing the changes of craving and EEG during all three phases of VRTP. The VRTP-ADP exhibited a greater decrease in craving after the 10th VRTP session, when compared to the nVRTP-ADP. Compared to the healthy control subjects, VRTP-ADP group showed higher magnitude of the change in craving throughout VRTP sessions. These results suggest that VRTP may be useful as an adjunct to treating alcohol dependence but may also serve as an evaluation tool to identify high-risk patients.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Licata, S. C., & Renshaw, P.F. (2010). Neurochemistry of drug action: insights from proton magnetic resonance spectroscopic imaging and the relevance to addiction. Annals of the New York Academy of Sciences, 1187, 148-171.
Proton magnetic resonance spectroscopy ((1)H MRS) is a noninvasive imaging technique that permits measurement of particular compounds or metabolites within the tissue of interest. In the brain, (1)H MRS provides a snapshot of the neurochemical environment within a defined volume of interest. A search of the literature demonstrates the widespread utility of this technique for characterizing tumors, tracking the progress of neurodegenerative disease, and for understanding the neurobiological basis of psychiatric disorders. As of relatively recently, (1)H MRS has found its way into substance abuse research, and it is beginning to become recognized as a valuable complement in the brain imaging toolbox that also contains positron emission tomography, single-photon-emission computed tomography, and functional magnetic resonance imaging. Drug abuse studies using (1)H MRS have identified several biochemical changes in the brain. The most consistent alterations across drug class were reductions in N-acetylaspartate and elevations in myo-inositol, whereas changes in choline, creatine, and amino acid transmitters also were abundant. Together, the studies discussed herein provide evidence that drugs of abuse may have a profound effect on neuronal health, energy metabolism and maintenance, inflammatory processes, cell membrane turnover, and neurotransmission, and these biochemical changes may underlie the neuropathology within brain tissue that subsequently gives rise to the cognitive and behavioral impairments associated with drug addiction.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Licata, S. C., Jensen, J. E., Penetar, D. M., Prescot, A. P., Lukas, S. E ., & Renshaw, P.F. (2009). A therapeutic dose of zolpidem reduces thalamic GABA in healthy volunteers: A proton MRS study at 4 T. Psychopharmacology, 203, 819-829.
BACKGROUND: Zolpidem is a nonbenzodiazepine sedative/hypnotic that acts at GABA(A) receptors to influence inhibitory neurotransmission throughout the central nervous system. A great deal is known about the behavioral effects of this drug in humans and laboratory animals, but little is known about zolpidem's specific effects on neurochemistry in vivo. OBJECTIVES: We evaluated how acute administration of zolpidem affected levels of GABA, glutamate, glutamine, and other brain metabolites. MATERIALS AND METHODS: Proton magnetic resonance spectroscopy ((1)H MRS) at 4 T was employed to measure the effects of zolpidem on brain chemistry in 19 healthy volunteers. Participants underwent scanning following acute oral administration of a therapeutic dose of zolpidem (10 mg) in a within-subject, single-blind, placebo-controlled, single-visit study. In addition to neurochemical measurements from single voxels within the anterior cingulate (ACC) and thalamus, a series of questionnaires were administered periodically throughout the experimental session to assess subjective mood states. RESULTS: Zolpidem reduced GABA levels in the thalamus, but not the ACC. There were no treatment effects with respect to other metabolite levels. Self-reported ratings of "dizzy," "nauseous," "confused," and "bad effects" were increased relative to placebo, as were ratings on the sedation/intoxication (PCAG) and psychotomimetic/dysphoria (LSD) scales of the Addiction Research Center Inventory. Moreover, there was a significant correlation between the decrease in GABA and "dizzy." CONCLUSIONS: Zolpidem engendered primarily dysphoric-like effects and the correlation between reduced thalamic GABA and "dizzy" may be a function of zolpidem's interaction with alpha1GABA(A) receptors in the cerebellum, projecting through the vestibular system to the thalamus.
Keywords: Brain & Biology
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Liu X, Jensen JE, Gillis TE, Zuo CS, Prescot AP, Brimson M, Cayetano K, Renshaw PF, Kaufman MJ. Chronic cocaine exposure induces putamen glutamate and glutamine metabolite abnormalities in squirrel monkeys. Psychopharmacology (Berl). 2011 Oct;217(3):367-75. Epub 2011 Apr 15.
RATIONALE: Chronic cocaine exposure has been associated with progressive brain structural and functional changes. Clarifying mechanisms underlying cocaine's progressive brain effects may help in the development of effective cocaine abuse treatments. OBJECTIVES: We used a controlled squirrel monkey model of chronic cocaine exposure (45 mg/kg/week for 9 months) combined with ultra-high magnetic field (9.4 T) proton magnetic resonance spectroscopy to prospectively measure putamen metabolite changes. METHODS: Proton metabolites were measured with a STEAM sequence, quantified with LCModel using a simulated basis set, and expressed as metabolite/total creatine (tCr) ratios. RESULTS: We found cocaine-induced time-dependent changes in putamen glutamate/tCr and glutamine/tCr metabolite ratios suggestive of altered glutamate compartmentalization, neurotransmission, and metabolism. By contrast, saline-treated monkeys exhibited no metabolite changes over time. The time course of cocaine-induced metabolite abnormalities we detected is consistent with the apparent time course of glutamate abnormalities identified in a cross-sectional study in human cocaine users, as well as with microdialysis findings in rodent models of repeated cocaine exposure. CONCLUSIONS: Together, these findings suggests that this squirrel monkey model may be useful for characterizing glutamatergic changes associated with cocaine exposure and for determining efficacies of treatments designed to mitigate cocaine-induced glutamatergic system dysfunction.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Lopez-Larson, M. P., Anderson, J. S., Ferguson, M. A., & Yurgelun-Todd, D. (2011). Local brain connectivity and associations with gender and age. Developmental Cognitive Neuroscience,1(2), 187-197.
Regional homogeneity measures synchrony of resting-state brain activity in neighboring voxels, or local connectivity. The effects of age and gender on local connectivity in healthy subjects are unknown. We performed regional homogeneity analyses on resting state BOLD time series data acquired from 58 normal, healthy participants, ranging in age from 11 to 35 (mean 18.1 ± 5.0 years, 32 males). Regional homogeneity was found to be highest for gray matter, with brain regions within the default mode network having the highest local connectivity values. There was a general decrease in regional homogeneity with age with the greatest reduction seen in the anterior cingulate and temporal lobe. Greater female local connectivity in the right hippocampus and amygdala was also noted, regardless of age. These findings suggest that local connectivity at the millimeter scale decreases during development as longer connections are formed, and underscores the importance of examining gender differences in imaging studies of healthy and clinical populations.
