VISN 19 MIRECC Recent Publications (2009-Present)

Recent Publications of Interest - 2010 to Present (N=105)

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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Allen MH, Daniel DG, Revicki DA, Canuso CM, Turkoz I, Fu DJ, Alphs L, Ishak KJ, Bartko JJ, Lindemayer JP. (2011).Development and Psychometric Evaluation of a Clinical Global Impression for Schizoaffective Disorder Scale. Innov Clin Neurosci. 2012;9(1):15–24

ABSTRACT: Objective: The Clinical Global Impression for Schizoaffective Disorder scale is a new rating scale adapted from the Clinical Global Impression scale for use in patients with schizoaffective disorder. The psychometric characteristics of the Clinical Global Impression for Schizoaffective Disorder are described. Design: Content validity was assessed using an investigator questionnaire. Inter-rater reliability was determined with 12 sets of videotaped interviews rated independently by two trained individuals. Test-retest reliability was assessed using 30 randomly selected raters from clinical trials who evaluated the same videos on separate occasions two weeks apart. Convergent and divergent validity and effect size were evaluated by comparing scores between the Clinical Global Impression for Schizoaffective Disorder and the Positive and Negative Syndrome Scale, 21-item Hamilton Rating Scale for Depression, and Young Mania Rating Scale scales using pooled patient data from two clinical trials. Clinical Global Impression for Schizoaffective Disorder scores were then linked to corresponding Positive and Negative Syndrome Scale scores. Results: Content validity was strong. Inter-rater agreement was good to excellent for most scales and subscales (intra-class correlation coefficient ³0.50). Test-retest showed good reproducibility, with intraclass correlation coefficients ranging from 0.444 to 0.898. Spearman correlations between Clinical Global Impression for Schizoaffective Disorder domains and corresponding symptom scales were 0.60 or greater, and effect sizes for Clinical Global Impression for Schizoaffective Disorder overall and domain scores were similar to Positive and Negative Syndrome Scale, Young Mania Rating Scale, and 21-item Hamilton Rating Scale for Depression scores. Raters anticipated that the scale might be less effective in distinguishing negative from depressive symptoms, and, in fact, the results here may reflect that clinical reality. Conclusion: Multiple lines of evidence support the reliability and validity of the Clinical Global Impression for Schizoaffective Disorder for studies in schizoaffective disorder.

Keywords: Assessment, Seriously Mentally Ill (SMI)

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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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Arciniegas, D. B., Frey, K. L., Newman, J., & Wortzel HS (2010). Evaluation and management of posttraumatic cognitive impairments. Psychiatric Annals, 40(11), 540-552.

Psychiatrists are increasingly called upon to care for individuals with cognitive, emotional, and behavioral disturbances after TBI, especially in settings serving military service personnel and Veterans. In both the early and late post-injury periods, cognitive impairments contribute to disability among persons with TBI and are potentially substantial sources of suffering for persons with TBI and their families. In this article, the differential diagnosis, evaluation, and management of posttraumatic cognitive complaints is reviewed. The importance of pre-treatment evaluation as well as consideration of non-cognitive contributors to cognitive problems and functional limitations is emphasized first. The course of recovery after TBI, framed as a progression through posttraumatic encephalopathy, is reviewed next and used to anchor the evaluation and treatment of posttraumatic cognitive impairments in relation to injury severity as well as time post-injury. Finally, pharmacologic and rehabilitative interventions that may facilitate cognitive and functional recovery at each stage of posttraumatic encephalopathy are presented.

Keywords: Traumatic Brain Injury (TBI)

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Bahraini NH, Gutierrez PM, Harwood JEF, Huggins JA, Hedegaard H, Chase M, Brenner LA. (2012). The Colorado Violent Death Reporting System (COVDRS): Validity and Utility of the Veteran Status Variable. Public Health Rep., May/Jun;127(3):304-309.

Objective. Using the Veterans Affairs Beneficiary Identification Record Locator Subsystem (BIRLS) as the criterion database, we evaluated the sensitivity and specificity of the death certificate information in the Colorado Violent Death Reporting System (COVDRS) to determine Veteran status for those who died by suicide. Methods. The study sample consisted of 3,820 individuals aged 18 years and older who died by suicide in Colorado from January 1, 2004, through December 31, 2008. To determine agreement on Veteran status, COVDRS data were submitted to the Veterans Benefits Administration for linkage to the BIRLS using Social Security numbers. Results. Sensitivity and specificity of the Veteran status information on the death certificate were 93.1% (95% confidence interval [CI] 90.7, 95.2) and 91.7% (95% CI 90.5, 92.8), respectively. The overall agreement between the death certificate and the BIRLS on Veteran status was very good (kappa 5 0.76; 95% CI 0.74, 0.79). Conclusions. This study of 3,820 suicide deaths in Colorado demonstrated a high level of agreement between the COVDRS Veteran status variable and the BIRLS. Such findings offer support for using the COVDRS in studying factors associated with suicide in the Veteran population.

Keywords: Suicide

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Bates MJ, Bradley JC, Bahraini NH, Goldenberg MN. (2012). Clinical Management of Suicide Risk with Military and Veteran Personnel. Chapter in Textbook of Suicide Assessment and Management, 2nd Edition Edited by Simon RI and Hales RE. The American Pyschiatric Publishing, Washington DC, 405-441.

No abstract available

Keywords: Suicide

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Betthauser LM, Bahraini N, Krengel MH, Brenner LA. Self-Report Measures to Identify Post Traumatic Stress Disorder and/or Mild Traumatic Brain Injury and Associated Symptoms in Military Veterans of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF). Neuropsychol Rev. 2012 Feb 19.

Individuals serving in Iraq and Afghanistan sustain injuries associated with physical and psychological trauma. Among such injuries, mild traumatic brain injury (mTBI) and post traumatic stress disorder (PTSD) are common. Self-report measures are frequently used to identify mTBI and/or PTSD and symptoms associated with these conditions. In addition to providing information regarding mTBI and PTSD, the goal of this literature review was to identify and present information on the psychometric properties of measures used to obtain information regarding these common conditions among Veterans who have returned from Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF). A comprehensive review of studies in which self-report measures were used to evaluate mTBI, PTSD, and associated symptoms among OEF/OIF Veterans is presented. Findings suggest that additional work is needed to identify psychometrically sound and clinically useful self-report measures that assess mTBI and PTSD and associated symptoms among OEF/OIF Veterans.

Keywords: OEF/OIF/OND, PTSD, Traumatic Brain Injury (TBI)

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Boyer, J., Wortzel HS, & Martinez, R. (2010). Ineffective counsel in a death penalty case. Legal Digest, 38(3), 427-429.

Keywords: Incarcerated Veterans

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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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Brausch, A. M. & Gutierrez, P. M. (2010). Differences in non-suicidal self-injury and suicide attempts in adolescents. Journal of Youth and Adolescence, 39(3), 233-244.

As suicide attempts and self-injury remain predominant health risks among adolescents, it is increasingly important to be able to distinguish features of self-harming adolescents from those who are at risk for suicidal behaviors. The current study examined differences between groups of adolescents with varying levels of self-harmful behavior in a sample of 373 high school students with a mean age of 15.04 (SD = 1.05). The sample was 48% female and the distribution of ethnicity was as follows: 35% Caucasian, 37.2% African-American, 16% Multi-ethnic, 9.2% Hispanic, and 2.3% Asian. The sample was divided into three groups: no history of self-harm, non-suicidal self-injury (NSSI) only, and NSSI in addition to a suicide attempt. Differences in depressive symptoms, suicidal ideation, social support, self-esteem, body satisfaction, and disordered eating were explored. Results indicated significant differences between the three groups on all variables, with the no self-harm group reporting the lowest levels of risk factors and highest levels of protective factors. Further analyses were conducted to examine specific differences between the two self-harm groups. Adolescents in the NSSI group were found to have fewer depressive symptoms, lower suicidal ideation, and greater self-esteem and parental support than the group that also had attempted suicide. The clinical implications of assessing these specific psychosocial correlates for at-risk adolescents are discussed.

