School of Behavioral and Brain Sciences
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The mission of the School of Behavioral and Brain Sciences is to understand the intersection of mind, brain and behavior; enhance the health, education, and quality of life of children and families; and create and implement technologies and therapies that repair and strengthen human abilities. We accomplish these goals by recruiting and supporting outstanding faculty to conduct innovative research and student training in a climate that fosters collaboration across
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Item 17-β-Estradiol Induces Spreading Depression and Pain Behavior in Alert Female Rats(Impact Journals LLC) Sandweiss, Alexander J.; Cottier, Karissa E.; McIntosh, Mary I.; Dussor, Gregory; Davis, Thomas P.; Vanderah, Todd W.; Largent-Milnes, Tally M.; Dussor, GregoryAims: Test the putative contribution of 17-β-estradiol in the development of spreading depression (SD) events and head pain in awake, non-restrained rats. Main Methods: Female, Sprague-Dawley rats were intact or underwent ovariectomy followed one week later by surgery to place electrodes onto the dura to detect epidural electroencephalographic activity (dEEG). dEEG activity was recorded two days later for 12 hours after systemic administration of 17-β-estradiol (180 μg/kg, i.p.). A separate set of rats were observed for changes in exploratory, ambulatory, fine, and rearing behaviors; periorbital allodynia was also assessed. Key Findings: A bolus of 17-β-estradiol significantly elevated serum estrogen levels, increased SD episodes over a 12-hour recording period and decreased rearing behaviors in ovariectomized rats. Pre-administration of ICI 182,780, an estrogen receptor antagonist, blocked 17-β-estradiol-evoked SD events and pain behaviors; similar results were observed when the antimigraine therapeutic sumatriptan was used. Significance: These data indicate that an estrogen receptor-mediated mechanism contributes to SD events in ovariectomized rats and pain behaviors in both ovariectomized -and intact-rats. This suggests that estrogen plays a different role in each phenomenon of migraine where intense fluctuations in concentration may influence SD susceptibility. This is the first study to relate estrogen peaks to SD development and pain behaviors in awake, freely moving female rats, establishing a framework for future preclinical migraine studies.Item 2019 Charles E. Williams II Advanced Leadership Institute Oratorical Contest Winning Speech(2019-01-17) Nnoromele, PatrickPatrick Nnoromele is a Eugene McDermott and National Merit Scholar. He is also a recipient of the Barry Goldwater Scholarship. He is majoring in Neuroscience and plans to attend medical school after graduation. This is the text of the winning speech he gave at the Charles E. Williams II Advanced Leadership Institute Oratorical Contest, held during the 2019 Southwestern Black Students Leadership Conference.Item A Multilevel Computational Characterization of Endophenotypes in Addiction(Society for Neuroscience) Fiore, Vincenzo G.; Ognibene, D.; Adinoff, B.; Gu, Xiaosi; Fiore, Vincenzo G.; Gu, XiaosiAddiction is characterized by a profound intersubject (phenotypic) variability in the expression of addictive symptomatology and propensity to relapse following treatment. However, laboratory investigations have primarily focused on common neural substrates in addiction and have not yet been able to identify mechanisms that can account for the multifaceted phenotypic behaviors reported in the literature. To fill this knowledge gap theoretically, here we simulated phenotypic variations in addiction symptomology and responses to putative treatments, using both a neural model, based on cortico-striatal circuit dynamics, and an algorithmic model of reinforcement learning (RL). These simulations rely on the widely accepted assumption that both the ventral, model-based, goal-directed system and the dorsal, model-free, habitual system are vulnerable to extra-physiologic dopamine reinforcements triggered by addictive rewards. We found that endophenotypic differences in the balance between the two circuit or control systems resulted in an inverted-U shape in optimal choice behavior. Specifically, greater unbalance led to a higher likelihood of developing addiction and more severe drug-taking behaviors. Furthermore, endophenotypes with opposite asymmetrical biases among cortico-striatal circuits expressed similar addiction behaviors, but responded differently to simulated treatments, suggesting personalized treatment development could rely on endophenotypic rather than phenotypic differentiations. We propose our simulated results, confirmed