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 First Impressions of Adults with Autism Improve with Diagnostic Disclosure and Increased Autism Knowledge of Peers(Sage Publications Ltd, 2017-10-17) Sasson, Noah J.; Morrison, Kerrianne E.; 81829133 (Sasson, NJ); Sasson, Noah J.; Morrison, Kerrianne E.A practical consideration for many intellectually able adults with autism spectrum disorder (ASD) is whether to disclose their diagnostic status or try to mask their autistic characteristics to avoid judgment and discrimination. Here, we assessed first impressions of adults with ASD and typically developing controls (N = 40) made by typically developing observers (N = 215) when their diagnostic status was either withheld, accurately provided, or inaccurately provided. First impressions were less favorable for ASD participants compared to typically developing controls across a range of judgments, but were significantly more positive when accurately labeled as ASD compared to when no label was provided, when mislabeled as typically developing, or when mislabeled as having schizophrenia. For typically developing participants, ratings did not change when accurately labeled but improved when mislabeled as ASD. Greater autistic traits for the ASD and typically developing participants were associated with less favorable first impressions, and females were rated more favorably than males. Autism knowledge of the raters, but not age, IQ, or autistic traits, was positively associated with more favorable impressions of ASD participants. Collectively, these findings suggest that first impressions for intellectually able adults with ASD improve with diagnostic disclosure and increased autism understanding on the part of peers.Item Protease Activated Receptor 2 (PAR2) Activation Causes Migraine-Like Pain Behaviors in Mice(Sage Publications Ltd, 2018-05-31) Hassler, Shayne N.; Ahmad, Fatima B.; Burgos-Vega, Carolina C.; Boitano, Scott; Vagner, Josef; Price, Theodore J.; Dussor, Gregory; 0000-0002-6971-6221 (Price, TJ); Hassler, Shayne N.; Ahmad, Fatima B.; Burgos-Vega, Carolina C.; Price, Theodore J.; Dussor, GregoryBackground Pain is the most debilitating symptom of migraine. The cause of migraine pain likely requires activation of meningeal nociceptors. Mast cell degranulation, with subsequent meningeal nociceptor activation, has been implicated in migraine pathophysiology. Degranulating mast cells release serine proteases that can cleave and activate protease activated receptors. The purpose of these studies was to investigate whether protease activated receptor 2 is a potential generator of nociceptive input from the meninges by using selective pharmacological agents and knockout mice. Methods Ratiometric Ca⁺⁺ imaging was performed on primary trigeminal and dural cell cultures after application of 2at-LIGRL-NH₂, a specific protease activated receptor 2 agonist. Cutaneous hypersensitivity and facial grimace was measured in wild-type and protease activated receptor 2⁻ᐟ⁻ mice after dural application of 2at-LIGRL-NH₂ or compound 48-80, a mast cell degranulator. Behavioral experiments were also conducted in mice after dural application of 2at-LIGRL-NH₂ (2AT) in the presence of either C391, a selective protease activated receptor 2 antagonist, or sumatriptan. Results 2at-LIGRL-NH₂ evoked Ca²⁺ signaling in mouse trigeminal neurons, dural fibroblasts and in meningeal afferents. Dural application of 2at-LIGRL-NH₂ or 48-80 caused dose-dependent grimace behavior and mechanical allodynia that were attenuated by either local or systemic application of C391 as well as in protease activated receptor 2⁻ᐟ⁻ mice. Nociceptive behavior after dural injection of 2at-LIGRL-NH₂ was also attenuated by sumatriptan. Conclusions Functional protease activated receptor 2 receptors are expressed on both dural afferents and fibroblasts and activation of dural protease activated receptor 2 produces migraine-like behavioral responses. Protease activated receptor 2 may link resident immune cells to meningeal nociceptor activation, driving migraine-like pain and implicating protease activated receptor 2 as a therapeutic target for migraine in humans.Item Non-Invasive Dural Stimulation in Mice: A Novel Preclinical Model of Migraine(Sage Publications Ltd, 2018-05-31) Burgos-Vega, Carolina Christina; Quigley, Lilyana D.; dos Santos, Gabriela Trevisan; Yan, Flora; Asiedu, Marina; Jacobs, Blaine; Motina, Marina; Safdar, Nida; Yousuf, Hayyan; Avona, Amanda; Price, Theodore J.; Dussor, Greg; Burgos-Vega, Carolina Christina; Quigley, Lilyana D.; Yan, Flora; Asiedu, Marina; Jacobs, Blaine; Motina, Marina; Safdar, Nida; Yousuf, Hayyan; Avona, Amanda; Price, Theodore