Keywords: Suicide

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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, Bahraini N and Hernández TD (2012). Perspectives on creating clinically relevant blast models for mild traumatic brain injury and post traumatic stress disorder symptoms. Front. Neur. 3:31.

Military personnel are returning from Iraq and Afghanistan and reporting non-specific physical (somatic), behavioral, psychological, and cognitive symptoms. Many of these symptoms are frequently associated with mild traumatic brain injury (mTBI) and/or post traumatic stress disorder (PTSD). Despite significant attention and advances in assessment and intervention for these two conditions, challenges persist. To address this, clinically relevant blast models are essential in the full characterization of this type of injury, as well as in the testing and identification of potential treatment strategies. In this publication, existing diagnostic challenges and current treatment practices for mTBI and/or PTSD will be summarized, along with suggestions regarding how what has been learned from existing models of PTSD and traditional mechanism (e.g., non-blast) TBI can be used to facilitate the development of clinically relevant blast models.

Keywords: PTSD, Traumatic Brain Injury (TBI)

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Brenner LA, Barnes SM. (2012). Facilitating Treatment Engagement During High-Risk Transition Periods: A Potential Suicide Prevention Strategy. American Journal of Public Health, Supplement 1, Vol 102, No. S1

Abstract not available

Keywords: Suicide

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Brenner, L. A., Betthauser, L.M., Homaifar, B. Y., Villarreal, E., Harwood, J. E., Staves, P. J., & Huggins, J. A. (2011). Posttraumatic stress disorder, traumatic brain injury, and suicide attempt history among Veterans receiving mental health services. Suicide & Life Threatening Behavior, 41, 416-423.

History of posttraumatic stress disorder (PTSD) or traumatic brain injury (TBI) has been found to increase risk of suicidal behavior. The association between suicide attempt history among veterans with PTSD and/or TBI was explored. Cases (N = 81) and 2:1 matched controls (N = 160) were randomly selected from a Veterans Affairs Medical Center clinical database. PTSD history was associated with an increased risk for a suicide attempt (OR = 2.8; 95% CI: 1.5, 5.1). This increased risk was present for those with and without a history of TBI. Results support incorporating PTSD history when assessing suicide risk among veterans with and without TBI.

Keywords: Suicide, PTSD, Traumatic Brain Injury (TBI)

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Brenner, L.A., Breshears, R.E., Betthauser, L.M., Bellon, K. K., Holman, E., Harwood, J. E., Silverman, M. M., Huggins, J. & Nagamoto, H. T. (2011). Implementation of a suicide nomenclature within two VA healthcare settings. Journal of Clinical Psychology in Medical Settings.

Implementation of a Suicide Nomenclature within Two VA Healthcare Settings Those who work in the field of Veteran’s care, as well as educators, researchers, and professionals providing direct mental health services agree that learning more about and preventing suicide represents a highly critical goal. Yet, up to now, researchers and mental health professionals lacked a shared language for defining suicidal behavior. This study discusses implementation of the Center for Disease Controls’ Self-Directed Violence Classification System (SDVCS) and an accompanying Clinical Tool (CT) at two VA healthcare facilities (in Denver and Grand Junction, CO). Results of this study show that implementing a more unified language is possible, while at the same time highlights some of the challenges and barriers to adoption of this system. This study provides important information regarding implementation of the SDVCS throughout the VA system.

Keywords: Suicide

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Brenner, L. A., Ignacio, R. V., & Blow, F. C. (2011). Suicide and traumatic brain injury among individuals seeking Veterans Health Administration services. Journal of Head Trauma Rehabilitation, 26(4), 257-264.

This manuscript examines associations between a history of traumatic brain injury (TBI) diagnosis and death by suicide among individuals receiving care within the Veterans Health Administration (VHA). Among VHA users, those with a diagnosis of TBI were at greater risk for suicide than those without this diagnosis. Further research is indicated to identify evidence-based means of assessment and treatment for those with TBI and suicidal behavior.

Keywords: Suicide, Traumatic Brain Injury (TBI)

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Brenner, L. A., Terrio, H., Homaifar, B. Y., Gutierrez, P. M., Staves, P. J., Harwood, J. E. F., et al. (2010). Neuropsychological test performance in soldiers with blast-related mild TBI. Neuropsychology,24(2), 160-175.

This exploratory study was conducted to increase understanding of neuropsychological test performance in those with blast-related mild traumatic brain injury (mTBI). The two variables of interest for their impact on test performance were presence of mTBI symptoms and history of posttraumatic stress disorder (PTSD). Forty-five soldiers postblast mTBI, 27 with enduring mTBI symptoms and 18 without, completed a series of neuropsychological tests. Seventeen of the 45 met criteria for PTSD. The Paced Auditory Serial Addition Test (Frencham, Fox, & Mayberry, 2005; Spreen & Strauss, 1998) was the primary outcome measure. Two-sided, 2-sample t tests were used to compare scores between groups of interest. Presence of mTBI symptoms did not impact test performance. In addition, no significant differences between soldiers with and without PTSD were identified. Standard neuropsychological assessment may not increase understanding about impairment associated with mTBI symptoms. Further research in this area is indicated.

Keywords: PTSD, Traumatic Brain Injury (TBI)

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Breshears, R. E., Brenner, L. A., Harwood, J. E. F., & Gutierrez, P. M. (2010). Predicting suicidal behavior in Veterans with traumatic brain injury: The utility of the Personality Assessment Inventory. Journal of Personality Assessment, 92,349-355.

In this study, we investigated the Personality Assessment Inventory's (PAI; Morey, 1991, 2007) Suicide Potential Index (SPI) and Suicide Ideation scale (SUI) as predictors of suicidal behavior (SB) in military Veterans with traumatic brain injury (TBI; N = 154). We analyzed electronic medical records were searched for SB in the 2 years post-PAI administration and data via logistic regressions. We obtained statistical support for the SPI and SUI as predictors of SB. Analyses we performed using receiver operating characteristics suggested an optimal SPI cutoff of > or = 15 for this sample. Findings suggest that SPI and SUI scores may assist in assessing suicide risk in those with TBI, particularly when population-based cutoffs are considered.

Keywords: Suicide, Traumatic Brain Injury (TBI)

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Bryan, C.J., Clemans, T.A., & Hernández, A.M. (2012). Perceived burdensomeness, fearlessness of death, and suicidality among deployed military personnel. Personality and Individual Differences, 52, 374-379.

Abstract: The interpersonal-psychological theory of suicide posits that the interaction of three elements is required for lethal suicidal behaviors: the perception that one is a burden on others, the perception that one does not belong, and fearlessness about death combined with high pain tolerance (termed "acquired capability" for suicide). Although an ever expanding research base supports the theory, very limited data exist supporting the theory among military personnel, a group that has experienced a rapid increase in suicides during the past several years. The current study tests the interpersonal-psychological theory in two clinical samples of military personnel while deployed to Iraq: those seeking treatment for mild traumatic brain injury, and those seeking outpatient mental health treatment. In both samples, perceived burdensomeness and acquired capability were significantly associated with suicidality, as was their interaction term. Results partially support the interpersonal-psychological theory of suicide, and indicate that perceptions of burdensomeness combined with fearlessness about death are associated with increased suicidality among deployed military personnel.

Keywords: Suicide

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DelMastro, K., Hellem, T., Kim, N., Kondo, D., Sung, Y. H., & Renshaw, P. F. (2011). Incidence of major depressive episode correlates with elevation of substate region of residence. Journal of Affective Disorders, 129(1-3), 376-379.

