Browsing by Author "Kareken, David A."
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Item Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking(Wiley Blackwell (Blackwell Publishing), 2015-07) Kosobud, Ann E. K.; Wetherill, Leah; Plawecki, Martin H.; Kareken, David A.; Liang, Tiebing; Nurnberger, John L.; Windisch, Kyle; Xuei, Xiaoling; Edenberg, Howard J.; Foroud, Tatiana M.; O’Connor, Sean J.; Department of Psychiatry, IU School of MedicineBACKGROUND: Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. METHODS: One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. RESULTS: Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. CONCLUSIONS: Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.Item Alcohol Affects the P3 Component of an Adaptive Stop Signal Task ERP(Elsevier, 2017) Plawecki, Martin H.; Windisch, Kyle A.; Wetherill, Leah; Kosubud, Ann E. K.; Dzemidzic, Mario; Kareken, David A.; O'Connor, Sean J.; Department of Psychiatry, School of MedicineBACKGROUND The P3 component of the event-related potential (ERP) has been particularly useful in alcohol research for identifying endophenotypes of alcohol use disorder (AUD) risk in sober subjects. However, practice and/or fatigue reduces P3 amplitude, limiting the ability to ascertain acute and adaptive effects of alcohol exposure. Here, we report acute alcohol effects on P3 amplitude and latency using an adaptive stop signal task (aSST). METHODS One hundred and forty eight nondependent moderate to heavy social drinkers, age 21 to 27, participated in 2 single-blind, alcohol or placebo, counterbalanced sessions approximately one week apart. During each session, subjects performed an adaptive stop signal task (aSST) at (1) baseline, (2) upon reaching the target 60 mg/dL breath alcohol concentration or at the equivalent time during the placebo session, and (3) approximately 135 minutes later while the breath alcohol concentration was clamped. Here, we report on differences between baseline and first subsequent measurements across the experimental sessions. During each aSST run, the stop signal delay (SSD, the time between stop and go signals) adjusted trial-by-trial based on the subject’s performance. RESULTS The aSST reliably generated a STOP P3 component that did not change significantly with repeated task performance. The pre-infusion SSD distribution was bimodal, with mean values several hundred msec apart (FAST: 153 msec and SLOW: 390 msec). This suggested different response strategies: FAST SSD favoring “going” over “stopping,” and SLOW SSD favoring “stopping” over “going”. Exposure to alcohol at 60 mg/dL differentially affected the amplitude and latency of the STOP P3 according to SSD group. Alcohol significantly reduced P3 amplitude in the SLOW SSD compared to FAST SSD group, but significantly increased P3 latency in the FAST SSD compared to SLOW SSD group. CONCLUSIONS The aSST is a robust and sensitive task for detecting alcohol induced changes in inhibition behavior as measured by the P3 component in a within subject design. Alcohol was associated with P3 component changes which varied by SSD group, suggesting a differential effect as a function of task strategy. Overall, the data support the potential utility of the aSST in the detection of alcohol response related AUD risk.Item Alcohol Use Disorder Interventions Targeting Brain Sites for Both Conditioned Reward and Delayed Gratification(SpringerLink, 2020-01) Oberlin, Brandon G.; Shen, Yitong I.; Kareken, David A.; Psychiatry, School of MedicineAlcohol use disorder is a destructive compulsion characterized by chronic relapse and poor recovery outcomes. Heightened reactivity to alcohol-associated stimuli and compromised executive function are hallmarks of alcohol use disorder. Interventions targeting these two interacting domains are thought to ameliorate these altered states, but the mutual brain sites of action are yet unknown. Although interventions on alcohol cue reactivity affect reward area responses, how treatments alter brain responses when subjects exert executive effort to delay gratification is not as well-characterized. Focusing on interventions that could be developed into effective clinical treatments, we review and identify brain sites of action for these two categories of potential therapies. Using activation likelihood estimation (ALE) meta-analysis, we find that interventions on alcohol cue reactivity localize to ventral prefrontal cortex, dorsal anterior cingulate, and temporal, striatal, and thalamic regions. Interventions for increasing delayed reward preference elicit changes mostly in midline default mode network regions, including posterior cingulate, precuneus, and ventromedial prefrontal cortex-in addition to temporal and parietal regions. Anatomical co-localization of effects appears in the ventromedial prefrontal cortex, whereas effects specific to delay-of-gratification appear in the posterior cingulate and precuneus. Thus, the current available literature suggests that interventions in the domains of cue reactivity and delay discounting alter brain activity