Keywords: Brain & Biology
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Lopez-Larson, M. P., Bogorodzki, P., Rogowska, J., McGlade, E., King, J. B., Terry, J., & Yurgelun-Todd, D. (2011). Altered prefrontal and insular cortical thickness in adolescent marijuana users. Behavioral Brain Research, 220(1), 164-172.
INTRODUCTION: There are limited data regarding the impact of marijuana (MJ) on cortical development during adolescence. Adolescence is a period of substantial brain maturation and cortical thickness abnormalities may be indicative of disruptions of normal cortical development. This investigation applied cortical-surface based techniques to compare cortical thickness measures in MJ using adolescents compared to non-using controls. METHODS: Eighteen adolescents with heavy MJ use and 18 non-using controls similar in age received MRI scans using a 3T Siemens scanner. Cortical reconstruction and volumetric segmentation was performed with FreeSurfer. Group differences in cortical thickness were assessed using statistical difference maps covarying for age and gender. RESULTS: Compared to non-users, MJ users had decreased cortical thickness in right caudal middle frontal, bilateral insula and bilateral superior frontal cortices. Marijuana users had increased cortical thickness in the bilateral lingual, right superior temporal, right inferior parietal and left paracentral regions. In the MJ users, negative correlations were found between frontal and lingual regions for urinary cannabinoid levels and between age of onset of use and the right superior frontal gyrus. CONCLUSION: This is one of the first studies to evaluate cortical thickness in a group of adolescents with heavy MJ use compared to non-users. Our findings are consistent with prior studies that documented abnormalities in prefrontal and insular regions. Our results suggest that age of regular use may be associated with altered prefrontal cortical gray matter development in adolescents. Furthermore, reduced insular cortical thickness may be a biological marker for increased risk of substance dependence.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Lopez-Larson, M. P., Breeze, J. A., Kennedy, D. N., Hodge, S. M., Tang, L., Moore, C. et al. (2010). Age-related changes in the corpus callosum in early-onset bipolar disorder assessed using volumetric and cross-sectional measurements. Brain Imaging and Behavior, 4(3-4), 220-231.
Corpus callosum (CC) area abnormalities have been reported in magnetic resonance imaging (MRI) studies of adults and youths with bipolar disorder (BPD), suggesting interhemispheric communication may be abnormal in BPD and may be present early in the course of illness and affect normal neuromaturation of this structure throughout the lifecycle. Neuroimaging scans from 44 youths with DSM-IV BPD and 22 healthy controls (HC) were analyzed using cross-sectional area measurements and a novel method of volumetric parcellation. Univariate analyses of variance were conducted on CC subregions using both volume and traditional area measurements. Youths with BPD had smaller middle and posterior callosal regions, and reduced typical age-related increases in CC size. The cross-sectional area and novel volumetric methodologies resulted in similar findings. Future longitudinal assessments of CC development would track the evolution of callosal abnormalities in youths with BPD and allow exploration of the functional significance of these findings.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Lyoo, I. K., Dager, S. R., Kim, J. E., Yoon, S. J., Friedman, S. D., Dunner, D. L., & Renshaw, P.F. (2010). Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: A longitudinal brain imaging study. Neuropsychopharmacology,35(8), 1743-1750.
Preclinical studies suggest that lithium may exert neurotrophic effects that counteract pathological processes in the brain of patients with bipolar disorder (BD). To describe and compare the course and magnitude of gray matter volume changes in patients with BD who are treated with lithium or valproic acid (VPA) compared to healthy comparison subjects, and to assess clinical relationships to gray matter volume changes induced by lithium in patients with BD, we conducted longitudinal brain imaging and clinical evaluations of treatment response in 22 mood-stabilizing and antipsychotic medications-naive patients with BD who were randomly assigned to either lithium or VPA treatment after baseline assessment. Fourteen healthy comparison subjects did not take any psychotropic medications during follow-up. Longitudinal data analyses of 93 serial magnetic resonance images revealed lithium-induced increases in gray matter volume, which peaked at week 10-12 and were maintained through 16 weeks of treatment. This increase was associated with positive clinical response. In contrast, VPA-treated patients with BD or healthy comparison subjects did not show gray matter volume changes over time. Results suggest that lithium induces sustained increases in cerebral gray matter volume in patients with BD and that these changes are related to the therapeutic efficacy of lithium.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Lyoo, I. K., Yoon, S. J., Musen, G., Simonson, D. C., Weinger, K., Bolo, N., et al. (Renshaw, P.F.) (2009). Altered prefrontal glutamate-glutamine-gama-aminobutyric acid levels and relation to low cognitive performance and depressive symptoms in type 1 diabetes mellitus. Archives of General Psychiatry, 66, 878-887.
CONTEXT: Neural substrates for low cognitive performance and depression, common long-term central nervous system-related changes in patients with type 1 diabetes mellitus, have not yet been studied. OBJECTIVE: To investigate whether prefrontal glutamate levels are higher in patients with type 1 diabetes and whether an elevation is related to lower cognitive performance and depression. DESIGN: Cross-sectional study. SETTING: General clinical research center. PARTICIPANTS: One hundred twenty-three patients with adult type 1 diabetes with varying degrees of lifetime glycemic control and 38 healthy participants. MAIN OUTCOME MEASURES: With the use of proton magnetic resonance spectroscopy, prefrontal glutamate-glutamine-gamma-aminobutyric acid (Glx) levels were compared between patients and control subjects. Relationships between prefrontal Glx levels and cognitive function and between Glx levels and mild depressive symptoms were assessed in patients with type 1 diabetes. RESULTS: Prefrontal Glx concentrations were 9.0% (0.742 mmol/L; P = .005) higher in adult patients with type 1 diabetes than in healthy control subjects. There were positive linear trends for the effects of lifetime glycemic control on prefrontal Glx levels (P for trend = .002). Cognitive performances in memory, executive function, and psychomotor speed were lower in patients (P = .003, .01, and
Keywords: Brain & Biology
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Marchand, W.R., Lee, J.N., Healy, L., Thatcher, J.W., Rashkin, E., Starr, J., & Hsu, E.W. (2009). An fMRI motor activation paradigm demonstrates abnormalities of putamen activation in females with panic disorder. J Affect Disord, 116: 121-125.