BACKGROUND: Major depressive disorder (MDD) is a common disorder that is often associated with suicide. We have recently suggested that elevation may play a role in regional variations in rates of suicide. We hypothesize that there is also a significant correlation between incidence of MDD and elevation of residence. METHODS: The substate estimates from the 2004 to 2006 National Surveys on Drug Use and Health (NSDUH) report from SAMHSA was used to extract substate level data related to percentages of people 18 years or older who experienced serious psychological distress or a major depressive episode in the past year. Mean elevation of each substate region was calculated by averaging the weighted elevations of its relevant counties. Average elevation for United States counties was calculated using the Shuttle Radar Topography Mission (SRTM) elevation dataset. Pearson correlation coefficients were computed to investigate the association between average substate elevation and rate of serious psychological distress or major depressive episode. RESULTS: There was a significant correlation between percentage of people experiencing serious psychological distress in the past year in a substate region and that substate region's mean elevation (r=0.18; p=0.0005), as well as between the percentage of people having at least one major depressive episode in the past year in a substate region and that substate region's mean elevation (r=0.27; p0.0001). CONCLUSIONS: Elevation appears to be a significant risk factor for MDD. Further studies are indicated to determine whether the increased incidence of depression with increased elevation may be due to the hypoxic effects on subjects with MDD.

Keywords: Suicide, Seriously Mentally Ill (SMI)

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Dennehy, E. B., Marangell, L. B., Allen, M. H., Chessick, C., Wisniewski, S. R., & Thase, M. E. (2011). Suicide and suicide attempts in the Systematic Treatment Enhancement Program for bipolar disorder (STEP-BD). 133, 423-427.

BACKGROUND: The current report describes individuals with bipolar disorder who attempted or completed suicide while participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. METHODS: Baseline and course features of individuals with suicide events are described. RESULTS: Among the 4360 people with bipolar disorder enrolled, 182 individuals made 270 prospectively observed suicidal acts, including 8 completed suicides. This represents a suicide rate of .014 per 100 person years in STEP-BD, which included frequent clinical visits, evidence based care, and standardized assessment at each patient contact. Approximately 1/3 of those who attempted suicide had more than one attempt during study participation. Those who completed suicide tended to do so early in study participation, and half of them did so on their first attempt. LIMITATIONS: While this study is limited to description of individuals and precipitants of completed suicides and attempts in STEP-BD, further analyses are planned to explore risk factors and potential interventions for prevention of suicidal acts in persons with bipolar disorder. CONCLUSIONS: Persons with bipolar disorder are at high risk for suicide. Overall rates of suicide events in STEP-BD were lower than expected, suggesting that the combination of frequent clinical visits (i.e., access to care), standardized assessment, and evidence-based treatment were helpful in this population.

Keywords: Suicide, Seriously Mentally Ill (SMI)

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Foote, A., Wortzel HS, & Martinez, R. (2010) Competency to waive postconviction review for a death sentence. Legal Digest, 38(3), 425-427.

In Corcoran v. Buss, 551 F.3d 703 (7th Cir. 2008), the Seventh Circuit Court of Appeals affirmed the U.S. District Court and Indiana Supreme Court decision ruling that a person with a diagnosis of schizophrenia is competent to waive postconviction review of the death sentence despite unanimous expert opinions to the contrary.

Keywords: Incarcerated Veterans

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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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Freedenthal, S., Lamis, D. A., Osman, A., Kahlo, D. & Gutierrez, P. M. (2011). Evaluation of the psychometric properties of the Interpersonal Needs Questionnaire-12 in samples of men and women. Journal of Clinical Psychology, 67(6), 609-623.

This study analyzed the psychometric properties of the Interpersonal Needs Questionnaire-12 (INQ-12; Van Orden, Witte, Gordon, Bender, & Joiner, 2008a), designed to test Joiner's interpersonal-psychological theory of suicide. Study participants included 785 U.S. undergraduates (58.6% female; 77.2% White; ages 18-25). Confirmatory bifactor analyses discerned a general factor for overall distress, while also supporting separate subfactors for perceived burdensomeness and thwarted belongingness. The scale's factor structure did not vary by gender, and internal consistency reliability was strong among the male and female samples. Correlational analyses supported the scale's content validity. Overall, the analyses preliminarily support continued use of the INQ-12.

Keywords: Suicide

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Freedman, R., & Goldowitz, D. (2010). Studies on the hippocampal formation: From basic development to clinical applications: Studies on schizophrenia. Progress in Neurobiology, 90(2), 263-275.

The hippocampal formation plays a critical role in cognitive function. The developmental events that shape the hippocampal formation are continuing to be elucidated and their implications for brain function are emerging as well as applying those advances to interventions that have important possibilities for the treatment of brain dysfunction. The story told in this chapter is about the use of the in oculo transplant method to illuminate intrinsic and extrinsic features that underlie the development of the dentate gyrus and adjacent hippocampus and the role of one molecule in the hippocampus and schizophrenia. Schizophrenia, originally conceptualized as a dysfunction in dopaminergic neurotransmission, is now known to involve multiple neuronal systems. Dysfunction of hippocampal neurons is emerging as one of its signature pathological features. Basic insights into the development and function of hippocampal interneurons form the basis of a new treatment initiative for this illness. Evidence for the role of the alpha 7-nicotinic acetylcholine receptor in the development and function of these neurons in rodents has led to human trials of nicotinic agonists for cognitive dysfunction in schizophrenia and the possibility of improving hippocampal development in children at risk for schizophrenia by perinatal supplementation with choline, which can act as an alpha 7-nicotinic acetylcholine receptor agonist.

Keywords: Seriously Mentally Ill (SMI)

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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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Gutierrez, P. M. (2010). The accidental suicidologist. In M. Pompili (Ed.), Suicide in the words of suicidologists (pp. 87-90). New York, NY: Nova Science Publishers, Inc.

No abstract available.

Keywords: Suicide

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Gutierrez, P. M., & Brenner, L. A. (2011). Helping military personnel/veterans and families manage stress reactions and navigate reintegration. In A. Palmo, W. Weikel & D. Borsos (Eds.), Foundations of mental health counseling, fourth edition (pp. 280-286). Springfield, IL: Charles C. Thomas.

No abstract available.

Keywords: Suicide

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Gutierrez PM, Freedenthal S, Wong JL, Osman A, Norizuki T. Validation of the Suicide Resilience Inventory-25 (SRI-25) in Adolescent Psychiatric Inpatient Samples. J Pers Assess. (2012) Jan;94(1):53-61.

Resilience has been associated with a markedly decreased chance for risky behaviors following a trauma or other negative life event. This study examined the factor structure and psychometric properties of a self-report measure of resilience, the Suicide Resilience Inventory-25 (SRI-25; Osman et al., 2004 ), among psychiatric inpatient adolescents. In Study 1, we conducted confirmatory factor analysis to provide additional empirical support for the structure and invariance of the 3-factor model of the SRI-25 in youth samples, ages 14 to 17 years (N = 152 boys, 220 girls). Scale reliability analyses provided good evidence for internal consistency reliability of scores on the SRI-25 total and scales. In Study 2 (N = 30 boys, 40 girls), we presented data in support for the concurrent validity (i.e., known groups) of scores on the SRI-25. Additionally, we identified potential correlates for the SRI-25 total scale scores.

Keywords: Suicide

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Haas, A. P., Eliason, M., Mays, V. M., Mathy, R. M., Cochran, S. D., D'Augelli, A. R. et al. (Silverman, M. M.) (2010). Suicide and suicide risk in lesbian, gay, bisexual, and transgender populations: Review and recommendations. Journal of Homosexuality, 58, 10-51.

Despite strong indications of elevated risk of suicidal behavior in lesbian, gay, bisexual, and transgender people, limited attention has been given to research, interventions or suicide prevention programs targeting these populations. This article is a culmination of a three-year effort by an expert panel to address the need for better understanding of suicidal behavior and suicide risk in sexual minority populations, and stimulate the development of needed prevention strategies, interventions and policy changes. This article summarizes existing research findings, and makes recommendations for addressing knowledge gaps and applying current knowledge to relevant areas of suicide prevention practice.

Keywords: Suicide

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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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Hart, T., Brenner, L. A., Clark, A. N., Bogner, J. A., Novack, T. A., Chervoneva, I. et al. (2011). Major and minor depression following traumatic brain injury. Archives of Physical Medicine, 92, 1211-1219.