across neural and algorithmic levels of analysis, inform on a fundamental and, to date, neglected quantitative method to characterize clinical heterogeneity in addiction. © 2018 Fiore et al.Item A Speech Processing Strategy Based on Sinusoidal Speech Model for Cochlear Implant Users(Institute of Electrical and Electronics Engineers Inc.) Lee, Sungmin; Akbarzadeh, Sara; Singh, Satnam; Tan, Chin-Tuan; 0000-0002-4676-4917 (Tan, C-T); 78509491 (Tan, C-T); Lee, Sungmin; Akbarzadeh, Sara; Singh, Satnam; Tan, Chin-TuanIn sinusoidal modeling (SM), speech signal, which is pseudo-periodic in structure, can be approximated by sinusoids and noise without losing significant speech information. A speech processing strategy based on this sinusoidal speech model will be relevant for encoding electric pulse streams in cochlear implant (CI) processing, where the number of channels available is limited. In this study, 5 normal hearing (NH) listeners and 2 CI users were asked to perform the task of speech recognition and perceived sound quality rating on speech sentences processed in 12 different test conditions. The sinusoidal analysis/synthesis algorithm was limited to 1, 3 or 6 sinusoids from the sentences low-pass filtered at either 1 kHz, 1.5 kHz, 3 kHz, or 6 kHz, re-synthesized as the test conditions. Each of 12 lists of AzBio sentences was randomly chosen and process with one of 12 test conditions, before they were presented to each participant at 65 dB SPL (Sound Pressure Level). Participant was instructed to repeat the sentence as they perceived, and the number of words correctly recognized was scored. They were also asked to rate the perceived sound quality of the sentences including original speech sentence, on the scale of 1 (distorted) to 10 (clean). Both speech recognition score and perceived sound quality rating across all participants increase when the number of sinusoids increases and low-pass filter broadens. Our current finding showed that three sinusoids may be sufficient to elicit the nearly maximum speech intelligibility and quality necessary for both NH and CI listeners. Sinusoidal speech model has the potential in facilitating the basis for a speech processing strategy in CI. ©2018 APSIPA.Item A Suite of Automated Tools to Quantify Hand and Wrist Motor Function after Cervical Spinal Cord Injury(BioMed Central Ltd.) Grasse, Katelyn M.; Hays, Seth A.; Rahebi, Kimiya C.; Warren, Victoria S.; Garcia, Elizabeth A.; Wigginton, Jane G.; Kilgardi Mchael P.; Rennaker, Robert L.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Grasse, Katelyn M.; Hays, Seth A.; Rahebi, Kimiya C.; Warren, Victoria S.; Garcia, Elizabeth A.; Wigginton, Jane G.; Kilgard, Michael P.; Rennaker, Robert L.Background: Cervical spinal cord injury (cSCI) often causes chronic upper extremity disability. Reliable measurement of arm function is critical for development of therapies to improve recovery after cSCI. In this study, we report a suite of automated rehabilitative tools to allow simple, quantitative assessment of hand and wrist motor function. Methods: We measured range of motion and force production using these devices in cSCI participants with a range of upper limb disability and in neurologically intact participants at two time points separated by approximately 4 months. Additionally, we determined whether measures collected with the rehabilitative tools correlated with standard upper limb assessments, including the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) and the Jebsen Hand Function Test (JHFT). Results: We find that the rehabilitative devices are useful to provide assessment of upper limb function in physical units over time in SCI participants and are well-correlated with standard assessments. Conclusions: These results indicate that these tools represent a reliable system for longitudinal evaluation of upper extremity function after cSCI and may provide a framework to assess the efficacy of strategies aimed at improving recovery of upper limb function. ©2019 The Author(s).Item Abnormal Emotional Learning in a Rat Model of Autism Exposed to Valproic Acid in Utero(Frontiers Research Foundation) Banerjee, Anwesha; Engineer, Crystal T.; Sauls, Bethany L.; Morales, Anna A.; Ploski, Jonathan E.\\Kilgard, Michael P.; Kilgard, Michael P.Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.Item Activation of the Integrated Stress Response in Nociceptors Drives Methylglyoxal-Induced Pain(Lippincott Williams & Wilkins, 2019-01) Barragan-Iglesias, Paulino; Kuhn, Jasper; Vidal-Cantu, Guadalupe C.; Belen Salinas-Abarca, Ana; Granados-Soto, Vinicio; Dussor, Gregory; Campbell, Zachary T.; Price, Theodore J.; 0000-0002-3768-6996 (Campbell, ZT); 0000-0002-6971-6221 (Price, TJ); Dussor, Gregory; Campbell, Zachary T.; Price, Theodore J.Methylglyoxal (MGO) is a reactive glycolytic metabolite associated with painful diabetic neuropathy at plasma concentrations between 500 nM and 5 μM. The mechanisms through which MGO causes neuropathic pain at these pathological concentrations are not known. Because MGO has been linked to diabetic neuropathic pain, which is prevalent and poorly treated, insight into this unsolved biomedical problem could lead to much needed therapeutics. Our experiments provide compelling evidence that ~ 1-μM concentrations of MGO activate the integrated stress response (ISR) in IB4-positive nociceptors in the dorsal root ganglion (DRG) of mice in vivo and in vitro. Blocking the integrated stress response with a specific inhibitor (ISRIB) strongly attenuates and reverses MGO-evoked pain. Moreover, ISRIB reduces neuropathic pain induced by diabetes in both mice and rats. Our work elucidates the mechanism of action of MGO in the production of pain at pathophysiologically relevant concentrations and suggests a new pharmacological avenue for the treatment of diabetic and other types of MGO-driven neuropathic pain.Item Adeno-associated viral serotypes produce differing titers and differentially transduce neurons within the rat basal and lateral amygdala(BioMed Central) Holehonnur, Roopashri; Luong, Jonathan A.; Chaturvedi, Dushyant; Ho, Anthony; Lella, Srihari K.; Hosek, Matthew P.; Ploski, Jonathan E.Background: In recent years, there has been an increased interest in using recombinant adeno-associated viruses (AAV) to make localized genetic manipulations within the rodent brain. Differing serotypes of AAV possess divergent capsid protein sequences and these variations greatly influence each serotype's ability to transduce particular cell types and brain regions. We therefore aimed to determine the AAV serotype that is optimal for targeting neurons within the Basal and Lateral Amygdala (BLA) since the transduction efficiency of AAV has not been previously examined within the BLA. This region is desirable to genetically manipulate due to its role in emotion, learning & memory, and numerous psychiatric disorders. We accomplished this by screening 9 different AAV serotypes (AAV2/1, AAV2/2, AAV2/5, AAV2/7, AAV2/8, AAV2/9, AAV2/rh10, AAV2/DJ and AAV2/DJ8) designed to express red fluorescent protein (RFP) under the regulation of an alpha Ca2+/calmodulin-dependent protein kinase II promoter (aCaMKII).; Results: We determined that these serotypes produce differing amounts of virus under standard laboratory production. Notably AAV2/2 consistently produced the lowest titers compared to the other serotypes examined. These nine serotypes were bilaterally infused into the rat BLA at the highest titers achieved for each serotype and at a normalized titer of 7.8E + 11 GC/ml. Twenty one days following viral infusion the degree of transduction was quantitated throughout the amygdala. These viruses exhibited differential transduction of neurons within the BLA. AAV2/7 exhibited a trend toward having the highest efficiency of transduction and AAV2/5 exhibited significantly lower transduction efficiency as compared to the serotypes examined. AAV2/5's decreased ability to transduce BLA neurons correlates with its significantly different capsid protein sequences as compared to the other serotypes examined.; Conclusions: For laboratories producing their own recombinant adeno-associated viruses, the use of AAV2/2 is likely less desirable since AAV2/2 produces significantly lower titers than many other serotypes of AAV. Numerous AAV serotypes appear to efficiently transduce BLA neurons, with the exception of AAV2/5. Taking into consideration the ability of certain serotypes to achieve high titers and transduce BLA neurons well, in our hands AAV2/DJ8 and AAV2/9 appear to be ideal serotypes to use when targeting neurons within the BLA.;Item Adolescents Show Differential Dysfunctions Related to Alcohol and Cannabis Use Disorder Severity in Emotion and Executive Attention Neuro-Circuitries(Elsevier Inc.) Aloi, J.; Blair, K. S.; Crum, K. I.; Meffert, H.; White, S. F.; Tyler, P. M.; Thornton, L. C.; Mobley, A. M.; Killanin, A. D.; Adams, K. O.; Filbey, Francesca M.; Pope, K.; Blair, R. J. R.; 0000 0001 3618 6298 (Filbey, FM); Filbey, Francesca M.Alcohol and cannabis are two substances that are commonly abused by adolescents in the United States and which, when abused, are associated with negative medical and psychiatric outcomes across the lifespan. These negative psychiatric outcomes may reflect the detrimental impact of substance abuse on neural systems mediating emotion processing and executive attention. However, work indicative of this has mostly