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Deborah Yurgelun-Todd is an Associate Director for the Rocky Mountain MIRECC and a USTAR Professor of Psychiatry at the University of Utah School of Medicine as well as the Director of the Cognitive Neuroimaging Laboratory at the Brain Institute at the University of Utah.
She received her PhD in Psychology from Harvard University and completed her clinical training at McLean Hospital, Harvard Medical School receiving her clinical license in 1990. Before relocating to the University of Utah she spent 19 years on the psychiatry faculty at Harvard Medical School where she established and directed the McLean Hospital Cognitive Neuroimaging Program.
Her research focus is on identifying the neuropsychological and neurobiological bases of major psychiatric disorders including substance abuse and mood disorders. Dr. Yurgelun-Todd is an expert in the application of structural and functional magnetic resonance imaging, the administration and analysis of neurocognitive tests, and the integration of the results obtained by using multiple imaging modalities combined with clinical assessment.
Dr. Yurgelun-Todd has received funding for her research from NIMH, NIDA, the Department of Veteran’s Affairs, and pharmaceutical companies as well as private foundations. Her recent work has focused on understanding the neurobiologic basis of suicide, impulsivity, mood regulation and decision-making and the impact of substance abuse on networks related to these functions. She is the Director of the Advanced Fellowship in Mental Illness Research and Treatment at the Salt Lake City MIRECC.
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.
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.
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.
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)
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.
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.
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.
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)
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.
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)
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)
White, R.F., Palumbo, C. L., Yurgelun-Todd, D.A., Heaton, K. J., Weihe, P., Debes, F., et al. 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.
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.