J.; Dussor, GregBackground Migraine is characterized by a collection of neurological symptoms in the absence of injury or damage. However, several common preclinical migraine models require significant damage to the skull to stimulate the dura mater, the likely source of afferent signaling leading to head pain. The goal of this study was to determine whether dural stimulation can be performed in mice using an injection that does not cause injury or damage. Methods Using mice, injections of stimuli were administered to the dura mater through the soft tissue at the intersection between the lambdoidal and sagittal sutures. This technique did not require a permanent cannula nor did it cause damage to the skull or dura. Following injection of noxious stimuli, migraine-like behaviors were measured including cutaneous allodynia and facial grimace. The retrograde tracer fluorogold was applied onto the dura using the same injection technique to label trigeminal ganglion cell bodies, which were then testing in vitro using patch-clamp electrophysiology. Results Dural injection of allyl-isothiocyanate, low pH, interleukin-6, or inflammatory soup but not vehicles, led to cephalic/extracephalic allodynia. Facial grimace responses were also observed with allyl-isothiocyanate, pH 6.0, and interleukin-6. Stimulation with interleukin-6 causes priming to normally subthreshold pH 7.0 stimulation of the dura following resolution of the initial interleukin-6 behavior. Systemic injection of sumatriptan at the time of dural stimulation with inflammatory soup decreased the resulting cutaneous hypersensitivity. Trigeminal ganglion cell bodies retrogradely labeled from the dura had low pH-evoked currents similar to those generated by acid-sensing ion channels. Conclusion Non-invasive dural stimulation in mice can be used as a model of migraine in the absence of injury.Item Hearing Healthcare in Remote or Resource-Constrained Environments(Cambridge Univ Press, 2018-07-19) Swanepoel, D.; Clark, Jackie L.; Clark, Jackie L.Background Hearing loss is a leading contributor to the global burden of disease, with more than 80 per cent of affected persons residing in low- and middle-income countries, typically where hearing health services are unavailable. Objectives This article discusses the challenges to hearing care in remote and resource-limited settings, and describes recommended service delivery models, taking personnel and equipment requirements into consideration. The paper also considers the novel roles of telemedicine approaches in these contexts for improving access to preventative care. Finally, two case studies illustrate the challenges and strategies for service provision in remote and underserved settings.Item Tinnitus and Neuropathic Pain Share a Common Neural Substrate in the Form of Specific Brain Connectivity and Microstate Profiles(Pergamon-Elsevier Science Ltd, 2018-08-22) Vanneste, Sven; To, Wing Ting; De Ridder, Dirk; 0000-0002-9906-1836 (Vanneste, S); Vanneste, Sven; To, Wing TingTinnitus and neuropathic pain share similar pathophysiological, clinical, and treatment characteristics. In this EEG study, a group of tinnitus (n = 100) and neuropathic pain (n = 100) patients are compared to each other and to a healthy control group (n = 100). Spectral analysis demonstrates gamma band activity within the primary auditory and somatosensory cortices in patients with tinnitus and neuropathic pain, respectively. A conjunction analysis further demonstrates an overlap of tinnitus and pain related activity in the anterior and posterior cingulate cortex as well as in the dorsolateral prefrontal cortex in comparison to healthy controls. Further analysis reveals that similar states characterize tinnitus and neuropathic pain patients, two of which differ from the healthy group and two of which are shared. Both pain and tinnitus patients spend half of the time in one specific microstate. Seed-based functional connectivity with the source within the predominant microstate shows delta, alpha1, and gamma lagged phase synchronization overlap with multiple brain areas between pain and tinnitus. These data suggest that auditory and somatosensory phantom perceptions share an overlapping brain network with common activation and connectivity patterns and are differentiated by specific sensory cortex gamma activation.Item Frontoparietal Cortical Thickness Mediates the Effect of COMT Val¹⁵⁸Met Polymorphism on Age-Associated Executive Function(Elsevier Science Inc, 2018-09-21) Miranda, Giuseppe G.; Rodrigue, Karen M.; Kennedy, Kristen