BACKGROUND: The neurobiology of panic disorder is incompletely understood. The aim of this study was to determine if functional abnormalities of the putamen occur in panic disorder. METHODS: Activation patterns of 12 female subjects with panic disorder were compared to 18 female healthy controls using functional MRI at 3 T. A motor activation paradigm was used to probe putamen function. RESULTS: A complex motor activation paradigm for the non-dominant hand revealed decreased activation of the bilateral putamen among subjects with panic disorder. LIMITATIONS: The sample size was a relatively small cohort of non-depressed females. Further, some panic disorder subjects were taking medications and/or had comorbid conditions. However, second-level regression analyses did not reveal any correlations between medication use or comorbidity and activation patterns demonstrated by the non-dominant hand complex task. Finally, we used a post-hoc approach to determine the magnitude of global fMRI signal as a surrogate index of the global cerebral blood flow as a means of controlling for possible confounds from reduction of BOLD signal secondary to cerebral vasoconstriction resulting from possible hyperventilation among panic subjects. A more compelling approach would have been to record the respiratory data from subjects during scanning. CONCLUSIONS: Our findings suggest that putamen dysfunction occurs in at least some cases of panic disorder. We also provide preliminary evidence that a complex motor task for the non-dominant hand is a useful probe of putamen function in this disorder.
Keywords: Brain & Biology
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Marchant BK, Reimherr FW, Halls C, Williams ED, Strong RE, Kondo D, Soni P, Robison RJ. Long-term open-label response to atomoxetine in adult ADHD: influence of sex, emotional dysregulation, and double-blind response to atomoxetine. Atten Defic Hyperact Disord. 2011 Sep;3(3):237-44. doi: 10.1007/s12402-011-0054-2. Epub 2011 Mar 27.
A three-year open-label study of atomoxetine in adults with ADHD followed two multicenter, double-blind trials. In the double-blind trials, female gender and higher levels of emotional symptoms were associated with better outcome. Following a 4-week placebo washout period, 384 (of 536) subjects continued into the open-label study. 61% of subjects entering this open-label study remained after 6 months at an average dose of 100 mg/day. Subjects who had previously responded to double-blind atomoxetine achieved maximum response after 8 weeks of open-label medication, but others continued to improve for 36 weeks. Women improved more (7.7 ± 6.4) than men (6.1 ± 6.4) on the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) (P = .007) and the Conners' Adult ADHD Rating Scale (P = .03). Subjects with emotional dysregulation improved more than others on the WRAADDS (P = .001). Responders ultimately improved approximately 60% in attentional, hyperactive/impulsive, and emotional symptoms. Thirty-nine percent of atomoxetine double-blind non-responders became responders during open-label treatment.
Keywords: Brain & Biology
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Mollica, Lyoo, Chernoff, Bui, Lavelle, Yoon, et al. (Renshaw, P.F.) (2009). Brain structural abnormalities and mental health sequelae in South Vietnamese ex-political detainees who survived traumatic head injury and torture. Archives of General Psychiatry, 66, 1221-1232.
CONTEXT: A pilot study of South Vietnamese ex-political detainees who had been incarcerated in Vietnamese reeducation camps and resettled in the United States disclosed significant mental health problems associated with torture and traumatic head injury (THI). OBJECTIVES: To identify structural brain alterations associated with THI and to investigate whether these deficits are associated with posttraumatic stress disorder and depression. DESIGN: Cross-sectional neuroimaging study. SETTING: Massachusetts General Hospital and McLean Hospital. PARTICIPANTS: A subsample of Vietnamese ex-political detainees (n = 42) and comparison subjects (n = 16) selected from a community study of 337 ex-political detainees and 82 comparison subjects. MAIN OUTCOME MEASURES: Scores on the Vietnamese versions of the Hopkins Symptom Checklist-25 (HSCL) and Harvard Trauma Questionnaire for depression and posttraumatic stress disorder, respectively; cerebral regional cortical thickness; and manual volumetric morphometry of the amygdala, hippocampus, and thalamus. RESULTS: Ex-political detainees exposed to THI (n = 16) showed a higher rate of depression (odds ratio, 10.2; 95% confidence interval, 1.2-90.0) than those without THI exposure (n = 26). Ex-political detainees with THI had thinner prefrontotemporal cortices than those without THI exposure (P < .001 by the statistical difference brain map) in the left dorsolateral prefrontal and bilateral superior temporal cortices, controlling for age, handedness, and number of trauma/torture events (left superior frontal cortex [SFC], P = .006; left middle frontal cortex, P = .01; left superior temporal cortex [STC], P = .007; right STC, P = .01). Trauma/torture events were associated with bilateral amygdala volume loss (left, P = .045; right, P = .003). Cortical thinning associated with THI in the left SFC and bilateral STC was related to HSCL depression scores in THI-exposed (vs non-THI-exposed) ex-political detainees (left SFC, P for interaction = .007; left STC, P for interaction = .03; right STC, P for interaction = .02). CONCLUSIONS: Structural deficits in prefrontotemporal brain regions are linked to THI exposures. These brain lesions are associated with the symptom severity of depression in Vietnamese ex-political detainees.
Keywords: Brain & Biology, Traumatic Brain Injury (TBI)
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Ongür, D., Lundy, M., Greenhouse, I., Shinn, A. K., Menon, V., Cohen, B. M., & Renshaw, P.F. (2010). Default mode network abnormalities in bipolar disorder and schizophrenia. Psychiatry Research,183(1), 59-68.
The default-mode network (DMN) consists of a set of brain areas preferentially activated during internally focused tasks. We used functional magnetic resonance imaging (fMRI) to study the DMN in bipolar mania and acute schizophrenia. Participants comprised 17 patients with bipolar disorder (BD), 14 patients with schizophrenia (SZ) and 15 normal controls (NC), who underwent 10-min resting fMRI scans. The DMN was extracted using independent component analysis and template-matching; spatial extent and timecourse were examined. Both patient groups showed reduced DMN connectivity in the medial prefrontal cortex (mPFC) (BD: x=-2, y=54, z=-12; SZ: x=-2, y=22, z=18). BD subjects showed abnormal recruitment of parietal cortex (correlated with mania severity) while SZ subjects showed greater recruitment of the frontopolar cortex/basal ganglia. Both groups had significantly higher frequency fluctuations than controls. We found ventral mPFC abnormalities in BD and dorsal mPFC abnormalities in SZ. The higher frequency of BOLD signal oscillations observed in patients suggests abnormal functional organization of circuits in both disorders. Further studies are needed to determine how these abnormalities are related to specific symptoms of each condition.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Ongur, D., Prescot, A. P., Jensen, J. E., Cohen, B. M., & Renshaw, P.F. (2009). Creatine abnormalities in schizophrenia and bipolar disorder. Psychiatry Research, 172(1), 44-48.