been conducted either in animal models or adults with Alcohol and/or Cannabis Use Disorder (AUD/CUD). Little work has been conducted in adolescent patients. In this study, we used the Affective Stroop task to examine the relationship in 82 adolescents between AUD and/or CUD symptom severity and the functional integrity of neural systems mediating emotional processing and executive attention. We found that AUD symptom severity was positively related to amygdala responsiveness to emotional stimuli and negatively related to responsiveness within regions implicated in executive attention and response control (i.e., dorsolateral prefrontal cortex, anterior cingulate cortex, precuneus) as a function of task performance. In contrast, CUD symptom severity was unrelated to amygdala responsiveness but positively related to responsiveness within regions including precuneus, posterior cingulate cortex, and inferior parietal lobule as a function of task performance. These data suggest differential impacts of alcohol and cannabis abuse on the adolescent brain.Item Affective Responses by Adults with Autism Are Reduced to Social Images but Elevated to Images Related to Circumscribed InterestsSasson, Noah J.; Dichter, Gabriel S.; Bodfish, James W.Individuals with autism spectrum disorders (ASD) demonstrate increased visual attention and elevated brain reward circuitry responses to images related to circumscribed interests (CI), suggesting that a heightened affective response to CI may underlie their disproportionate salience and reward value in ASD. To determine if individuals with ASD differ from typically developing (TD) adults in their subjective emotional experience of CI object images, non-CI object images and social images, 213 TD adults and 56 adults with ASD provided arousal ratings (sensation of being energized varying along a dimension from calm to excited) and valence ratings (emotionality varying along dimension of approach to withdrawal) for a series of 114 images derived from previous research on CI. The groups did not differ on arousal ratings for any image type, but ASD adults provided higher valence ratings than TD adults for CI-related images, and lower valence ratings for social images. Even after co-varying the effects of sex, the ASD group, but not the TD group, gave higher valence ratings to CI images than social images. These findings provide additional evidence that ASD is characterized by a preference for certain categories of non-social objects and a reduced preference for social stimuli, and support the dissemination of this image set for examining aspects of the circumscribed interest phenotype in ASD. © 2012 Sasson et al.Item Age-Related Differences in Prestimulus Subsequent Memory Effects Assessed with Event-Related Potentials(MIT Press Journals) Koen, Joshua D.; Horne, Erin D.; Hauck, Nedra; Rugg, Michael D.; Koen, Joshua D.; Horne, Erin D.; Hauck, Nedra; Rugg, Michael D.; 0000 0001 1596 5452 (Rugg, MD)Prestimulus subsequent memory effects (preSMEs)-differences in neural activity elicited by a task cue at encoding that are predictive of later memory performance-are thought to reflect differential engagement of preparatory processes that benefit episodic memory encoding. We investigated age differences in preSMEs indexed by differences in ERP amplitude just before the onset of a study item. Young and older adults incidentally encoded words for a subsequent memory test. Each study word was preceded by a task cue that signaled a judgment to perform on the word. Words were presented for either a short (300 msec) or long (1000 msec) duration with the aim of placing differential benefits on engaging preparatory processes initiated by the task cue. ERPs associated with subsequent successful and unsuccessful recollection, operationalized here by source memory accuracy, were estimated time-locked to the onset of the task cue. In a late time window (1000-2000 msec after onset of the cue), young adults demonstrated frontally distributed preSMEs for both the short and long study durations, albeit with opposite polarities in the two conditions. This finding suggests that preSMEs in young adults are sensitive to perceived task demands. Although older adults showed no evidence of preSMEs in the same late time window, significant preSMEs were observed in an earlier time window (500-1000 msec) that was invariant with study duration. These results are broadly consistent with the proposal that older adults differ from their younger counterparts in how they engage preparatory processes during memory encoding.Item Altered Amygdala Connectivity in Individuals with Chronic Traumatic Brain Injury and Comorbid Depressive Symptoms(Frontiers Media S.A.) Han, Kihwan; Chapman, Sandra