OBJECTIVE: To examine minor as well as major depression at 1 year posttraumatic brain injury (TBI), with particular attention to the contribution of depression severity to levels of societal participation. DESIGN: Observational prospective study with a 2-wave longitudinal component. SETTING: Inpatient rehabilitation centers, with 1-year follow up conducted primarily by telephone. PARTICIPANTS: Persons with TBI (N=1570) enrolled in the TBI Model System database and followed up at 1-year postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FIM, Patient Health Questionnaire-9, Participation Assessment with Recombined Tools-Objective, Glasgow Outcome Scale-Extended, and the Satisfaction With Life Scale. RESULTS: Twenty-two percent of the sample reported minor depression, and 26% reported major depression at 1-year post-TBI. Both levels of depression were associated with sex (women), age (younger), preinjury mental health treatment and substance abuse, and cause of injury (intentional). There was a monotonic dose-response relationship between severity of depression and all 1-year outcomes studied, including level of cognitive and physical disability, global outcome, and satisfaction with life. With other predictors controlled, depression severity remained significantly associated with the level of societal participation at 1-year post-TBI. CONCLUSIONS: Minor depression may be as common as major depression after TBI and should be taken seriously for its association to negative outcomes related to participation and quality of life. Findings suggest that, as in other populations, minor and major depression are not separate entities, but exist on a continuum. Further research should determine whether people with TBI traverse between the 2 diagnoses as in other patient groups.

Keywords: Traumatic Brain Injury (TBI), Seriously Mentally Ill (SMI)

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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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Homaifar, B. Y., Bahraini, N.H., Silverman, M.M., Brenner, L.A.. (2012). Executive Functioning as a Component of Suicide Risk Assessment: Clarifying its Role in Standard Clinical Applications. Journal of Mental Health Counseling, 34(2), 110-120.

Clinically, because executive dysfunction (e.g., impulsivity, insight, thinking process) is often thought of in the context of those with traumatic brain injuries and other neurologic conditions, its formal assessment has historically been seen as the domain of those who assess and treat patients with neurologic disease. However, mental health counselors (MHCs) could benefit from learning how executive functioning relates to suicide risk assessment and coping strategies. Assessment of executive functions can be incorporated in routine clinical practice without the need for formal neuropsychological measures or other time-consuming procedures. In fact, during standard clinical assessment, mental health professionals often informally assess components of executive functioning such as impulsivity, insight, and thinking processes. This article highlights aspects of executive functioning with which MHCs may already be familiar and demonstrates their clinical utility in enhancing assessment and management of suicide-related thoughts and behaviors.

Keywords: Assessment, Suicide Prevention, Traumatic Brain Injury (TBI)

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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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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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Jobes, D. A., Comtois, K., Brenner, L.A. & Gutierrez, P.M. (2011). Clinical trial feasibility studies of the collaborative assessment and management of suicidality (CAMS). In R. O'Connor, S. Platt & J. Gordon (Eds.), International handbook of suicide prevention research, policy, and practice. (pp. 383-400). West Sussex, United Kingdom: John Wiley & Sons Ltd.

Abstract not available

Keywords: Suicide

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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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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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Kim, N., Mickelson, J. B., Brenner, B. E., Haws, C. A., Yurgelun-Todd, D.A., & Renshaw, P.F. (2011). Altitude, Gun Ownership, Rural Areas, and Suicide. American Journal of Psychiatry,168(1), 49-54.

OBJECTIVE: The authors recently observed a correlation between state altitude and suicide rate in the United States, which could be explained by higher rates of gun ownership and lower population density in the intermountain West. The present study evaluated the relationship between mean county and state altitude in the United States and total age-adjusted suicide rates, firearm-related suicide rates, and non-firearm-related suicide rates. The authors hypothesized that altitude would be significantly associated with suicide rate. METHOD: Elevation data were calculated with an approximate spatial resolution of 0.5 km, using zonal statistics on data sets compiled from the National Geospatial-Intelligence Agency and the National Aeronautics and Space Administration. Suicide and population density data were obtained through the Centers for Disease Control and Prevention (CDC) WONDER database. Gun ownership data were obtained through the CDC's Behavioral Risk Factor Surveillance System. RESULTS: A significant positive correlation was observed between age-adjusted suicide rate and county elevation (r=0.51). Firearm (r=0.41) and non-firearm suicide rates (r=0.32) were also positively correlated with mean county elevation. CONCLUSIONS: When altitude, gun ownership, and population density are considered as predictor variables for suicide rates on a state basis, altitude appears to be a significant independent risk factor. This association may be related to the effects of metabolic stress associated with mild hypoxia in individuals with mood disorders.

Keywords: Suicide

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Kirschner, K. L., Mukherjee, D., Gittler, M., Brenner, L.A., & Kelly, J. P. (2011). Setting limits: The threat of violence in the health care setting. The American Academy of Physical Medicine and Rehabilitation, 3, 68-72.

Abstract not available

Keywords: Suicide

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Knox KL, Stanley B, Currier GW, Brenner LA, Ghahramanlou-Holloway M, Brown GK. An emergency based brief intervention for veterans at risk for suicide (SAFE VET). Am J Public Health. 2012;102(S1):S33 – S37.

Reducing deaths from veteran suicide is a public health priority for veterans who receive their care from the Department of Veterans Affairs (VA) and those who receive services in community settings. Emergency departments frequently function as the primary or sole point of contact with the health care system for suicidal individuals; therefore, they represent an important venue in which to identify and treat veterans who are at risk for suicide. We describe the design, implementation and initial evaluation of a brief behavioral intervention for suicidal veterans seeking care at VA emergency departments. Initial findings of the feasibility and acceptability of the intervention suggest it may be transferable to diverse VA and non-VA settings, including community emergency departments and urgent care centers.

Keywords: Suicide

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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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Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, Spyker DA, Kehne JH, Cassella JV. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012 Feb;14(1):31-40.

Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, Spyker DA, Kehne JH, Cassella JV. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord 2012: 14: 31-40. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder. Methods: A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5mg or 10mg, or inhaled placebo using the Staccato(®) system. Following baseline assessments, patients received Dose 1 and were evaluated for 24hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10min through 24hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests. Results: For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo). Conclusions: Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

Keywords: Seriously Mentally Ill

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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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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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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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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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Maxey, J. J., Wortzel HS, & Martinez, R. (2011). Duty to warn or protect. The Journal of the American Academy of Psychiatry and the Law, 39, 430-432.

No abstract available.

Keywords: Incarcerated Veterans

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McFadden, K. L., Healy, K.M., Dettmann, M. L., Kaye, J. T., Ito, T. A., & Hernández, TD. (2011). Acupressure as a non-pharmacological intervention for traumatic brain injury (TBI). Journal of Neurotrauma, 28, 21-34.

Acupressure is a complementary and alternative medicine (CAM) treatment using fingertips to stimulate acupoints on the skin. Although suggested to improve cognitive function, acupressure has not been previously investigated with a controlled design in traumatic brain injury (TBI) survivors, who could particularly benefit from a non-pharmacological intervention for cognitive impairment. A randomized, placebo-controlled, single-blind design assessed the effects of acupressure (eight treatments over 4 weeks) on cognitive impairment and state of being following TBI, including assessment of event-related potentials (ERPs) during Stroop and auditory oddball tasks. It was hypothesized that active acupressure treatments would confer greater cognitive improvement than placebo treatments, perhaps because of enhanced relaxation response induction and resulting stress reduction. Significant treatment effects were found comparing pre- to post-treatment change between groups. During the Stroop task, the active-treatment group showed greater reduction in both P300 latency (p=0.010, partial η²=0.26) and amplitude (p=0.011, partial η²=0.26), as well as a reduced Stroop effect on accuracy (p=0.008, partial η²=0.21) than did the placebo group. Additionally, the active-treatment group improved more than did the placebo group on the digit span test (p=0.043, Cohen's d=0.68). Together, these results suggest an enhancement in working memory function associated with active treatments. Because acupressure emphasizes self-care and can be taught to novice individuals, it warrants further study as an adjunct treatment for TBI.

Keywords: Traumatic Brain Injury, Complementary and Alternative Medicine 

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McFadden KL, Hernández TD, Ito TA. Attitudes toward complementary and alternative medicine influence its use. Explore (NY). 2010 Nov-Dec;6(6):380-8.