M.; 0000-0001-5373-9026 (Kennedy, KM); Miranda, Giuseppe G.; Rodrigue, Karen M.; Kennedy, Kristen M.Proper dopamine (DA) signaling is likely necessary for maintaining optimal cognitive performance as we age, particularly in prefrontal-parietal networks and in fronto-striatal networks. Thus, reduced DA availability is a salient risk factor for accelerated cognitive aging. A common polymorphism that affects DA D1 receptor dopamine availability, COMT Val¹⁵⁸Met (rs4680), influences enzymatic breakdown of DA, with COMT Val carriers having a 3- to 4-fold reduction in synaptic DA compared to COMT Met carriers. Furthermore, dopamine receptors and postsynaptic availability are drastically reduced with aging, as is executive function performance that ostensibly relies on these pathways. Here, we investigated in 176 individuals aged 20-94 years whether: (1) COMT Val carriers differ from their Met counterparts in thickness of regional cortices receiving D1 receptor pathways: prefrontal, parietal, cingulate cortices; (2) this gene-brain association differs across the adult lifespan; and (3) COMT-related regional thinning evidences cognitive consequences. We found that COMT Val carriers evidenced thinner cortex in prefrontal, parietal, and posterior cingulate cortices than COMT Met carriers and this effect was not age-dependent. Further, we demonstrate that thickness of these regions significantly mediates the effect of COMT genotype on an executive function composite measure. These results suggest that poorer executive function performance is due partly to thinner association cortex in dopaminergic-rich regions, and particularly so in individuals who are genetically predisposed to lower postsynaptic dopamine availability, regardless of age.Item Vagus Nerve Stimulation Promotes Generalization of Conditioned Fear Extinction and Reduces Anxiety in Rats(Elsevier Science Inc, 2018-09-21) Noble, Lindsey J.; Meruva, Venkat B.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Christa K.; 0000-0003-4225-241X (Hays, SA); 13146094343400332984 (Hays, SA); Noble, Lindsey J.; Meruva, Venkat B.; Hays, Seth A.; Rennaker, Robert L.; Kilgard, Michael P.; McIntyre, Christa K.Background: Exposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans. Objective: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event. Methods: Male Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable auditory stimuli. Following fear conditioning, extinction training consisted of exposure to only one of the conditioned sounds. Half of the rats received VNS and half received sham stimulation during with sound presentations. VNS effects on anxiety were examined in a separate study where VNS was administered prior to testing on the elevated plus maze. Results: Sham stimulated rats given 20 presentations of a conditioned stimulus (CS) during the extinction session showed performance that was matched to VNS-treated rats given only 4 presentations of the CS. Despite comparable levels of freezing to the presented CS, only the VNS-treated rats showed a significant decrease in freezing to the CS that was not presented. VNS-induced generalization of extinction was observed only when the two sounds were paired with footshock within the same fear conditioning session; VNS did not promote generalization of extinction when the two sounds were conditioned on different days or in different contexts. On the anxiety test, VNS administration significantly increased time spent in the open arms of the elevated plus maze. Conclusion: These results provide evidence that VNS can promote generalization of extinction to other stimuli associated with a specific fear experience. Furthermore, non-contingent VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy and tolerability of exposure-based therapies.Item The Role of Nonverbal Working Memory in Morphosyntactic Processing by Children with Specific Language Impairment and Autism Spectrum Disorders(BioMed Central, 2018-09-24) Ellis Weismer, S.; Davidson, Meghan M.; Gangopadhyay, I.; Sindberg, H.; Roebuck, H.; Kaushanskaya, M.; Davidson, Meghan M.Background: Both children with autism spectrum disorders (ASD) and children with specific language impairment (SLI) have been shown to have difficulties with grammatical processing. A comparison of these two populations with neurodevelopmental disorders was undertaken to examine similarities and differences in the mechanisms that may underlie grammatical processing. Research has shown that working memory (WM) is recruited during grammatical processing. The goal of this study was to examine morphosyntactic processing on a grammatical