along midline default mode regions, specifically in the ventromedial prefrontal cortex for both domains, and the posterior cingulate/precuneus for delay-of-gratification. We believe that these findings could facilitate targeting and development of new interventions, and ultimately treatments of this challenging disorder.Item The apéritif effect: Alcohol's effects on the brain's response to food aromas in women(Wiley Blackwell (John Wiley & Sons), 2015-07) Eiler, William J. A.; Džemidžić, Mario; Case, K. Rose; Soeurt, Christina M.; Armstrong, Cheryl L. H.; Mattes, Richard D.; O'Connor, Sean J.; Harezlak, Jaroslaw; Acton, Anthony J.; Considine, Robert V.; Kareken, David A.; Department of Neurology, IU School of MedicineOBJECTIVE: Consuming alcohol prior to a meal (an apéritif) increases food consumption. This greater food consumption may result from increased activity in brain regions that mediate reward and regulate feeding behavior. Using functional magnetic resonance imaging, we evaluated the blood oxygenation level dependent (BOLD) response to the food aromas of either roast beef or Italian meat sauce following pharmacokinetically controlled intravenous infusion of alcohol. METHODS: BOLD activation to food aromas in non-obese women (n = 35) was evaluated once during intravenous infusion of 6% v/v EtOH, clamped at a steady-state breath alcohol concentration of 50 mg%, and once during infusion of saline using matching pump rates. Ad libitum intake of roast beef with noodles or Italian meat sauce with pasta following imaging was recorded. RESULTS: BOLD activation to food relative to non-food odors in the hypothalamic area was increased during alcohol pre-load when compared to saline. Food consumption was significantly greater, and levels of ghrelin were reduced, following alcohol. CONCLUSIONS: An alcohol pre-load increased food consumption and potentiated differences between food and non-food BOLD responses in the region of the hypothalamus. The hypothalamus may mediate the interplay of alcohol and responses to food cues, thus playing a role in the apéritif phenomenon.Item Assessment of the dopamine system in addiction using positron emission tomography(2014) Albrecht, Daniel Strakis; Hutchins, Gary D.; Saykin, Andrew J.; Kareken, David A.; Yoder, Karmen K.; Grahame, Nicholas J.Drug addiction is a behavioral disorder characterized by impulsive behavior and continued intake of drug in the face of adverse consequences. Millions of people suffer the financial and social consequences of addiction, and yet many of the current therapies for addiction treatment have limited efficacy. Therefore, there is a critical need to characterize the neurobiological substrates of addiction in order to formulate better treatment options. In the first chapter, the striatal dopamine system is interrogated with [11C]raclopride PET to assess differences between chronic cannabis users and healthy controls. The results of this chapter indicate that chronic cannabis use is not associated with a reduction in striatal D2/D3 receptor availability, unlike many other drugs of abuse. Additionally, recent cannabis consumption in chronic users was negatively correlated with D2/D3 receptor availability. Chapter 2 describes a retrospective analysis in which striatal D2/D3 receptor availability is compared between three groups of alcohol-drinking and tobacco-smoking subjects: nontreatment-seeking alcoholic smokers, social-drinking smokers, and social-drinking non-smokers. Results showed that smokers had reduced D2/D3 receptor availability throughout the striatum, independent of drinking status. The results of the first two chapters suggest that some combustion product of marijuana and tobacco smoke may have an effect on striatal dopamine concentration. Furthermore, they serve to highlight the effectiveness of using baseline PET imaging to characterize dopamine dysfunction in addictions. The final chapter explores the use of [18F]fallypride PET in a proof-of-concept study to determine whether changes in cortical dopamine can be detected during a response inhibition task. We were able to detect several cortical regions of significant dopamine changes in response to the task, and the amount of change in three regions was significantly associated with task performance. Overall, the results of Chapter 3 validate the use of [18F]fallypride PET to detect cortical dopamine changes during a impulse control task. In summary, the results reported in the current document demonstrate the effectiveness of PET imaging as a tool for probing resting and activated dopamine systems in addiction. Future studies will expand on these results, and incorporate additional methods to further elucidate the neurobiology of addiction.Item Association of structural brain imaging markers with alcoholism incorporating structural connectivity information: a regularized statistical approach(Office of the Vice Chancellor for Research, 2016-04-08) Karas, Marta; Dzemidzic, Mario; Goñi, Joaquin; Kareken, David A.; Harezlak, JaroslawAbstract: Brain imaging studies collect multiple