OBJECTIVE: The aim of this study was to explore how attitudes toward complementary and alternative medicine (CAM) and conventional medicine influence CAM use in a healthy population, and how health locus of control and exercise further affect CAM use. DESIGN: A cross-sectional survey design was used. PARTICIPANTS: The sample consisted of 65 healthy graduate students. MAIN OUTCOME MEASURES: Since previous studies have focused on the attitudes of medical providers toward CAM, there are currently no standard, widely used measures of attitudes toward CAM from the perspective of the healthcare recipient. Thus, a new measure, the Complementary, Alternative, and Conventional Medicine Attitudes Scale (CACMAS) was created to address how attitudes of healthcare recipients affect CAM use. The Multidimensional Health Locus of Control Scale (MHLC) was used to investigate effects of health locus of control on CAM use, and participants reported which of 17 listed CAM treatments they had used in the past, were currently using, or would likely use in the future. Participants also reported days of exercise in the past month to explore if those engaging in healthy behaviors might report more CAM use. RESULTS: Having a philosophical congruence with CAM and agreement with holistic balance was associated with increased CAM use. Dissatisfaction with conventional medicine was also related to increased CAM use, but to a lesser extent. Those attributing health to personal behaviors (an internal health locus of control) reported more CAM use, as did those engaging in more resistance training in the previous month.

Keywords: Complementary and Alternative Medicine 

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McFadden KL, Hernández TD. Cardiovascular benefits of acupressure (Jin Shin) following stroke. Complement Ther Med. 2010 Feb;18(1):42-8. Epub 2010 Feb 6.

OBJECTIVES: Acupressure, a complementary and alternative medicine (CAM) treatment, uses fingertips, rather than needles, to stimulate acupoints on the skin and has been implicated as a successful treatment for a variety of medical disorders. However, acupressure's underlying mechanisms remain unclear. One theory is that acupoint stimulation modulates autonomic nervous system activity. Previous studies have suggested that acupressure may positively affect heart rate and blood pressure. The current study investigated the effects of a type of acupressure, Jin Shin, on cardiovascular function in stroke survivors, a population that could especially benefit from a treatment promoting cardiovascular health. The study tested the hypothesis that active acupressure treatments would reduce heart rate and blood pressure (i.e., induce a greater relaxation response) above and beyond that seen during placebo acupressure treatments. METHODS: A randomised, placebo-controlled, single-blind crossover design was utilised, in which 16 participants received 8 weeks of either active or placebo acupressure followed by washout and crossover into the opposite treatment condition. Heart rate and blood pressure measurements were taken throughout treatments. RESULTS: Active acupressure treatments were associated with a significantly greater (p=.043, eta(2)=.30) and faster (p=.002, eta(2)=.76) reduction in heart rate compared to that seen during placebo treatments. No treatment effect on blood pressure was found. CONCLUSIONS: Active acupressure reduced heart rate significantly more than did placebo acupressure during treatments. Although no treatment effect on blood pressure was found, this could be due to 67% of participants taking antihypertensive medications during the study.

Keywords: Complementary and Alternative Medicine 

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Muehlenkamp, J. J., Cowles, M. L., & Gutierrez, P.M. (2010). Validity of the self-harm behavior questionnaire with diverse adolescents. Journal of Psychopathology and Behavioral Assessment, 32, 236-245.

Suicide and non-suicidal self-injurious behavior (NSSI) continue to be significant health problems for adolescents. Although there are many instruments available to assess self-harm behaviors, few have been validated for use with adolescents, and even fewer have been validated for use with different racial/ethnic groups. The Self-Harm Behavior Questionnaire (SHBQ) assesses NSSI, suicidal ideation, suicide threats, and past suicide attempts. Data from 1,386 racially/ethnically diverse adolescents (57.5% minority) were collected to examine the validity of the SHBQ in this age group. Analyses supported the four-factor structure, revealed the SHBQ is internally consistent, and provided evidence for convergent validity within Caucasian, African American, and Hispanic adolescents. However, slight differences were noted. Overall, the findings suggest the SHBQ is a useful assessment tool appropriate for use with Caucasian, African American, and Hispanic adolescents.

Keywords: Suicide

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Olincy, A., Braff, D. L., Adler, L. E., Cadenhead, K. S., Calkins, M. E., Dobie, D. J. et al. (Freedman, R.) (2010). Inhibition of the P50 cerebral evoked response to repeated auditory stimuli. Results from the Consortium on Genetics of Schizophrenia. Schizophrenia Research; June; 119(1-3), 175-1782.

Inhibition of the P50 evoked electroencephalographic response to the second of paired auditory stimuli has been frequently examined as a neurophysiological deficit in schizophrenia. The Consortium on the Genetics of Schizophrenia (COGS), a 7-site study funded by the National Institute of Mental Health, examined this endophenotype in recordings from 181 probands with schizophrenia, 429 of their first degree relatives, and 333 community comparison control subjects. Most probands were treated with second generation antipsychotic medications. Highly significant differences in P50 inhibition, measured as either the ratio of amplitudes or their difference in response to the two stimuli, were found between the probands and the community comparison sample. There were no differences between the COGS sites for these findings. For the ratio parameter, an admixture analysis found that nearly 40% of the relatives demonstrated deficiencies in P50 inhibition that are comparable to the deficit found in the probands. These results indicate that P50 auditory evoked potentials can be recorded across multiple sites and reliably demonstrate a physiological abnormality in schizophrenia. The appearance of the physiological abnormality in a substantial proportion of clinically unaffected first degree relatives is consistent with the hypothesis that deficits in cerebral inhibition are a familial neurobiological risk factor for the illness.

Keywords: Seriously Mentally Ill (SMI)

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Olson-Madden, J., Brenner, L.A., Harwood, J. E., Emrick, C. D., Corrigan, J. D., & Thompson, C. (2010). Traumatic brain injury and psychiatric diagnoses in Veterans seeking outpatient substance abuse treatment. Journal of Head Trauma and Rehabilitation, 25(6), 470-479.

OBJECTIVES: Explore the incidence of traumatic brain injury (TBI) in veterans seeking outpatient substance abuse treatment and the association between TBI and psychiatric diagnoses. MAIN MEASURE: The Ohio State University TBI identification method (OSU TBI-ID) was administered to veterans with positive TBI-4 screens; substance-related and psychiatric diagnoses were extracted from the medical record. PARTICIPANTS: : Over an 18-month period, 247 veterans completed the TBI-4. Of the 136 who screened positive, 70 were administered the OSU TBI-ID. RESULTS: On the basis of the TBI-4, 55% (95% CI: 49%-61%) of veterans screened positive for a history of TBI. The OSU TBI-ID was used to confirm screening results. Those who completed the OSU TBI-ID sustained an average of 3.4 lifetime TBIs. For each additional TBI sustained, after initial injury, there was an estimated 9% increase in the number of psychiatric diagnoses documented (99% CI: 1%-17%). For each additional documented psychiatric diagnosis, there was an estimated increase of 11% in the number of injuries sustained (99% CI: 1%-22%). Also, 54% (38/70) had a positive history of TBI prior to adulthood. CONCLUSION: These results emphasize the need for TBI screening in this vulnerable population, as well as the importance of increasing brain injury awareness among those abusing substances and their care providers. These findings also highlight the need for specialized services for those with TBI and co-occurring substance misuse aimed at decreased future TBIs or negative psychiatric outcomes or both. Further study is needed to clarify best practices.

Keywords: Traumatic Brain Injury (TBI), Substance Use Disorders (SUD)

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Ongur, D., Haddad, S., Prescot, A. P., Jensen, J. E., Siburian, R., Cohen, B. M., Renshaw, P.F., & Smoller, J. W. (2011). Relationship between genetic variation in the glutaminase gene GLS1 and brain glutamine/glutamate ratio measured in vivo. Biological Psychiatry, 70(2), 169-174.