judgment task in children who varied in clinical diagnosis and language abilities and to assess the extent to which performance is predicted by nonverbal working memory (WM). Two theoretical perspectives were evaluated relative to performance on the grammatical judgment task - the "working memory" account and the "wrap-up" account. These accounts make contrasting predictions about the detection of grammatical errors occurring early versus late in the sentence. Methods: Participants were 84 school-age children with SLI (n = 21), ASD (n = 27), and typical development (TD, n = 36). Performance was analyzed based on diagnostic group as well as language status (normal language, NL, n = 54, and language impairment, LI, n = 30). A grammatical judgment task was used in which the position of the error in the sentence (early versus late) was manipulated. A visual WM task (N-back) was administered and the ability of WM to predict morphosyntactic processing was assessed. Results: Groups differed significantly in their sensitivity to grammatical errors (TD > SLI and NL > LI) but did not differ in nonverbal WM. Overall, children in all groups were more sensitive and quicker at detecting errors occurring late in the sentence than early in the sentence. Nonverbal WM predicted morphosyntactic processing across groups, but the specific profile of association between WM and early versus late error detection was reversed for children with and without language impairment. Conclusions: Findings primarily support a "wrap up" account whereby the accumulating sentence context for errors positioned late in the sentence (rather than early) appeared to facilitate morphosyntactic processing. Although none of the groups displayed deficits in visual WM, individual differences in these nonverbal WM resources predicted proficiency in morphosyntactic processing.Item Event-Related Neural Oscillation Changes Following Reasoning Training in Individuals with Mild Cognitive Impairment(Elsevier Science B.V., 2018-10-17) Mudar, Raksha A.; Nguyen, Lydia T.; Eroh, Justin; Chiang, Hsueh-Sheng; Rackley, Audette; Chapman, Sandra B.; Eroh, Justin; Rackley, Audette; Chapman, Sandra B.Emerging evidence suggests cognitive training programs targeting higher-order reasoning may strengthen not only cognitive, but also neural functions in individuals with Mild Cognitive Impairment (MCI). However, research on direct measures of training-induced neural changes, derivable from electroencephalography (EEG), is limited. The current pilot study examined effects of Gist Reasoning training (n = 16) compared to New Learning training (n = 16) in older adults with amnestic MCI on measures of event-related neural oscillations (theta and alpha band power) corresponding to Go/NoGo tasks during basic and superordinate semantic categorization. EEG data were recorded while participants performed the Go/NoGo task pre- and post-training, and power in theta and alpha frequency bands was examined. Both groups were comparable at pre-training on all measures and both groups showed greater event-related theta synchronization post-training. Furthermore, the Gist Reasoning group had enhanced event-related desynchronization in low-frequency alpha band (8-10 Hz)on response inhibition (NoGo) trials and high-frequency alpha band (11-13 Hz) on response execution (Go) trials during superordinate categorization, relative to the New Learning group. These findings suggest that Gist Reasoning training in MCI impacted neural processing linked to strategic processing of Go and NoGo trials during the more complex superordinate categorization task. Targeting higher-order top-down cognitive processing seems to better harness residual neuroplastic potential in MCI.Item Mapping the Operational Landscape of MicroRNAs in Synthetic Gene Circuits.(Nature Partner Journals, 2018-10-22) Quarton, Tyler; Ehrhardt, Kristina; Lee, James; Kannan, Srijaa; Li, Yi; Ma, Lan; Bleris, Leonidas; Quarton, Tyler; Ehrhardt, Kristina; Lee, James; Kannan, Srijaa; Li, Yi; Ma, Lan; Bleris, LeonidasMicroRNAs are a class of short, noncoding RNAs that are ubiquitous modulators of gene expression, with roles in development, homeostasis, and disease. Engineered microRNAs are now frequently used as regulatory modules in synthetic biology. Moreover, synthetic gene circuits equipped with engineered microRNA targets with perfect complementarity to endogenous microRNAs establish an interface with the endogenous milieu at the single-cell level. The function of engineered microRNAs and sensor systems is typically optimized through extensive trial-and-error. Here, using a combination