imaging data types, but most analyses are done for each modality separately. Statistical methods that simultaneously utilize and combine multiple data types can instead provide a more holistic view of brain function. Here we model associations between alcohol abuse phenotypes and imaging data while incorporating prior scientific knowledge. Specifically, we utilize cortical thickness and integrated rectified mean curvature measures obtained by FreeSurfer software [1] to predict the alcoholism-related phenotypes while incorporating prior information from the structural connectivity between cortical regions. The sample consisted of 148 young (21-35 years) social-to-heavy drinking male subjects from several alcoholism risk studies [2,3,4]. Structural connectivity model [5] was used to estimate the density of connections between 66 cortical regions based on Desikan-Killiany atlas [6]. We employed a functional linear model with a penalty operator to quantify the relative contributions of imaging markers obtained from high resolution structural MRI (cortical thickness and curvature) as predictors of drinking frequency and risk-relevant personality traits, while co-varying for age. Model parameters were estimated by a unified approach directly incorporating structural connectivity information into the estimation by exploiting the joint eigenproperties of the predictors and the penalty operator [7]. We found that the best predictive imaging markers of the Alcohol Use Disorders Identification Test (AUDIT) score were the average thickness of left frontal pole (-), right transverse temporal gyrus (+), left inferior parietal lobule (+), right supramarginal gyrus (-), right rostral middle frontal gyrus (+), right precentral gyrus (+), left superior parietal lobule (-), left lateral orbitofrontal cortex (+), left rostral middle frontal gyrus (+), left postcentral gyrus (+) and left supramarginal gyrus (-), where (+) denotes positive and (-) negative association. In summary, the use of structural connectivity information allowed the incorporation of different modalities in associating cortical measures and alcoholism risk.Item Associations between regional brain physiology and trait impulsivity, motor inhibition, and impaired control over drinking(Elsevier, 2015-08-30) Weafer, Jessica; Dzemidzic, Mario; Eiler, William J. A. II; Oberlin, Brandon G.; Wang, Yang; Kareken, David A.; Department of Neurology, IU School of MedicineTrait impulsivity and poor inhibitory control are well-established risk factors for alcohol misuse, yet little is known about the associated neurobiological endophenotypes. Here we examined correlations among brain physiology and self-reported trait impulsive behavior, impaired control over drinking, and a behavioral measure of response inhibition. A sample of healthy drinkers (n = 117) completed a pulsed arterial spin labeling (PASL) scan to quantify resting regional cerebral blood flow (rCBF), as well as measures of self-reported impulsivity (Eysenck I7 Impulsivity scale) and impaired control over drinking. A subset of subjects (n = 40) performed a stop signal task during blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging to assess brain regions involved in response inhibition. Eysenck I7 scores were inversely related to blood flow in the right precentral gyrus. Significant BOLD activation during response inhibition occurred in an overlapping right frontal motor/premotor region. Moreover, impaired control over drinking was associated with reduced BOLD response in the same region. These findings suggest that impulsive personality and impaired control over drinking are associated with brain physiology in areas implicated in response inhibition. This is consistent with the idea that difficulty controlling behavior is due in part to impairment in motor restraint systems.Item Brain Connectivity-Informed Regularization Methods for Regression(Springer, 2017-12-06) Karas, Marta; Brzyski, Damian; Dzemidzic, Mario; Goñi, Joaquín; Kareken, David A.; Randolph, Timothy W.; Harezlak, Jaroslaw; Neurology, School of MedicineOne of the challenging problems in brain imaging research is a principled incorporation of information from different imaging modalities. Frequently, each modality is analyzed separately using, for instance, dimensionality reduction techniques, which result in a loss of mutual information. We propose a novel regularization method to estimate the association between the brain structure features and a scalar outcome within the linear regression framework. Our regularization technique provides a principled approach to use external information from the structural brain connectivity and inform the estimation of the regression coefficients. Our proposal extends the classical Tikhonov regularization framework by defining a penalty term based on the structural connectivity-derived Laplacian matrix. Here, we address both theoretical and computational issues. The approach is first illustrated using simulated data and compared with other penalized regression methods. We then apply our regularization