Bond; Krawczyk, Daniel C.; 0000 0003 5170 3614 (Chapman, SB); 0000-0002-4574-7306 (Han, K); Han, Kihwan; Chapman, Sandra Bond; Krawczyk, Daniel C.Depression is one of the most common psychiatric conditions in individuals with chronic traumatic brain injury (TBI). Though depression has detrimental effects in TBI and network dysfunction is a "hallmark" of TBI and depression, there have not been any prior investigations of connectivity-based neuroimaging biomarkers for comorbid depression in TBI. We utilized resting-state functional magnetic resonance imaging to identify altered amygdala connectivity in individuals with chronic TBI (8 years post injury on average) exhibiting comorbid depressive symptoms (N = 31), relative to chronic TBI individuals having minimal depressive symptoms (N = 23). Connectivity analysis of these participant sub-groups revealed that the TBI-plus-depressive symptoms group showed relative increases in amygdala connectivity primarily in the regions that are part of the salience, somatomotor, dorsal attention, and visual networks P(voxel) < 0.01, P(cluster) < 0.025). Relative increases in amygdala connectivity in the TBI-plus-depressive symptoms group were also observed within areas of the limbic cortical mood regulating circuit (the left dorsomedial and right dorsolateral prefrontal cortices and thalamus) and the brainstem. Further analysis revealed that spatially dissociable patterns of correlation between amygdala connectivity and symptom severity according to subtypes (Cognitive and Affective) of depressive symptoms (p(voxel) < 0.01, p(duster) < 0.025). Taken together, these results suggest that amygdala connectivity may be a potentially effective neuroimaging biomarker for comorbid depressive symptoms in chronic TBI.Item Anterior Thalamic High Frequency Band Activity Is Coupled with Theta Oscillations at Rest(Frontiers Media S.A.) Sweeney-Reed, Catherine M.; Zaehle, Tino; Voges, Juergen; Schmitt, Friedhelm C.; Buentjen, Lars; Borchardt, Viola; Walter, Martin; Hinrichs, Hermann; Heinze, Hans-Jochen; Rugg, Michael D.; Knight, Robert T.; Rugg, Michael D.Cross-frequency coupling (CFC) between slow and fast brain rhythms, in the form of phase-amplitude coupling (PAC), is proposed to enable the coordination of neural oscillatory activity required for cognitive processing. PAC has been identified in the neocortex and mesial temporal regions, varying according to the cognitive task being performed and also at rest. PAC has also been observed in the anterior thalamic nucleus (ATN) during memory processing. The thalamus is active during the resting state and has been proposed to be involved in switching between task-free cognitive states such as rest, in which attention is internally-focused, and externally-focused cognitive states, in which an individual engages with environmental stimuli. It is unknown whether PAC is an ongoing phenomenon during the resting state in the ATN, which is modulated during different cognitive states, or whether it only arises during the performance of specific tasks. We analyzed electrophysiological recordings of ATN activity during rest from seven patients who received thalamic electrodes implanted for treatment of pharmacoresistant focal epilepsy. PAC was identified between theta (4-6 Hz) phase and high frequency band (80-150 Hz) amplitude during rest in all seven patients, which diminished during engagement in tasks involving an external focus of attention. The findings are consistent with the proposal that theta-gamma coupling in the ATN is an ongoing phenomenon, which is modulated by task performance.Item The Anti-Diabetic Drug Metformin Protects Against Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model(Public Library of Science) Mao-Ying, Qi; Kavelaars, Annemieke; Krukowski, Karen; Huo, Xiao-Jiao; Zhou, Wenjun; Price, Theodore J.; Cleeland, Charles; Heijnen, Cobi J.Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs) in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved. ;Item Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits That Result from Perinatal Ketamine TreatmentPhensy, Aarron; Duzdabanian, Hasmik E.; Brewer, Samantha; Panjabi, Anurag; Driskill, Christopher; Berz, Annuska; Peng, George; Kroener, Sven; 0000-0003-1728-8111 (Kroener, S); Phensy, Aarron; Duzdabanian, Hasmik E.; Brewer, Samantha; Panjabi, Anurag; Driskill, Christopher; Berz, Annuska; Peng, George; Kroener, SvenAlterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70-120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.Item ASL-MRICloud: An Online Tool for the Processing of ASL MRI Data(Wiley, 2018-12-26) Li, Yang; Liu, Peiying; Li, Yue; Fan, Hongli; Su, Pan; Peng, Shin-Lei; Park, Denise