of synthetic biology experimentation in human embryonic kidney cells and quantitative analysis, we investigate the relationship between input genetic template abundance, microRNA concentration, and output under microRNA control. We provide a framework that employs the complete operational landscape of a synthetic gene circuit and enables the stepwise development of mathematical models. We derive a phenomenological model that recapitulates experimentally observed nonlinearities and contains features that provide insight into the microRNA function at various abundances. Our work facilitates the characterization and engineering of multi-component genetic circuits and specifically points to new insights on the operation of microRNAs as mediators of endogenous information and regulators of gene expression in synthetic biology.Item Genetic Predisposition for Inflammation Exacerbates Effects of Striatal Iron Content on Cognitive Switching Ability in Healthy Aging(Academic Press Inc Elsevier Science, 2018-10-25) Daugherty, Ana M.; Hoagey, David A.; Kennedy, Kristen M.; Rodrigue, Karen M.; 0000-0001-5373-9026 (Kennedy, KM); Hoagey, David A.; Kennedy, Kristen M.; Rodrigue, Karen M.Non-heme iron homeostasis interacts with inflammation bidirectionally, and both contribute to age-related decline in brain structure and function via oxidative stress. Thus, individuals with genetic predisposition for inflammation may be at greater risk for brain iron accumulation during aging and more vulnerable to cognitive decline. We examine this hypothesis in a lifespan sample of healthy adults (N = 183, age 20 - 94 years) who underwent R2*-weighted magnetic resonance imaging to estimate regional iron content and genotyping of interleukin-1beta (IL-1β), a pro-inflammatory cytokine for which the T allelle of the single nucleotide polymorphism increases risk for chronic neuroinflammation. Older age was associated with greater striatal iron content that in turn accounted for poorer cognitive switching performance. Heterozygote IL-1β T-carriers demonstrated poorer switching performance in relation to striatal iron content as compared to IL-1β C/C counterparts, despite the two groups being of similar age. With increasing genetic inflammation risk, homozygote IL-1β T/T carriers had lesser age-related variance in striatal iron content as compared to the other groups but showed a similar association of greater striatal iron content predicting poorer cognitive switching. Non-heme iron and inflammation, although necessary for normal neuronal function, both promote oxidative stress that when accumulated in excess, drives a complex mechanism of neural and cognitive decline in aging.Item Meta-Analysis of Functional Subdivisions within Human Posteromedial Cortex(Springer Heidelberg, 2018-10-26) Huang, Yuefeng; Hullfish, Jeffrey; De Ridder, Dirk; Vanneste, Sven; Huang, Yuefeng; Hullfish, Jeffrey; Vanneste, SvenThe posteromedial cortex (PMC) comprising posterior cingulate cortex (PCC), retrosplenial cortex (RSC), and the precuneus (PrC) is perhaps best known for its involvement in the default mode network. There is no consensus regarding the specific functions of PMC, however, and its component regions each exhibit distinct, but partially overlapping functional profiles. To date, there has been minimal effort to disentangle the functions of these regions. In the present study, we use Neurosynth (http://neurosynth.org) to conduct an unbiased meta-analysis of the PMC based on fMRI coactivation and semantic information extracted from 11,406 studies. Our analyses revealed six PMC clusters with distinct functional profiles: superior and inferior dorsal PCC, anterior and posterior PrC, ventral PCC, and RSC. We discuss these findings in the context of the existing literature and suggest several fruitful avenues for continued research.Item The Antidiabetic Drug Metformin Prevents and Reverses Neuropathic Pain and Spinal Cord Microglial Activation in Male but not Female Mice(Academic Press Ltd- Elsevier Science Ltd, 2018-11-01) Inyang, Kufreobong E.; Szabo-Pardi, Thomas; Wentworth, Emma; McDougal, Timothy A.; Dussor, Gregory; Burton, Michael D.; Price, Theodore J.; 0000-0002-6971-6221 (Price, TJ); Dussor, Gregory; Price, Theodore J.; Inyang, Kufreobong E.; Szabo-Pardi, Thomas; Wentworth, Emma; McDougal, Timothy A.Metformin is a widely prescribed drug used in the treatment of type II diabetes. While the drug has many mechanisms of action, most of these converge on AMP activated protein kinase (AMPK), which metformin activates. AMPK is a multifunctional kinase that is a negative regulator of mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling. Activation of AMPK decreases the excitability of dorsal root ganglion neurons and AMPK activators are effective in reducing chronic pain in inflammatory, post-surgical and neuropathic rodent models. We have previously shown that metformin leads to an enduring resolution of neuropathic pain in the spared nerve injury (SNI) model in male mice and rats. The precise mechanism underlying this long-lasting effect is not known. We conducted experiments to investigate the effects of metformin on SNI-induced microglial activation, a process implicated in the maintenance of neuropathic pain that has recently been shown to be sexually dimorphic. We find that metformin is effective at inhibiting development of neuropathic pain when treatment is given around the time of injury and that metformin is likewise effective at reversing neuropathic mechanical hypersensitivity when treatment is initiation weeks after injury. This effect is linked to decreased Iba-1 staining in the dorsal horn, a marker of microglial activation. Importantly, these positive behavioral and microglia effects of metformin were only observed in male mice. We conclude that the neuropathic pain modifying effects of metformin are sex-specific supporting a differential role for microglial activation in male and female mice.Item The Relationship Between Age, Neural Differentiation, and Memory Performance(Society for Neuroscience, 2018-11-02) Koen, Joshua D.; Hauck, Nedra; Rugg, Michael D.; 0000-0002-7286-5084 (Koen, JD); 0000-0002-0397-5749 (Rugg, MD); Koen, Joshua D.; Hauck, Nedra; Rugg, Michael D.Healthy aging is associated with decreased neural selectivity (dedifferentiation) in category-selective cortical regions. This finding has prompted the suggestion that dedifferentiation contributes to age-related cognitive decline. Consistent with this possibility, dedifferentiation has been reported to negatively correlate with fluid intelligence in older adults. Here, we examined whether dedifferentiation is associated with performance in another cognitive domain- episodic memory-that is also highly vulnerable to aging. Given the proposed role of dedifferentiation in age-related cognitive decline, we predicted there would be a stronger link between dedifferentiation and episodic memory performance in older than in younger adults. Young (18 -30 years) and older (64 -75 years) male and female humans underwent fMRI scanning while viewing images of objects and scenes before a subsequent recognition memory test. We computed a differentiation index in two regions of interest (ROIs): parahippocampal place area (PPA) and lateral occipital complex (LOC). This index quantified the selectivity of the BOLD response to preferred versus nonpreferred category of an ROI (scenes for PPA, objects for LOC). The differentiation index in the PPA, but not the LOC, was lower in older than in younger adults. Additionally, the PPA differentiation index predicted recognition memory performance for the studied items. This relationship was independent of and not moderated by age. The PPA differentiation index also predicted performance on a latent "fluency" factor derived from a neuropsychological test battery; this relationship was also age invariant. These findings suggest that two independent factors, one associated with age, and the other with cognitive performance, influence neural differentiation.Item Gamma Oscillations During Episodic Memory Processing Provide Evidence for Functional Specialization in the Longitudinal Axis of the Human Hippocampus(Wiley, 2018-11-05) Lin, Jui-Jui; Umbach, Gray; Rugg, Michael D.; Lega, Bradley; Rugg, Michael D.The question of whether the anterior and posterior hippocampus serve different or complementary functional roles during episodic memory processing has been motivated by noteworthy findings in rodent experiments and from noninvasive studies in humans. Researchers have synthesized these data to postulate several models of functional specialization, However, the issue has not been explored in detail using direct brain recordings. We recently published evidence that theta power increases during episodic memory encoding occur in the posterior hippocampus in humans. In our current investigation we analyzed an expanded data set of 32 epilepsy patients undergoing stereo EEG seizure mapping surgery with electrodes precisely targeted to the anterior and posterior hippocampus simultaneously who performed an episodic memory task. Using a repeated measures design, we looked for an interaction between encoding versus retrieval differences in gamma oscillatory