method to study the associations between the alcoholism phenotypes and brain cortical thickness using a diffusion imaging derived measure of structural connectivity. Using the proposed methodology in 148 young male subjects with a risk for alcoholism, we found a negative associations between cortical thickness and drinks per drinking day in bilateral caudal anterior cingulate cortex, left lateral OFC, and left precentral gyrus.Item Cerebral hypometabolism and grey matter density in MAPT intron 10 +3 mutation carriers(e-Century Publishing Corporation, 2014) Deters, Kacie D.; Risacher, Shannon L.; Farlow, Martin R.; Unverzagt, Frederick W.; Kareken, David A.; Hutchins, Gary D.; Yoder, Karmen K.; Murrell, Jill R.; Spina, Salvatore; Epperson, Francine; Gao, Sujuan; Saykin, Andrew J.; Ghetti, Bernardino; Department of Radiology and Imaging Sciences, IU School of MedicineMultiple systems tauopathy with presenile dementia (MSTD), a form of frontotemporal dementia with parkinsonism-17 with tau inclusions (FTDP-17T), is a neurodegenerative disorder caused by an (a) to (g) transition at position +3 of intron 10 of the microtubule associated protein tau (MAPT) gene. The mutation causes overexpression of 4 repeat (4R) tau isoforms with increased 4R/3R ratio leading to neurodegeneration. Clinically, these patients primarily present with behavioral variant FTD (bvFTD) and show disinhibition, disordered social comportment, and impaired executive function, memory, and speech. While altered glucose metabolism has been reported in subjects with sporadic bvFTD, it has yet to be investigated in an FTDP-17 sample of this size. In this study, eleven mutation carriers (5 males; mean age = 48.0 ± 6.9 years) and eight non-carriers (2 males; mean age = 43.7 ± 12.0 years) from a MSTD family were imaged using [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Eight of the MAPT intron 10 +3 mutation carriers met diagnostic criteria for bvFTD at the time of the PET scan, while three MAPT intron 10 +3 carriers were not cognitively impaired at the time of scan. Non-carriers had no clinically-relevant cognitive impairment at the time of the PET scan. Additionally, ten mutation carriers (5 males; mean age = 48.04 ± 2.1 years) and seven non-carriers (2 males; mean age 46.1 ± 4.1 years) underwent magnetic resonance imaging (MRI) which is an expanded sample size from a previous study. Seven MAPT mutation carriers met diagnostic criteria for bvFTD at the time of the MRI scan. Images were assessed on a voxel-wise basis for the effect of mutation carrier status. SPM8 was used for preprocessing and statistical analyses. Compared to non-carriers, MAPT mutation carriers showed lower [(18)F]FDG uptake bilaterally in the medial temporal lobe, and the parietal and frontal cortices. Anatomical changes were predominantly seen bilaterally in the medial temporal lobe areas which substantially overlapped with the hypometabolism findings. These anatomical and metabolic changes overlap previously described patterns of neurodegeneration in MSTD patients and are consistent with the characteristics of their cognitive dysfunction. These results suggest that neuroimaging can describe the neuropathology associated with this MAPT mutation.Item Comparison of rhyming and word generation with FMRI(Wiley Open Access, 2000-06-06) Lurito, Joseph T.; Kareken, David A.; Lowe, Mark J.; Chen, Shen Hsing A.; Mathews, Vincent P.; Neurology, School of MedicineFunctional magnetic resonance imaging (FMRI) has been successfully used to non‐invasively map language function, but has several disadvantages. These include severe motion sensitivity, which limits overt verbal responses in behavioral paradigms, such as word generation. The lack of overt responses prevents behavioral validation, making data interpretation difficult. Our objective was to compare the FMRI activation patterns of a novel silent rhyme determination task requiring a non‐verbal response, to covert word generation from visually presented letters. Five strongly right‐handed subjects performed both tasks during multi‐slice coronal echo‐planar T2*–weighted FMRI. Single subject activation maps were generated for each task by correlation analysis of single pixel time series to a boxcar reference function. These maps for the two tasks were separately interpolated to 2563, transformed into Talairach space, summed, and thresholded at t>6. Combined activation maps from both tasks showed similar robust perisylvian language area activation, including inferior frontal gyrus, posterior superior temporal lobe, and fusiform gyrus. Subjects performed well on the rhyming task, which activated left hemisphere cortical regions more selectively than the word generation task. The rhyming task showed less activation than the word generation task in areas typically not considered specifically related to language function, such as the dorsolateral prefrontal cortex and anterior cingulate. The rhyming task is a useful tool for brain mapping and clinical applications, potentially more specific to cortical language areas than verbal fluency.