C.; Rodrigue, Karen M.; Jiang, Hangyi; Faria, Andreia V.; Ceritoglu, Can; Miller, Michael; Mori, Susumu; Lu, Hanzhang; 74141364 (Park, DC); Park, Denise C.; Rodrigue, Karen M.Arterial spin labeling (ASL) MRI is increasingly used in research and clinical settings. The purpose of this work is to develop a cloud-based tool for ASL data processing, referred to as ASL-MRICloud, which may be useful to the MRI community. In contrast to existing ASL toolboxes, which are based on software installation on the user's local computer, ASL-MRICloud uses a web browser for data upload and results download, and the computation is performed on the remote server. As such, this tool is independent of the user's operating system, software version, and CPU speed. The ASL-MRICloud tool was implemented to be compatible with data acquired by scanners from all major MRI manufacturers, is capable of processing several common forms of ASL, including pseudo-continuous ASL and pulsed ASL, and can process single-delay and multi-delay ASL data. The outputs of ASL-MRICloud include absolute and relative values of cerebral blood flow, arterial transit time, voxel-wise masks indicating regions with potential hyper-perfusion and hypo-perfusion, and an image quality index. The ASL tool is also integrated with a T₁-based brain segmentation and normalization tool in MRICloud to allow generation of parametric maps in standard brain space as well as region-of-interest values. The tool was tested on a large data set containing 309 ASL scans as well as on publicly available ASL data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study.Item Assessment of Unconstrained Cerebrovascular Reactivity Marker for Large Age-Range fMRI Studies(Public Library of Science) Kannurpatti, S. S.; Motes, Michael A.; Biswal, B. B.; Rypma, BartBreath hold (BH), a commonly used task to measure cerebrovascular reactivity (CVR) in fMRI studies varies in outcome among individuals due to subject-physiology and/or BH-inspiration/expiration differences (i.e., performance). In prior age-related fMRI studies, smaller task-related BOLD response variability is observed among younger than older individuals. Also, a linear CVR versus task relationship exists in younger individuals which maybe useful to test the accuracy of CVR responses in older groups. Hence we hypothesized that subject-related physiological and/or BH differences, if present, may compromise CVR versus task linearity in older individuals. To test the hypothesis, empirical BH versus task relationships from motor and cognitive areas were obtained in younger (mean age = 26 years) and older (mean age = 58 years) human subjects. BH versus task linearity was observed only in the younger group, confirming our hypothesis. Further analysis indicated BH responses and its variability to be similar in both younger and older groups, suggesting that BH may not accurately represent CVR in a large age range. Using the resting state fluctuation of amplitude (RSFA) as an unconstrained alternative to BH, subject-wise correspondence between BH and RSFA was tested. Correlation between BH versus RSFA was significant within the motor but was not significant in the cognitive areas in the younger and was completely disrupted in both areas in the older subjects indicating that BH responses are constrained by subject-related physiology and/or performance-related differences. Contrasting BH to task, RSFA-task relationships were independent of age accompanied by age-related increases in CVR variability as measured by RSFA, not observed with BH. Together the results obtained indicate that RSFA accurately represents CVR in any age range avoiding multiple and yet unknown physiologic and task-related pitfalls of BH.Item Atypical Right Hemisphere Specialization for Object Representations in an Adolescent with Specific Language Impairment(Frontiers Research Foundation) Brown, Timothy T.; Erhart, Matthew; Avesar, Daniel; Dale, Anders M.; Halgren, Eric; Evans, Julia L.; 0000 0003 8601 2186 (Evans, JL); 306453126 (Evans, JL)Individuals with a diagnosis of specific language impairment (SLI) show abnormal spoken language occurring alongside normal non-verbal abilities. Behaviorally, people with SLI exhibit diverse profiles of impairment involving phonological, grammatical, syntactic, and semantic aspects of language. In this study, we used a multimodal neuroimaging technique called anatomically constrained magnetoencephalography (aMEG) to measure the dynamic functional brain organization of an adolescent with SLI. Using single-subject statistical maps of cortical activity, we compared this patient to a sibling and to a cohort of typically developing subjects during the performance of tasks designed to evoke