power and anterior versus posterior hippocampal location. Our findings are consistent with a recently articulated model (the HERNET model) favoring posterior hippocampal activation during retrieval related processing. We also tested for encoding versus retrieval differences in the preferred gamma frequency band (high versus low gamma oscillations) motivated by published rodent data.Item Sensorimotor Network Segregation Declines with Age and is Linked to GABA and to Sensorimotor Performance(Academic Press Inc Elsevier Science, 2018-11-09) Cassady, Kaitlin; Gagnon, Holly; Lalwani, Poortata; Simmonite, Molly; Foerster, Bradley; Park, Denise C.; Peltier, Scott J.; Petrou, Myria; Taylor, Stephan F.; Weissman, Daniel H.; Seidler, Rachael D.; Polk, Thad A.; 74141364 (Park, DC); Park, Denise C.Aging is typically associated with declines in sensorimotor performance. Previous studies have linked some age-related behavioral declines to reductions in network segregation. For example, compared to young adults, older adults typically exhibit weaker functional connectivity within the same functional network but stronger functional connectivity between different networks. Based on previous animal studies, we hypothesized that such reductions of network segregation are linked to age-related reductions in the brain's major inhibitory transmitter, gamma aminobutyric acid (GABA). To investigate this hypothesis, we conducted graph theoretical analyses of resting state functional MRI data to measure sensorimotor network segregation in both young and old adults. We also used magnetic resonance spectroscopy to measure GABA levels in the sensorimotor cortex and collected a battery of sensorimotor behavioral measures. We report four main findings. First, relative to young adults, old adults exhibit both less segregated sensorimotor brain networks and reduced sensorimotor GABA levels. Second, less segregated networks are associated with lower GABA levels. Third, less segregated networks and lower GABA levels are associated with worse sensorimotor performance. Fourth, network segregation mediates the relationship between GABA and performance. These findings link age-related differences in network segregation to age-related differences in GABA levels and sensorimotor performance. More broadly, they suggest a neurochemical substrate of age-related dedifferentiation at the level of large-scale brain networks.Item Gulf War Illness Associated with Abnormal Auditory P1 Event-Related Potential: Evidence of Impaired Cholinergic Processing Replicated in a National Sample(Elsevier Ireland Ltd, 2018-11-10) Tillman, Gail D.; Spence, Jeffrey S.; Briggs, Richard W.; Haley, Robert W.; Hart, John; Kraut, Michael A.; Tillman, Gail D.; Hart, John, Jr.Our team previously reported event-related potential (ERP) and hyperarousal patterns from a study of one construction battalion of the U.S. Naval Reserve who served during the 1991 Persian Gulf War. We sought to replicate these findings in a sample that was more representative of the entire Gulf War-era veteran population, including male and female participants from four branches of the military. We collected ERP data from 40 veterans meeting Haley criteria for Gulf War syndromes 1-3 and from 22 matched Gulf War veteran controls while they performed an auditory oddball task. Reports of hyperarousal from the ill veterans were significantly greater than those from the control veterans, and P1 amplitudes in Syndromes 2 and 3 were significantly higher than P1 amplitudes in Syndrome 1, replicating our previous findings. Many of the contributors to the generation of the P1 potential are also involved in the regulation of arousal and are modulated by cholinergic and dopaminergic systems-two systems whose dysfunction has been implicated in Gulf War illness. These differences among the three syndrome groups where their means were on either side of controls is a replication of our previous ERP study and is consistent with previous imaging studies of this population.Item Emerging Neurotechnology for Antinoceptive Mechanisms and Therapeutics Discovery(Elsevier Advanced Technology, 2018-11-13) Black, Bryan J.; Atmaramani, Rahul; Plagens, Sarah; Campbell, Zachary T.; Dussor, Gregory; Price, Theodore J.; Pancrazio, Joseph J.; 0000-0002-3768-6996 (Campbell, ZT); 0000-0002-6971-6221 (Price, TJ); 0000-0001-8276-3690 (Pancrazio, JJ); Black, Bryan J.; Atmaramani, Rahul; Plagens, Sarah; Campbell, Zachary T.; Dussor, Gregory; Price, Theodore J.; Pancrazio, Joseph J.The tolerance, abuse, and potential exacerbation associated with classical chronic pain medications such as