BACKGROUND: Abnormalities in glutamatergic neurotransmission are implicated in several psychiatric disorders, but in vivo neurochemical studies of the glutamate (Glu) system have been hampered by a lack of adequate probes. By contrast, glutamine (Gln) and Glu can be quantified separately in proton magnetic resonance spectroscopy studies in vivo. Accumulating evidence suggests that the Gln/Glu ratio is a putative index of glutamatergic neurotransmission but interpretation of changes in the Gln/Glu ratio depends on the conditions of the system, including ammonia levels. METHODS: Here, we explored whether variation in GLS1 (the gene encoding the brain isoform of glutaminase, which catalyzes Gln-to-Glu conversion) is associated with Gln/Glu measured in vivo in two brain regions (anterior cingulate cortex, parieto-occipital cortex). RESULTS: A specific haplotype of four single nucleotide polymorphisms within GLS1 was significantly associated with Gln/Glu in the parieto-occipital cortex in an magnetic resonance spectroscopy-genetics dataset optimized for Gln/Glu detection (n = 42). This finding was replicated in a second magnetic resonance spectroscopy dataset that was optimized for γ-aminobutyric acid detection where Gln and Glu measurements could still be extracted (n = 40). CONCLUSIONS: These findings suggest that genetic variation in a key component of glutamatergic machinery is associated with a putative in vivo index of glutamatergic neurotransmission. Thus, GLS1 genotype might provide insight into normal brain function and into the pathophysiology of many psychiatric conditions where glutamatergic neurotransmission has been implicated. It might also serve as a biomarker for predicting response to existing and novel therapeutic interventions in psychiatry that target glutamatergic neurotransmission.

Keywords: Brain & Biology

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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., 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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Osman, A., Bagge, C. L., Freedenthal, S., Gutierrez, P.M., & Emmerich, A. (2011). Development and evaluation of the social anxiety and depression life interference-24 (SADLI-24) inventory. Journal of Clinical Psychology, 67(1), 82-98.

We describe the development of a new self-report instrument, the Social Anxiety and Depression Life Interference-24 (SADLI-24) inventory. We initially retained 30 content specific items for the instrument (Study 1). In Study 2 (N = 438), we established a 2-factor solution, Social Anxiety Life Interference-12 (SALI-12) and Depression Life Interference-12 (DLI-12). We also examined estimates of known-groups and concurrent validity. Confirmatory factor analysis in Study 3 (N = 430) provided support for the oblique two-factor structure. In Study 4 (N = 179), we provided additional support for estimates of known-groups validity. In Study 5 (N = 63), we evaluated estimates of test-retest reliability. Both SADLI-24 scale scores showed good estimates of internal consistency.

Keywords: Assessment, Evidence Based Treatment, Seriously Mentally Ill (SMI)

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Osman, A., Freedenthal, S., Fang, Q., Willis, J., Norizuki, T., & Gutierrez, P.M. (2011). The UTSA Future Disposition Inventory: Further analyses of reliability, validity, and potential correlates in non-clinical samples. In A. M. Columbus (Ed.) Advances in psychology research. Hauppauge, NY: Nova Science Publishers, Inc.

Abstract not available

Keywords: Assessment, Evidence Based Treatment, Seriously Mentally Ill (SMI)

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Osman, A., Freedenthal, S., Gutierrez, P.M., Wong, J. L., Emmerich, A., & Lozano, G. (2011). The Anxiety Depression Distress Inventory-27 (ADDI-27): A short version of the Mood and Anxiety Symptom Questionnaire-90. Journal of Clinical Psychology, 67(6), 591-608.

The authors conducted three studies to construct and examine the psychometric properties of a 27-item version of the Mood and Anxiety Symptom Questionnaire-90 (MASQ-90; Watson & Clark, 1991a). The Anxiety Depression Distress Inventory-27 (ADDI-27) contains three empirically derived scales: Positive Affect, Somatic Anxiety, and General Distress, which are relevant dimensions of the tripartite model of affect. Each scale is composed of nine items, and the estimate of scale reliability for each scale score was ≥ .80 across the three studies. Results of exploratory and confirmatory factor analyses provided adequate support for a 3-factor model. Additional estimates of concurrent validity documented the ADDI-27 scales' convergent and discriminant validity. We also identified three construct relevant correlates for each scale score. Overall, the ADDI-27 appears to be a content valid, reliable, and multidimensional measure of the tripartite model of affect.

Keywords: Assessment, Evidence Based Treatment, Seriously Mentally Ill (SMI)

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Osman, A., Gutierrez, P.M., Bagge, C. L., Fang, Q., & Emmerich, A. (2010). Reynolds adolescent depression scale-second edition: A reliable and useful instrument. Journal of Clinical Psychology, 66(12), 1324-1345.

The authors conducted two studies to address issues of the dimensionality, scale reliability, and psychometric properties of scores on the Reynolds Adolescent Depression Scale-Second Edition (RADS-2; Reynolds, 2002) in samples of adolescent psychiatric inpatients. In Study 1 (N=262), they used bifactor analysis to further evaluate the general and specific components of the RADS-2. In Study 2 (N=196), they used confirmatory factor analysis to evaluate the fit of a 1-factor model, the original 4-factor model, a second-order model, and a bifactor model to a new sample data. In both studies, the total RADS-2 and content-specific subscale scores showed acceptable estimates of reliability (i.e., scale reliability estimates >.80). Estimates of concurrent validity were also examined. Scores of the RADS-2 total and content-specific subscale scores were useful in differentiating between the responses of youth with mood disorder diagnoses and those with other primary psychiatric disorder diagnoses. The authors also conducted correlation analyses to identify potential correlates for the total RADS-2 scale and the proposed subscale scores.

Keywords: Assessment, Evidence Based Treatment, Seriously Mentally Ill (SMI)

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Osman, A., Gutierrez, P.M., Barrios, F., Wong, J. L., Freedenthal, S., & Lozano, G. (2010). Development and Initial Psychometric Properties of the UTSA Future Disposition Inventory. Journal of Clinical Psychology, 66(4), 1-20.

We describe the development and initial psychometric properties of a 24-item self-report measure, the University of Texas at San Antonio Future Disposition Inventory (UTSA FDI). This instrument is designed to evaluate future related thoughts and feelings that are associated with suicide-related risk behaviors: positive focus, suicide orientation, and negative focus. The items were generated by clinical and nonclinical samples. The structure of the instrument was defined in a sample of 350 university undergraduate students (Study 1). Using CFA, we confirmed the fit of the 3-factor solution in an independent sample of college age students (n=452; Study 2). Scale reliability estimates were good (all rho's>or=.80) in both studies. Known-groups validation analyses showed that scores on each scale were useful in differentiating the responses of the study groups. Correlates for the scales were identified when scores on measures of suicide-related risk and general psychological symptoms were included as validation self-report instruments.

Keywords: Assessment, Evidence Based Treatment, Seriously Mentally Ill (SMI)

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Osman, A., Gutierrez, P.M., Schweers, R., Fang, Q., Holguin-Mills, R. L., & Cashin, M. (2010). Psychometric Evaluation of the Body Investment Scale for Use with Adolescents. Journal of Clinical Psychology, 66(3), 259-276.

We conducted two studies to examine the psychometric properties of the Body Investment Scale (BIS; Orbach & Mikulincer, 1998) in U.S. adolescent samples. The BIS was designed to assess bodily experiences that are associated with suicide-related behaviors. In Study 1, confirmatory factor analysis (CFA) with data from a combined sample of 204 high school adolescents (83 boys, 121 girls) and 197 psychiatric inpatient (101 boys, 96 girls) adolescents provided moderate support for the oblique four-factor solution: Body Feelings (rho=.86, 95% CI=.83-.89), Body Touch (rho=.71, 95% CI=.65-.76), Body Care (rho=.78, 95% CI=.71-.81), and Body Protection (rho=.78, 95% CI=.73-.82); robust comparative fit index=.88 and the robust Tucker Lewis Index=.83. The second-order factor model also provided moderate fit to the data. In Study 2, results of the CFA with data from adolescent psychiatric inpatients (N=205; 101 boys, 104 girls) provided additional support for the four-factor solution. In addition, results of the receiver operating characteristic and logistic regression analyses showed that scores on the Body Feelings and Body Protection scales were most useful in differentiating the responses of suicidal and nonsuicidal adolescents, all Cohen's d values >.30. The study also examined associations between scores on the BIS scales and the validation self-report measures of hopelessness, suicide-related behavior, and reasons for living.