semantic representations of concrete objects. Localized patterns of brain activity within the language impaired patient showed marked differences from the typical functional organization, with significant engagement of right hemisphere heteromodal cortical regions generally homotopic to the left hemisphere areas that usually show the greatest activity for such tasks. Functional neuroanatomical differences were evident at early sensoriperceptual processing stages and continued through later cognitive stages, observed specifically at latencies typically associated with semantic encoding operations. Our findings show with real-time temporal specificity evidence for an atypical right hemisphere specialization for the representation of concrete entities, independent of verbal motor demands. More broadly, our results demonstrate the feasibility and potential utility of using aMEG to characterize individual patient differences in the dynamic functional organization of the brain.;Item Auditory Cortex tACS and tRNS for Tinnitus: Single Versus Multiple SessionsClaes, Laura; Stamberger, Hannah; de Heyning, Paul Van; De Ridder, Dirk; Vanneste, Sven; 0000-0002-9906-1836 (Vanneste, S); Lab for Clinical & Integrative NeuroscienceTinnitus is the perception of a sound in the absence of an external acoustic source, which often exerts a significant impact on the quality of life. Currently there is evidence that neuroplastic changes in both neural pathways are involved in the generation and maintaining of tinnitus. Neuromodulation has been suggested to interfere with these neuroplastic alterations. In this study we aimed to compare the effect of two upcoming forms of transcranial electrical neuromodulation: alternating current stimulation (tACS) and random noise stimulation (tRNS), both applied on the auditory cortex. A database with 228 patients with chronic tinnitus who underwent noninvasive neuromodulation was retrospectively analyzed. The results of this study show that a single session of tRNS induces a significant suppressive effect on tinnitus loudness and distress, in contrast to tACS. Multiple sessions of tRNS augment the suppressive effect on tinnitus loudness but have no effect on tinnitus distress. In conclusion this preliminary study shows a possibly beneficial effect of tRNS on tinnitus and can be a motivation for future randomized placebo-controlled clinical studies with auditory tRNS for tinnitus. Auditory alpha-modulated tACS does not seem to be contributing to the treatment of tinnitus.Item Autism Symptoms, Depression, and Active Social Avoidance in Schizophrenia: Association with Self-Reports and Informant Assessments of Everyday Functioning(Elsevier Ltd, 2019-05-09) Harvey, P. D.; Deckler, E.; Jones, M. T.; Jarskog, L. F.; Penn, D. L.; Pinkham, Amy E.Autistic traits are a feature of schizophrenia and has been found to impair social functioning and social cognition. Other influences on social outcomes in schizophrenia include depression and social avoidance. However, challenges in self-assessment of abilities and functioning (i.e., introspective accuracy)and self-assessment bias also contribute to disability. Depression has been studied for its association with introspective accuracy and bias, but autistic traits have not. Participants were 177 patients with schizophrenia who self-reported their everyday functioning and social cognitive ability as well as their depression. All were rated with the PANSS and a separate rater generated all-sources ratings of everyday functioning and social cognitive ability. Correlations between self-reported everyday functioning and social cognitive ability, ratings of everyday functioning and social cognitive ability, and the discrepancies between those ratings were examined for correlations with depression, autistic features and social avoidance. Accuracy was defined by the absolute value of the difference between self-reports and all-sources ratings and bias was defined by the direction of discrepancy (positive vs. negative). There was a statistically significant difference between sources on every measure. Bias was not directional on average, but patients with the lowest levels of depression overestimated their abilities on every measure and those with the highest depression underestimated. Autistic traits were associated with impairments in everyday functioning and underestimation of those impairments, while social avoidance was associated with impaired social functioning and accurate self-assessment. Features of schizophrenia have differential implications for impaired functioning and self-assessment, with autistic features and low levels of depression associated with consistent self-assessment biases. ©2019 Elsevier Ltd