Total creatine (Cr) levels are widely used as an internal reference for the quantification of other metabolites in (1)H magnetic resonance spectroscopy (MRS). However, Cr plays an important role in brain energy metabolism, and its levels can be modulated by conditions of energy production and demand. Therefore, abnormal Cr levels in patient vs. control populations could confound the utility of this metabolite as an internal reference. We quantified Cr levels in 22 healthy controls, 15 acutely manic patients with bipolar disorder and 15 acutely ill patients with schizophrenia using (1)H MRS in the anterior cingulate cortex, and the parieto-occipital cortex at 4 Tesla. Patients with schizophrenia had a statistically significant reduction in Cr levels as compared with controls; bipolar disorder patients showed no difference in Cr as compared with controls. In addition, older age was associated with reductions in Cr in healthy controls, but not in patients with either disorder. These findings indicate that the use of Cr as an internal reference in schizophrenia MRS research is problematic unless Cr levels are shown to be normal in the study population. They also add to the literature on bioenergetic abnormalities in schizophrenia.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Ongur, D., Prescot, A. P., McCarthy, J., Cohen, B. M., & Renshaw, P.F. (2010). Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Biological Psychiatry, 68(7), 667-670.
BACKGROUND: Despite widely replicated abnormalities of gamma-aminobutyric acid (GABA) neurons in schizophrenia postmortem, few studies have measured tissue GABA levels in vivo. We used proton magnetic resonance spectroscopy to measure tissue GABA levels in participants with schizophrenia and healthy control subjects in the anterior cingulate cortex and parieto-occipital cortex. METHODS: Twenty-one schizophrenia participants effectively treated on a stable medication regimen (mean age 39.0, 14 male) and 19 healthy control subjects (mean age 36.3, 12 male) underwent a proton magnetic resonance spectroscopy scan using GABA-selective editing at 4 Tesla after providing informed consent. Data were collected from two 16.7-mL voxels and analyzed using LCModel. RESULTS: We found elevations in GABA/creatine in the schizophrenia group compared with control subjects [F(1,65) = 4.149, p = .046] in both brain areas (15.5% elevation in anterior cingulate cortex, 11.9% in parieto-occipital cortex). We also found a positive correlation between GABA/creatine and glutamate/creatine, which was not accounted for by % GM or brain region. CONCLUSIONS: We found elevated GABA/creatinine in participants with chronically treated schizophrenia. Postmortem studies report evidence for dysfunctional GABAergic neurotransmission in schizophrenia. Elevated GABA levels, whether primary to illness or compensatory to another process, may be associated with dysfunctional GABAergic neurotransmission in chronic schizophrenia.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Prescot, A. P., Locatelli, A. E., Renshaw, P.F., & Yurgelun-Todd, D.A. (2011). Neurochemical alterations in adolescent chronic marijuana smokers: A proton MRS study. Neuroimage, 57(1), 69-75.
Converging evidence from neuroimaging and neuropsychological studies indicates that heavy marijuana use is associated with cingulate dysfunction. However, there has been limited human data documenting in vivo biochemical brain changes after chronic marijuana exposure. Previous proton magnetic resonance spectroscopy studies have demonstrated reduced basal ganglia glutamate and dorsolateral prefrontal cortex N-acetyl aspartate levels in adult chronic marijuana users. Similar studies have not been reported in adolescent populations. The present study used proton magnetic resonance spectroscopy to determine whether reductions in glutamate, N-acetyl aspartate and/or other proton metabolite concentrations would be found in the anterior cingulate cortex (ACC) of adolescent marijuana users compared with non-using controls. Adolescent marijuana users (N=17; average age 17.8 years) and similarly aged healthy control subjects (N=17; average age 16.2 years) were scanned using a Siemens 3T Trio MRI system. Proton magnetic resonance spectroscopy data were acquired from a 22.5 mL voxel positioned bilaterally within the ACC. Spectra were fitted using commercial software and all metabolite integrals were normalized to the scaled unsuppressed water integral. Analysis of variance and analysis of covariance were performed to compare between-group metabolite levels. The marijuana-using cohort showed statistically significant reductions in anterior cingulate glutamate (-15%, p<0.01), N-acetyl aspartate (-13%, p=0.02), total creatine (-10%, p<0.01) and myo-inositol (-10%, p=0.03). Within-voxel tissue-type segmentation did not reveal any significant differences in gray/white matter or cerebrospinal fluid content between the two groups. The reduced glutamate and N-acetyl aspartate levels in the adolescent marijuana-using cohort are consistent with precedent human (1)H MRS data, and likely reflect an alteration of anterior cingulate glutamatergic neurotransmission and neuronal integrity within these individuals. The reduced total creatine and myo-inositol levels observed in these subjects might infer altered ACC energetic status and glial metabolism, respectively. These results expand on previous functional MRI data reporting altered cingulate function in individuals with marijuana-abuse.
Keywords: Brain & Biology
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Preston, G., Anderson, E., Silva, C., Goldberg, T., & Wassermann, E. (2009). Effects of 10Hz rTMS on the neural efficiency of working memory. Journal of Cognitive Neuroscience, 2009/03/25 ePub ahead of print.
Working memory (WM) has been described as short-term retention of information that is no longer accessible in the environment, and the manipulation of this information for subsequent use in guiding behavior. WM is viewed as a cognitive process underlying higher-order cognitive functions. Evidence supports a critical role for PFC in mediating WM performance. Studies show psychomotor processing speed and accuracy account for considerable variance in neural efficiency (Ne). This study compared the relative effects of active and sham 10 Hz rTMS applied to dorsolateral prefrontal cortex (DLPFC) on indices of Ne in healthy participants performing a WM paradigm that models the association between WM load and task behavior [Sternberg, S. High-speed scanning in human memory. Science, 153, 652–654, 1966]. Previous studies identified a relationship between diminished Ne and impaired WM across a broad array of clinical disorders. In the present study, the authors predicted there would be a main effect of stimulation group (STM) on accuracy (SCR) and processing speed (RT), hence, Ne. We observed a main effect of STM for RT without an effect on SCR; even so, there was a robust effect of STM on Ne.
Keywords: Brain & Biology
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Renshaw, P. F., Parsegian, A., Yang, C. K., Novero, A. Yoon, S. J., Lyoo, I. K., et al. (2009). Lovastatin potentiates the antidepressant efficacy of fluoxetine in rats. Pharmacology, Biochemistry & Behavior, 92(1), 88-92.