Keywords: Assessment, Evidence Based Treatment, Seriously Mentally Ill (SMI)

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Osman, A., Gutierrez, P.M., Smith, K., Fang, Q., Lozano, G., & Devine, A. (2010). The Anxiety Sensitivity Index-3: Analyses of Dimensions, Reliability Estimates, and Correlates in Nonclinical Samples. Journal of Personality Assessment, 92(1), 45-52.

We investigated the factor structure, reliability estimates, and correlates of the Anxiety Sensitivity Index-3 (ASI-3; Taylor et al., 2007) in 2 studies. We established a bifactor model in Study 1 as an alternative representation of the structure of the ASI-3. Analyses of gender differences on the total ASI-3 and subscale scores were not statistically significant (Study 1, N = 462). In Study 2 (N = 293), results of a series of confirmatory factor analyses provided stronger support for the fit of the bifactor model compared with 2 alternative models. Estimates of scale reliability were adequate (all rho values > or = .80) and not "p" (as in italic p for significance). in the 2 studies. In addition, using simultaneous regression analyses, we found anxiety-specific correlates for the total ASI-3 and subscale scores to include responses on self-report measures of interpersonal sensitivity, obsessive-compulsive anxiety, paranoid ideation, and phobic anxiety.

Keywords: Assessment, Evidence Based Treatment, Seriously Mentally Ill (SMI)

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Osman, A., Gutierrez, P.M., Wong, J. L., Freedenthal, S., Bagge, C. L., & Smith, K. D. (2010). Development and Psychometric Evaluation of the Suicide Anger Expression Inventory--28. Journal of Psychopathology and Behavior Assessment, 32, 595-608.

Abstract not available

Keywords: Assessment, Evidence Based Treatment, 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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Ribeiro JD, Pease JL, Gutierrez PM, Silva C, Bernert RA, Rudd MD, Joiner TE Jr. Sleep problems outperform depression and hopelessness as cross-sectional and longitudinal predictors of suicidal ideation and behavior in young adults in the military. J Affect Disord. 2012 Feb;136(3):743-50.

Background: Sleep problems appear to represent an underappreciated and important warning sign and risk factor for suicidal behaviors. Given past research indicating that disturbed sleep may confer such risk independent of depressed mood, in the present report we compared self-reported insomnia symptoms to several more traditional, well-established suicide risk factors: depression severity, hopelessness, PTSD diagnosis, as well as anxiety, drug abuse, and alcohol abuse symptoms.

Methods: Using multiple regression, we examined the cross-sectional and longitudinal relationships between insomnia symptoms and suicidal ideation and behavior, controlling for depressive symptom severity, hopelessness, PTSD diagnosis, anxiety symptoms, and drug and alcohol abuse symptoms in a sample of military personnel (N=311).

Results: In support of a priori hypotheses, self-reported insomnia symptoms were crosssectionally associated with suicidal ideation, even after accounting for symptoms of depression, hopelessness, PTSD diagnosis, anxiety symptoms and drug and alcohol abuse. Selfreported insomnia symptoms also predicted suicide attempts prospectively at one-month follow up at the level of a non-significant trend, when controlling for baseline self-reported insomnia symptoms, depression, hopelessness, PTSD diagnosis and anxiety, drug and alcohol abuse symptoms. Insomnia symptoms were unique predictors of suicide attempt longitudinally when only baseline self-reported insomnia symptoms, depressive symptoms and hopelessness were controlled.

Limitations: The assessment of insomnia symptoms consisted of only three self-report items. Findings may not generalize outside of populations at severe suicide risk. Conclusions: These findings suggest that insomnia symptoms may be an important target for suicide risk assessment and the treatment development of interventions to prevent suicide.

Keywords: Suicide, PTSD, Substance Use Disorders (SUD) 

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Rings, J. A. (2010). My time with June: Overcoming my grief and loss "expertise." In Trotter-Mathison, M., Koch, J. M., Sanger, S. E. & Skovholt, T. (Eds.). Voices from the field: Defining moments in counselor and therapist development. (pp. 119-122) New York: Routledge.

Abstract not available

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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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Ross, R. G., Stevens, K. E., Proctor, W. R., Leonard, S., Kisley, M. A., Hunter, S. K., et al. (Freedman, R.) (2010). Research review: Cholinergic mechanisms, early brain development, and risk for schizophrenia. Child Psychology and Psychiatry, 51, 535-549.

The onset of diagnostic symptomology for neuropsychiatric diseases is often the end result of a decades-long process of aberrant brain development. Identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal. However, there are few models for how this goal might be achieved. This review uses the development of a psychophysiological correlate of attentional deficits in schizophrenia to propose a developmental model with translational primary prevention implications. Review of genetic and neurobiological studies suggests that an early interaction between alpha7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Therapeutic implications, including perinatal dietary choline supplementation, are discussed.

Keywords: Seriously Mentally Ill (SMI)

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Sanders, A. R., Levinson, D. F., Duan J., Dennis, J. M., Li, R., et al. (Freedman, R.) (2010). An internet-based NIMH control sample for genetic studies: Self report of mental illness. American Journal of Psychiatry, 167(7), 854-865.

OBJECTIVE: The Molecular Genetics of Schizophrenia (MGS2) project recruited an adult control sample of non-Hispanic European-ancestry (N=3,364) and African American (N=1,301) subjects. METHOD: Subjects gave consent to deposit phenotypic data and blood samples into a repository for general research use, with full anonymization of the sample. The authors compared the control sample with population census data for demographic data and with previous population surveys for anthropometrics and prevalences of psychiatric disorders as estimated by an Internet-administered questionnaire. RESULTS: The full MGS2 control sample includes 4,665 subjects (European-ancestry: N=3,364; African American: N=1,301), of whom 3,626 were included in the MGS2 genome-wide association study (GWAS). The sample is generally demographically representative of the U.S. population, except for being older and more female, educated, and affluent, although all strata are represented. Self-reported ancestry was consistent with genotypic and census data. Lifetime prevalences for depressive, anxiety, and substance use diagnoses were higher than in previous population-based surveys, probably due to use of an abbreviated self-report instrument. However, patterns such as sex ratios, comorbidity, and demographic associations were consistent with previous reports. DNA quality for the Internet collected/evaluated control sample was comparable to that of the face-to-face case sample. CONCLUSIONS: The Internet-based methods facilitated the rapid collection of large and anonymized non-Hispanic European-ancestry and African American control samples that have been validated as being generally representative for many aspects of demography, ancestry, and morbidity. Utilization of clinical screening data shared with the scientific community may permit investigators to select appropriate controls for some studies.

Keywords: Seriously Mentally Ill (SMI)

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Selby, E. A., Anestis, M. D., Bender, T. W., Ribeiro, J. D, Nock, M. K., Rudd, et al. (Gutierrez, P.M.) (2010). Overcoming the fear of lethal injury: Evaluating suicide in the military through the lens of the interpersonal-psychological theory of suicide. Clinical Psychology Review, 30, 298-307.

Suicide rates have been increasing in military personnel since the start of Operation Enduring Freedom and Operation Iraqi Freedom, and it is vital that efforts be made to advance suicide risk assessment techniques and treatment for members of the military who may be experiencing suicidal symptoms. One potential way to advance the understanding of suicide in the military is through the use of the Interpersonal-Psychological Theory of Suicide. This theory proposes that three necessary factors are needed to complete suicide: feelings that one does not belong with other people, feelings that one is a burden on others or society, and an acquired capability to overcome the fear and pain associated with suicide. This review analyzes the various ways that military service may influence suicidal behavior and integrates these findings into an overall framework with relevant practical implications. Findings suggest that although there are many important factors in military suicide, the acquired capability may be the most impacted by military experience because combat exposure and training may cause habituation to fear of painful experiences, including suicide. Future research directions, ways to enhance risk assessment, and treatment implications are also discussed.