BACKGROUND: Cholesterol may have a role in the pathophysiology of depression. Lowering cholesterol levels with statins reduces risks for cardiovascular events, and there is clinical evidence that statins exert neuroprotective properties not fully explained by their effects on serum cholesterol levels. Altered cholesterol levels can affect serotonergic neurotransmission, which might be involved in the clinical efficacy of standard antidepressants. METHODS: We examined interactions between a statin (lovastatin) and a selective serotonin reuptake inhibitor (fluoxetine) using the forced swim test (FST) in rats, a behavioral assay that identifies treatments with antidepressant effects in humans. Specifically, we determined if the addition of lovastatin to the diet would increase the efficacy of a subeffective dose of fluoxetine. RESULTS: Rats maintained on a lovastatin-enriched diet for 30 days were more sensitive to the antidepressant-like effects of a low (subthreshold) dose of fluoxetine. The behavior of rats treated with this combination resembled that normally seen with higher doses of fluoxetine. No effects were observed in rats maintained on a lovastatin-enriched diet for 3 days. CONCLUSIONS: Lovastatin can augment the antidepressant-like effects of a low dose of fluoxetine in rats, raising the possibility that statins could be used to facilitate the effects of antidepressants in humans.
Keywords: Brain & Biology
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Robinson, T. N., Raeburn, C. D., Tran, Z. V., Brenner, L.A., & Moss, M. (2011). Motor subtypes of postoperative delirium in older adults. Archives of Surgery, 146(3), 295-300.
HYPOTHESIS: Increased knowledge about motor subtypes of delirium may aid clinicians in the management of postoperative geriatric patients. DESIGN: Prospective cohort study defining preoperative risk factors, outcomes, and adverse events related to motor subtypes of postoperative delirium. SETTING: Referral medical center. PATIENTS: Persons 50 years and older with planned postoperative intensive care unit (ICU) admission following an elective operation were recruited. MAIN OUTCOME MEASURES: Before surgery, a standardized frailty assessment was performed. After surgery, delirium and its motor subtypes were measured using the validated tools of the Confusion Assessment Method-ICU and the Richmond Agitation-Sedation Scale. Statistical analysis included the univariate t and χ(2) tests and analysis of variance with post hoc analysis. RESULTS: Delirium occurred in 43.0% (74 of 172) of patients, representing 67.6% (50 of 74) hypoactive, 31.1% (23 of 74) mixed, and 1.4% (1 of 74) hyperactive motor subtypes. Compared with those having mixed delirium, patients having hypoactive delirium were older (mean [SD] age, 71 [9] vs 65 [9] years) and more anemic (mean [SD] hematocrit, 36% [8%] vs 41% [6%]) (P = .002 for both). Patients with hypoactive delirium had higher 6-month mortality (32.0% [16 of 50] vs 8.7% [2 of 23], P = .04). Delirium-related adverse events occurred in 24.3% (18 of 74) of patients with delirium; inadvertent tube or line removals occurred more frequently in the mixed group (P = .006), and sacral skin breakdown was more common in the hypoactive group (P = .002). CONCLUSIONS: Motor subtypes of delirium alert clinicians to differing prognosis and adverse event profiles in postoperative geriatric patients. Hypoactive delirium is the most common motor subtype and is associated with worse prognosis (6-month mortality, 1 in 3 patients). Knowledge of differing adverse event profiles can modify clinicians' management of older patients with postoperative delirium.
Keywords: Brain & Biology
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Robinson, T. N., Raeburn, C. D., Zung, V. T., Angles, E. M., Brenner, L.A., & Moss, M. (2009) Post-operative delirium in the elderly – Risk factors and outcomes. Annals of Surgery, 249(1), 173-178.
OBJECTIVE: The purpose of this study was to describe the natural history, identify risk factors, and determine outcomes for the development of postoperative delirium in the elderly. BACKGROUND: Postoperative delirium is a common and deleterious complication in geriatric patients. METHODS: Subjects older than 50 years scheduled for an operation requiring a postoperative intensive care unit admission were recruited. After preoperative informed written consent, enrolled subjects had baseline cognitive and functional assessments. Postoperatively, subjects were assessed daily for delirium using the confusion assessment method-intensive care unit. Patients were also followed for outcomes. RESULTS: During the study period, 144 patients were enrolled before major abdominal (40%), thoracic (53%), or vascular (7%) operations. The overall incidence of delirium was 44% (64/144). The average time to onset of delirium was 2.1 +/- 0.9 days and the mean duration of delirium was 4.0 +/- 5.1 days. Several preoperative variables were associated with an increased risk of delirium including older age (P < 0.001), hypoalbuminemia (P < 0.001), impaired functional status (P < 0.001), pre-existing dementia (P < 0.001), and pre-existing comorbidities (P < 0.001). In a multivariable logistic regression model, pre-existing dementia remains the strongest risk factor for the development of postoperative delirium. Worse outcomes, including increased length of stay (P < 0.001), postdischarge institutionalization (P < 0.001), and 6 month mortality (P = 0.001), occurred in subjects who developed delirium. CONCLUSIONS: In the current study, delirium occurred in 44% of elderly patients after a major operation. Pre-existing cognitive dysfunction was the strongest predictor of the development of postoperative delirium. Outcomes, including an increased rate of 6 month mortality, were worse in patients who developed postoperative delirium.
Keywords: Brain & Biology
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Sava, S., McCafrey, A. M., & Yurgelun-Todd, D. A. (2009). Cognitive Neuroscience. Women and Addiction. Sudie Black, Guilford Publications pp 133-146.
No abstract available.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Silveri, M. M., & Yurgelun-Todd, D.A. (2009) Developmental neuropsychology: normative trajectories and risk for psychiatric illness. In: Wood, S. J., Allen, N. B., & Pantellis, C., editors. The Neuropsychology of Mental Illness. Cambridge: Cambridge University Press; p. 4-14.
No abstract available.
Keywords: Brain & Biology
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Silveri, M. M., Jensen, J. E., Rosso, I. M., Sneider, J. T., & Yurgelun-Todd, D.A. (2011). Preliminary evidence for white matter metabolite differences in marijuana-dependent young men using 2D J-resolved magnetic resonance spectroscopic imaging at 4 Tesla. Psychiatry Research, 191(3), 201-211.
Chronic marijuana (MRJ) use is associated with altered cognition and mood state, altered brain metabolites, and functional and structural brain changes. The objective of this study was to apply proton magnetic resonance spectroscopic imaging (MRSI) to compare proton metabolite levels in 15 young men with MRJ dependence and 11 healthy non-using (NU) young men. Spectra were acquired at 4.0 Tesla using 2D J-resolved MRSI to resolve coupled resonances in J-space and to quantify the entire J-coupled spectral surface of metabolites from voxels containing basal ganglia and thalamus, temporal and parietal lobes, and occipital white and gray matter. This method permitted investigation of high-quality spectra for regression analyses to examine metabolites relative to tissue type. Distribution of myo-inositol (mI)/creatine (Cr) was altered in the MRJ group whereas the NU group exhibited higher mI/Cr in WM than GM, this pattern was not observed in MRJ subjects. Significant relationships observed between global mI/Cr and distribution in WM, and self-reported impulsivity and mood symptoms were also unique between MRJ and NU groups. These preliminary findings suggest that mI, and distribution of this glial metabolite in WM, is altered by MRJ use and is associated with behavioral and affective features reported by young MRJ-dependent men.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Silveri, M. M., Rogowska, J., McCaffrey, A., & Yurgelun-Todd, D. (2011). Adolescents at risk for alcohol abuse demonstrate altered frontal lobe activation during Stroop performance. Alcoholism: Clinical & Experimental Research, 35(2), 218-228.