Keywords: Suicide

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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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Simpson, G., & Brenner, L.A. (2011). Perspectives on suicide and traumatic brain injury. Journal of Head Trauma and Rehabilitation, 26(4), 241-243.

Abstract not available

Keywords: Suicide, Traumatic Brain Injury (TBI)

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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 and Alternative Medicine

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Swogger, M. T., Walsh, Z., Homaifar, B. Y., Caine, E. D., & Conner, K. R. (2011). Predicting self- and other-directed violence among discharged psychiatric patients: the roles of anger and psychopathic traits. Psychological Medicine. Jul 18:1-9.

BACKGROUND: We examined the extent to which trait anger and psychopathic traits predicted post-discharge self-directed violence (SDV) and other-directed violence (ODV) among psychiatric patients.MethodParticipants were 851 psychiatric patients sampled from in-patient hospitals for the MacArthur Violence Risk Assessment Study (MVRAS). Participants were administered baseline interviews at the hospital and five follow-up interviews in the community at approximately 10-week intervals. Psychopathy and trait anger were assessed with the Psychopathy Checklist: Screening Version (PSC:SV) and the Novaco Anger Scale (NAS) respectively. SDV was assessed during follow-ups with participants and ODV was assessed during interviews with participants and collateral informants. Psychopathy facets and anger were entered in logistic regression models to predict membership in one of four groups indicating violence status during follow-up: (1) SDV, (2) ODV, (3) co-occurring violence (COV), and (4) no violence. RESULTS: Anger predicted membership in all three violence groups relative to a non-violent reference group. In unadjusted models, all psychopathy facets predicted ODV and COV during follow-up. In adjusted models, interpersonal and antisocial traits of psychopathy predicted membership in the ODV group whereas only antisocial traits predicted membership in the COV group. CONCLUSIONS: Although our results provide evidence for a broad role for trait anger in predicting SDV and ODV among discharged psychiatric patients, they suggest that unique patterns of psychopathic traits differentially predict violence toward self and others. The measurement of anger and facets of psychopathy during discharge planning for psychiatric patients may provide clinicians with information regarding risk for specific types of violence.

Keywords: Suicide

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Terrio, H. P., Nelson, L. A., Betthsuser, L. M., Harwood, J. E., & Brenner, L.A. (2011). Postdeployment traumatic brain injury screening questions: Sensitivity, specificity, and predictive values in returning soldiers. Rehabilitation Psychology, 56(1), 26-31.

OBJECTIVE: To evaluate the sensitivity, specificity, and predictive values of Post-Deployment Health Assessment traumatic brain injury (TBI) screening questions employed by the Department of Defense (DOD). Participants: Complete data was obtained from 3,072 soldiers upon return from a 15-month deployment to Iraq. METHOD: Comparisons were made between responses to the DOD four-item screener and a brief structured clinical interview for likely deployment-related TBI history. The interview process was facilitated using responses to the Warrior Administered Retrospective Casualty Assessment Tool (WARCAT). RESULTS: The sensitivity and specificity of the DOD screening tool (positive response to all four items) in comparison to the clinician-confirmed diagnosis was 60% and 96%, respectively. The sensitivity increased to 80%, with a slight decrease in specificity to 93%, for positive TBI screening when affirmative responses to questions 1 and 2 only were included. CONCLUSIONS: Affirmative responses to questions 1 and 2 of the DOD TBI screening tool demonstrated higher sensitivity for clinician-diagnosed deployment-related TBI. These two items perform better than positive responses to all four questions; the criteria presently being used for documentation and referral of a deployment-related TBI. These findings support further exploration of TBI screening and assessment procedures.

Keywords: Traumatic Brain Injury (TBI), OEF/OIF/OND

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Thurman, M. T., Wortzel HS, & Martinez, R. (2011). Mental health evaluation/counseling as a special condition of supervised release. The Journal of the American Academy of Psychiatry and the Law, 39, 432-434.

Abstract not available

Keywords: Incarcerated Veterans

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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 & BiologySeriously 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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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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Waldo, M. C., Woodward, L., & Adler, L. E. (2010). Varenicline and p50 auditory gating in medicated schizophrenic patients: A pilot study. Psychiatry Research.

Most schizophrenic patients have a deficit in auditory sensory gating that appears to be mediated by the alpha-7 nicotinic receptor. This pilot study examines the effects of varenicline, an alpha-7 agonist, on the P50 auditory evoked potential in six schizophrenic patients. The study was canceled because of concerning side effects consistent with those reported by the FDA. However, in this small group of subjects, varenicline did not consistently enhance P50 auditory gating.

Keywords: Seriously Mentally Ill (SMI)

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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 & Arciniegas, D. B. (2010). Combat veterans and the death penalty: A forensic neuropsychiatric perspective. Journal of the American Academy of Psychiatry and the Law, 38(3), 407-414.

With our nation's present conflicts, a new generation of veterans are returning home, many of whom have substantial psychopathology and are encountering significant barriers in accessing care. Headlines from around the nation reflect that some of these wounded warriors go on to commit offenses that are potentially punishable by death. Existing circumstances speak to the urgency with which the subject of combat veterans with post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), or both facing capital crimes ought to be addressed. This publicity has led to a recent call for a legislatively or judicially enacted, narrow, categorical exclusion for combat veterans who were affected by either PTSD or TBI at the time of their capital offenses. In the present article, we illustrate the reality that combat veterans who commit capital offenses may face execution, summarize legal arguments offered in favor of a categorical exclusion, and provide a neuropsychiatric perspective on PTSD, TBI, and aggression, to help inform further dialogue on this weighty subject.

Keywords: Incarcerated Veterans

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Wortzel HS & Arciniegas, D. B. (2011). Cognitive impairment and rehabilitation. In C. Coffey & J. Cummings (Eds.), Textbook of Geriatric Neuropsychiatry, Third Edition. (pp. 331-351). Arlington, VA: American Psychiatric Publishing.

Abstract not available

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Wortzel HS, Gutierrez PM, Homaifar BY, Breshears RE, Harwood JE. Surrogate endpoints in suicide research. Suicide Life Threat Behav. 2010 Oct;40(5):500-5.

Surrogate endpoints frequently substitute for rare outcomes in research. The ability to learn about completed suicides by investigating more readily available and proximate outcomes, such as suicide attempts, has obvious appeal. However, concerns with surrogates from the statistical science perspective exist, and mounting evidence from psychometric, neurochemical, genetic, and neuroimaging studies suggests that surrogates may be particularly problematic in suicide research. The need for greater phenotypic refinement of suicide-related behaviors, development of and adherence to a shared suicide nomenclature, and conservative interpretation of investigational results that are limited to the precise population and suicide-related behavior under examination are discussed.

Keywords: Suicide

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Wortzel HS, Kraus MF, Filley CM, Anderson CA, Arciniegas DB. Diffusion tensor imaging in mild traumatic brain injury litigation. J Am Acad Psychiatry Law. 2011;39(4):511-23.

A growing body of literature addresses the application of diffusion tensor imaging (DTI) to traumatic brain injury (TBI). Most TBIs are of mild severity, and their diagnosis and prognosis are often challenging. These challenges may be exacerbated in medicolegal contexts, where plaintiffs seek to present objective evidence that supports a clinical diagnosis of mild (m)TBI. Because DTI permits quantification of white matter integrity and because TBI frequently involves white matter injury, DTI represents a conceptually appealing method of demonstrating white matter pathology attributable to mTBI. However, alterations in white matter integrity are not specific to TBI, and their presence does not necessarily confirm a diagnosis of mTBI. Guided by rules of evidence shaped by Daubert v. Merrell Dow Pharmaceuticals, Inc., we reviewed and analyzed the literature describing DTI findings in mTBI and related neuropsychiatric disorders. Based on this review, we suggest that expert testimony regarding DTI findings will seldom be appropriate in legal proceedings focused on mTBI.

Keywords: Incarcerated Veterans, Traumatic Brain Injury (TBI)

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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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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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