BACKGROUND: Children and adolescents, family history positive (FH+) for alcoholism, exhibit differences in brain structure and functional activation when compared to family history negative (FH-) counterparts. Given that frontal brain regions, and associated reciprocal connections with limbic structures, undergo the most dramatic maturational changes during adolescence, the objective of this study was to compare functional brain activation during a frontally mediated test of response inhibition in 32 adolescents separated into low-risk (FH-) and high-risk (FH+) groups. METHODS: Functional magnetic resonance (fMRI) blood oxygen level-dependent data were acquired at 1.5 Tesla during performance of Stroop Color Naming, Word Reading, and Interference. Preprocessing and statistical analyses, covaried for age, were conducted in SPM99 using a search territory that included superior, middle, and inferior frontal gyri (trigone region), anterior cingulate gyrus (CG), and left and right amygdala. RESULTS: Significantly greater activation in the fronto-limbic search territory was observed in FH+ relative to FH- subjects during Stroop Interference. In addition, a significant regression between brain activation and family history density was observed, with a greater density being associated with increased activation in regions including middle frontal gyrus (BA9) and CG (BA24). CONCLUSIONS: These data demonstrate a significant influence of FH status on brain activation during the performance of a response inhibition task, perhaps reflecting a neurobiological vulnerability associated with FH status that may include reduced neuronal efficiency and/or recruitment of additional neuronal resources. These findings are important given that the adolescent developmental period is already associated with reduced inhibitory capacity, even prior to the onset of alcohol use.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Streeter, C. C., Whitfield, T. H., Owen, L., Rein, T., Karri, S. K., Yakhkind, A., & Renshaw, P.F. (2010). Effects of yoga versus walking on mood, anxiety, and brain GABA levels: A randomized controlled MRS study. Journal of Alternative & Complementary Medicine, 16(11), 1145-1152.
OBJECTIVES: Yoga and exercise have beneficial effects on mood and anxiety. γ-Aminobutyric acid (GABA)-ergic activity is reduced in mood and anxiety disorders. The practice of yoga postures is associated with increased brain GABA levels. This study addresses the question of whether changes in mood, anxiety, and GABA levels are specific to yoga or related to physical activity. METHODS: Healthy subjects with no significant medical/psychiatric disorders were randomized to yoga or a metabolically matched walking intervention for 60 minutes 3 times a week for 12 weeks. Mood and anxiety scales were taken at weeks 0, 4, 8, 12, and before each magnetic resonance spectroscopy scan. Scan 1 was at baseline. Scan 2, obtained after the 12-week intervention, was followed by a 60-minute yoga or walking intervention, which was immediately followed by Scan 3. RESULTS: The yoga subjects (n=19) reported greater improvement in mood and greater decreases in anxiety than the walking group (n=15). There were positive correlations between improved mood and decreased anxiety and thalamic GABA levels. The yoga group had positive correlations between changes in mood scales and changes in GABA levels. CONCLUSIONS: The 12-week yoga intervention was associated with greater improvements in mood and anxiety than a metabolically matched walking exercise. This is the first study to demonstrate that increased thalamic GABA levels are associated with improved mood and decreased anxiety. It is also the first time that a behavioral intervention (i.e., yoga postures) has been associated with a positive correlation between acute increases in thalamic GABA levels and improvements in mood and anxiety scales. Given that pharmacologic agents that increase the activity of the GABA system are prescribed to improve mood and decrease anxiety, the reported correlations are in the expected direction. The possible role of GABA in mediating the beneficial effects of yoga on mood and anxiety warrants further study.
Keywords: Brain & Biology, Complementary Arts Medicine
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Terry, J., Lopez-Larson, M., & Frazier, J. A. (2009). Magnetic resonance imaging studies in early onset bipolar disorder: An updated review. Child and Adolescent Psychiatric Clinics of North America, 18, 421-439.
Over the past 5-10 years, advances in neuroimaging methods and study designs have begun to appear in the literature of early-onset bipolar disorder (onset before 18 years of age). This article contains an updated review of the literature regarding neuroimaging in youths with bipolar disorder (BPD), highlighting important new study designs and techniques. Overall, structural, functional (fMRI) and magnetic resonance spectroscopy (MRS) report consistent abnormalities in regions of the frontal lobe and limbic structures. Functional MRI and MRS studies also frequently report striatal and thalamic abnormalities in early-onset BPD. Future neuroimaging studies in youths with BPD should include longitudinal studies incorporating multimodal neuroimaging techniques.
Keywords: Brain & Biology
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Tregellas, J. R., Olincy, A., Johnson, L., Tanabe, J., Shatti, S., Martin, L. F., Singel, D., Du, Y. P., Soti, F., Kern, W. R., & Freedman, R. (2010). Functional magnetic resonance imaging of effects of a nicotinic agonist in schizophrenia. Neuropsychopharmacology, 35(4), 938-942.
3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at alpha7-nicotinic acetylcholine receptors and is now in early clinical development for treatment of deficits in neurocognition and sensory gating in schizophrenia. During its initial phase 2 test, functional magnetic resonance imaging (fMRI) studies were conducted to determine whether the drug had its intended effect on hippocampal inhibitory interneurons. Increased hemodynamic activity in the hippocampus in schizophrenia is found during many tasks, including smooth pursuit eye movements, and may reflect inhibitory dysfunction. Placebo and two doses of drug were administered in a random, double-blind crossover design. After the morning drug/placebo ingestion, subjects underwent fMRI while performing a smooth pursuit eye movement task. Data were analyzed from 16 nonsmoking patients, including 7 women and 9 men. The 150-mg dose of DMXB-A, compared with placebo, diminished the activity of the hippocampus during pursuit eye movements, but the 75-mg dose was ineffective. The effect at the 150-mg dose was negatively correlated with plasma drug levels. The findings are consistent with the previously established function of alpha7-nicotinic receptors on inhibitory interneurons in the hippocampus and with genetic evidence for deficits in these receptors in schizophrenia. Imaging of drug response is useful in planning future clinical tests of this compound and other nicotinic agonists for schizophrenia.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Trksak, G. H., Jensen, J. E., Plante, D. T., Penetar, D. M., Tartarini, W. L., Maywalt, M. A., Brendel, M., Dorsey, C. M., Renshaw, P.F., & Lukas, S. E. (2010). Effects of sleep deprivation on sleep homeostasis and restoration during methadone-maintenance: a [31]P MRS brain imaging study. Drug and Alcohol Dependence,106(2-3), 79-91.
Insomnia afflicts many individuals, but particularly those in chronic methadone treatment. Studies examining sleep deprivation (SD) have begun to identify sleep restoration processes involving brain bioenergetics. The technique ([31])P magnetic resonance spectroscopy (MRS) can measure brain changes in the high-energy phosphates: alpha-, beta-, and gamma-nucleoside triphosphate (NTP). In the present study, 21 methadone-maintained (MM) and 16 control participants underwent baseline (BL), SD (40 wakeful hours), recovery1 (RE1), and recovery2 (RE2) study nights. Polysomnographic sleep was recorded each night and ([31])P MRS brain scanning conducted each morning using a 4T MR scanner (dual-tuned proton/phosphorus head-coil). Interestingly, increases in total sleep time (TST) and sleep efficiency index (SEI) commonly associated with RE sleep were not apparent in MM participants. Analysis of methadone treatment duration revealed that the lack of RE sleep increases in TST and SEI was primarily exhibited by short-term MM participants (methadone 12 months) participants was more comparable to control participants. Slow wave sleep increased during RE1, but there was no difference between MM and control participants. Spectral power analysis revealed that compared to control participants; MM participants had greater delta, theta, and alpha spectral power during BL and RE sleep. ([31])P MRS revealed that elevations in brain beta-NTP (a direct measure of ATP) following RE sleep were greater in MM compared to control participants. Results suggest that differences in sleep and brain chemistry during RE in MM participants may be reflective of a disruption in homeostatic sleep function.
Keywords: Brain & Biology, Substance Use Disorders (SUD)
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Vimal, R. L., Pandey-Vimal, M. U., Vimal, L. S., Frederick, B. B., Stopa, E. G., Renshaw, P.F., et al. (2009). Activation of suprachiasmatic nuclei and primary visual cortex depends upon time of day. European Journal of Neuroscience, 29, 399-410.
The human suprachiasmatic nucleus (SCN), the master biological clock, is a small (approximately 2 mm(3)) and deep structure located in the anterior hypothalamus. Previous methods do not allow in vivo study of the human SCN in a non-invasive manner. Therefore, we explored blood oxygen level-dependent (BOLD)-functional magnetic resonance imaging (fMRI) with OFF-ON-OFF block-designed visual stimuli to record the activities in the 'SCN and peri SCN in the anterior hypothalamus' (SCN+) and the primary visual area V1 using a 3T Siemens scanner and six normal subjects. We found that: (i) the BOLD-fMRI response to light and the mean of percentage activation in the SCN+ at midday was significantly less than that at night; and (ii) the number of activated voxels in most of the visual area V1 at midday was significantly higher than that at night. We conclude that BOLD-fMRI responses to light in the SCN+ and the V1 areas vary with time of day. This conclusion is consistent with: (i) the previously measured phase-response curve to light [J. Physiol., 549.3 (2003) 945] for the SCN activity at critical intensity threshold; and (ii) the interaction of the melanopsin-based signals with the rod-cone signals at the 'giant' retinal ganglion cells [Nature, 433 (2005) 749] for the V1 activity.
Keywords: Brain & Biology
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Wagner PJ, Wortzel HS, Frey KL, Anderson CA, Arciniegas DB. (2011) Clock-Drawing Performance Predicts Inpatient Rehabilitation Outcomes After Traumatic Brain Injury. The Journal of Neuropsychiatry and Clinical Neurosciences 2011; 23:449–453
The authors used clock-drawing performance to assess cognition and predict inpatient rehabilitation outcomes among persons with traumatic brain injury. Clock-drawing performance, as assessed with the Clock Drawing Interpretation Scale, predicts rehabilitation length of stay as well as Functional Independence Measure scores at the time of neurobehavioral assessment and rehabilitation discharge.
Keywords: Brain & Biology, Traumatic Brain Injury (TBI)
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White RF, Palumbo CL, Yurgelun-Todd DA, Heaton KJ, Weihe P, Debes F, Grandjean P. Functional MRI approach to developmental methylmercury and polychlorinated biphenyl neurotoxicity. Neurotoxicology. 2011 Dec;32(6):975-80. Epub 2011 Apr 27.
Prenatal and early childhood exposure to methylmercury (MeHg) or polychlorinated biphenyls (PCBs) are associated with deficits in cognitive, sensory, motor and other functions measured by neurobehavioral tests. The main objective of this pilot study was to determine whether functional magnetic resonance imaging (fMRI) is effective for visualization of brain function alterations related to neurobehavior in subjects with high prenatal exposure to the two neurotoxicants, MeHg and PCBs. Twelve adolescents (all boys) from a Faroese birth cohort assembled in 1986-1987 were recruited based on their prenatal exposures to MeHg and PCB. All underwent fMRI scanning during behavioral tasks at age 15 years. Subjects with high mixed exposure to MeHg and PCBs were compared to those with low mixed exposure on fMRI photic stimulation and a motor task. Boys with low mixed exposures showed patterns of fMRI activation during visual and motor tasks that are typical of normal control subjects. However, those with high exposures showed activation in more areas of the brain and different and wider patterns of activation than the low mixed exposure group. The brain activation patterns observed in association with increased exposures to MeHg and PCBs are meaningful in regard to the known neurotoxicity of these substances. This methodology therefore has potential utility in visualizing structural neural system determinants of exposure-induced neurobehavioral dysfunction.
Keywords: Brain & Biology
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Winkelman, J. W., Benson, K. L., Buxton, O. M., Lyoo, I. K., Yoon, S., O'Connor, S., & Renshaw, P.F.. (2010). Lack of hippocampal volume differences in primary insomnia and good sleeper controls: an MRI volumetric study at 3 Tesla. Sleep Med., 11(6), 576-582.
BACKGROUND: A recent pilot study reported that hippocampal volume (HV) was reduced in patients with primary insomnia (PI) relative to normal sleepers. Loss of HV in PI might be due to chronic hyperarousal and/or chronic sleep debt. The aim of this study was to replicate the earlier pilot report while employing a larger sample, more rigorous screening criteria, and objective sleep data. METHODS: This cross-sectional design included community recruits meeting DSM-IV criteria for PI (n=20, 10 males, mean age 39.3+/-8.7) or good sleeper controls (n=15, 9 males, mean age 38.8+/-5.3). All subjects were unmedicated and rigorously screened to exclude comorbid psychiatric and medical illness. PI subjects underwent overnight polysomnography to screen for sleep-related breathing and movement disorders. HV and total brain volumes were derived by MRI employing a Siemens/Trio scanner operating at 3 Tesla. Data also included 2 weeks of sleep diaries and wrist actigraphy. RESULTS: Mean HV was 4322.0+/-299.7 mm(3) for the good sleeper controls and 4601.55+/-537.4 mm(3) for the PI group. The dependent variable, HV, was analyzed by ANCOVA. Main effects were diagnosis and gender; whole brain volume served as the covariate. Although the overall model was significant (F=6.3, p=0.001), the main effects of diagnosis (F=2.14) and gender (F=0.04) were not significant. The covariate of whole brain volume was significant (F=5.74, p=0.023) as was the interaction of diagnosis with gender (F=10.22, p=0.003), with male insomniacs having larger HVs than male controls. CONCLUSIONS: This study did not replicate a previously published report of HV loss in primary insomnia. Differences between our finding and the previous report might be due to sample composition and method of MRI assessment. Furthermore, we demonstrated no objective differences between the controls and PIs in actigraphic measures of sleep maintenance. Within the PIs, however, actigraphic measures of poor sleep maintenance were associated with smaller HV.
Keywords: Brain & Biology
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Wortzel HS, Strom LA, Anderson AC, Maa EH, Spitz M. Disrobing Associated with Epileptic Seizures and Forensic Implications. J Forensic Sci. 2011 Dec 8. doi: 10.1111/j.1556-4029.2011.01995.x. [Epub ahead of print]
Little is known about the clinical aspects and medico-legal consequences of disrobing in the context of epileptic seizures. Seizure-related disrobing may occur either as an ictal automatism or during the postictal period. Some patients may experience a seizure while already in the unclothed state, engage in ictal wandering, and thereby appear in public in the nude. Two cases involving disrobing associated with seizures captured via video-monitored electroencephalography are offered. An additional case reveals the legal consequences endured by one patient who experienced a nocturnal seizure and began wandering in an unclothed state. Collectively, these cases illustrate the medical reality of seizure-related disrobing and the related adverse effects on patients' quality of life. Disrobing associated with epileptic seizures carries the potential for serious legal consequences if not properly identified as an ictal phenomenon.
Keywords: Brain & Biology
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Yildiz, A., Gokmen, N., Kucukguctu, S., Yurt, A., Olson, D., Rouse, E. D., & Renshaw, P.F. (2010). In vivo proton magnetic resonance spectroscopic examination of benzodiazepine action in humans. Psychiatry Research, 184(3), 162-170.
In an examination of the effect of benzodiazepines on brain chemistry, 44 healthy controls underwent a short echo-time proton magnetic resonance spectroscopy ((1)H MRS) session after induced sedation with intravenous midazolam (0.03mg/kg) plus fentanyl (2μg/kg). The regions of interest were the anterior cingulate cortex, right basal ganglia, right frontal lobe, and right hippocampus. Twenty-five of these subjects underwent the second (1)H MRS session while awake. The measured (1)H MRS metabolites included N-acetyl-aspartate, creatine-containing compounds (PCr+Cr), choline-containing compounds, myo-inositol, and glutamate plus glutamine, which were quantified both as absolute values and metabolite/PCr+Cr ratios. The results were analyzed using independent group t tests and repeated measures analysis of variance (ANOVA, with alpha values set at 0.025 to minimize the risk of false-positive findings arising from multiple comparisons. No significant difference between subjects under midazolam plus fentanyl induced sedation and awake could be detected with unpaired analyses. Paired comparisons by ANOVA with repeated measures found that neither drug (midazolam plus fentanyl) nor the drug by time (interval between two scan times) interaction had a significant effect on the quantified metabolites. These findings encourage utilization of benzodiazepine-induced brief sedation during in vivo (1)H MRS experiments of the brain, and may help with elucidation of state-dependent neurochemical alterations during the course of bipolar and schizoaffective disorders.
Keywords: Brain & Biology, Seriously Mentally Ill (SMI)
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Yoon, S. J., Lyoo, I. K., Haws, C., Kim, T. S., Cohen, B. M., & Renshaw, P.F. (2009). Decreased glutamate/glutamine levels may mediate cytidine’s efficacy in treating bipolar depression: A longitudinal magnetic resonance spectroscopy study. Neuropsychopharmacology, 34, 1810-1818.
Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidine's efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamate/glutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamate/glutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. Cytidine supplementation was associated with an earlier improvement in depressive symptoms (weeks 1-4; p=0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral glutamate/glutamine levels in patients with bipolar depression (weeks 2, 4, and 12; p=0.004, 0.004, and 0.02, respectively). Cytidine-related glutamate/glutamine decrements correlated with a reduction in depressive symptoms (p=0.001). In contrast, these relationships were not observed in the placebo add-on group. The study results suggest that cytidine supplementation of valproate is associated with an earlier treatment response in bipolar depression. Furthermore, cytidine's efficacy in bipolar depression may be mediated by decreased levels of cerebral glutamate and/or glutamine, consistent with alterations in excitatory neurotransmission.
Keywords: Brain & Biology
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Yurgelun-Todd, D.A., Bueler, C. E., McGlade, E., Churchwell, J., Brenner, L.A., & Lopez-Larson, M. (2011). Neuroimaging correlates of traumatic brain injury and suicidal behavior. Journal of Head Trauma Rehabilitation, 26(4), 276-289.
INTRODUCTION: There is an urgent need to define the neurobiological and cognitive underpinnings of suicidal ideation and behavior in veterans with traumatic brain injury (TBI). Separate studies implicate frontal white matter systems in the pathophysiology of TBI, suicidality, and impulsivity. We examined the relationship between the integrity of major frontal white matter (WM) systems on measures of impulsivity and suicidality in veterans with TBI. METHODS: Fifteen male veterans with TBI and 17 matched healthy controls (HC) received clinical ratings, measures of impulsivity and MRI scans on a 3T magnet. Diffusion tensor imaging (DTI) data for the genu and cingulum were analyzed using Freesurfer and FSL. Correlations were performed for fractional anisotropy (FA) (DTI) values and measures of suicidality and impulsivity for veterans with TBI. RESULTS: Significantly decreased in FA values in the left cingulum (P = 0.02), and left (P = 0.02) and total genu (P = 0.01) were observed in the TBI group relative to controls. Measures of impulsivity were significantly greater for the TBI group and total and right cingulum FA positively correlated with current suicidal ideation and measures of impulsivity (P <0.03). CONCLUSION: These data demonstrate a significant reduction in FA in frontal WM tracts in veterans with mild TBI that was associated with both impulsivity and suicidality. These findings may reflect a neurobiological vulnerability to suicidal risk related to white matter microstructure.
Keywords: Brain & Biology, Suicide, Traumatic Brain Injury (TBI)
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