opioids creates a need for alternative therapeutics. Phenotypic screening provides a complementary approach to traditional target-based drug discovery. Profiling cellular phenotypes enables quantification of physiologically relevant traits central to a disease pathology without prior identification of a specific drug target. For complex disorders such as chronic pain, which likely involves many molecular targets, this approach may identify novel treatments. Sensory neurons, termed nociceptors, are derived from dorsal root ganglia (DRG) and can undergo changes in membrane excitability during chronic pain. In this review, we describe phenotypic screening paradigms that make use of nociceptor electrophysiology. The purpose of this paper is to review the bioelectrical behavior of DRG neurons, signaling complexity in sensory neurons, various sensory neuron models, assays for bioelectrical behavior, and emerging efforts to leverage microfabrication and microfluidics for assay development. We discuss limitations and advantages of these various approaches and offer perspectives on opportunities for future development.Item Estimation of Brain Functional Connectivity from Hypercapnia BOLD MRI Data: Validation in a Lifespan Cohort of 170 Subjects(Academic Press Inc Elsevier Science, 2018-11-16) Hou, Xirui; Liu, Peiying; Gu, Hong; Chan, Micaela; Li, Yang; Peng, Shin-Lei; Wig, Gagan; Yang, Yihong; Park, Denise C.; Lu, Hanzhang; 74141364 (Park, DC); Chan, Micaela; Park, Denise C.Functional connectivity MRI, based on Blood-Oxygenation-Level-Dependent (BOLD) signals, is typically performed while the subject is at rest. On the other hand, BOLD is also widely used in physiological imaging such as cerebrovascular reactivity (CVR) mapping using hypercapnia (HC) as a modulator. We therefore hypothesize that hypercapnia BOLD data can be used to extract FC metrics after factoring out the effects of the physiological modulation, which will allow simultaneous assessment of neural and vascular function and may be particularly important in populations such as aging and cerebrovascular diseases. The present work aims to systematically examine the feasibility of hypercapnia BOLD-based FC mapping using three commonly applied analysis methods, specifically dual-regression Independent Component Analysis (ICA), region-based FC matrix analysis, and graph-theory based network analysis, in a large cohort of 170 healthy subjects ranging from 20 to 88 years old. To validate the hypercapnia BOLD results, we also compared these FC metrics with those obtained from conventional resting-state data. ICA analysis of the hypercapnia BOLD data revealed FC maps that strongly resembled those reported in the literature. FC matrix using region-based analysis showed a correlation of 0.97 on the group-level and 0.54 ± 0.10 on the individual-level, when comparing between hypercapnia and resting-state results. Although the correspondence on the individual-level was moderate, this was primarily attributed to variations intrinsic to FC mapping, because a corresponding resting-vs-resting comparison in a sub-cohort (N = 39) revealed a similar correlation of 0.57 ± 0.09. Graph-theory computations were also feasible in hypercapnia BOLD data and indices of global efficiency, clustering coefficient, modularity, and segregation were successfully derived. Hypercapnia FC results revealed age-dependent differences in which within-network connections generally exhibited an age-dependent decrease while between-network connections showed an age-dependent increase.Item The Time Course of Semantic and Relational Processing During Verbal Analogical Reasoning(Academic Press Inc Elsevier Science, 2018-12-01) Kmiecik, Matthew J.; Brisson, Ryan J.; Morrison, Robert G.; Kmiecik, Matthew J.Analogy is an important ability that allows humans to discover relationships between information domains that often vary in surface and relational characteristics. Cognitive neuroscience studies of analogy have demonstrated the importance of the prefrontal cortex during relational comparisons, but little is known about how semantic and relational similarity interact throughout its time course. We used scalp electroencephalography (EEG) analyzed with event-related potentials (ERPs) to examine the neural time course of analogical reasoning while 16 participants solved four-term verbal analogies. Semantic similarity was manipulated by increasing the semantic distance between source and target analogs creating semantically near and far analogies. Relational similarity was manipulated by creating relationally valid and invalid analogies. Only valid analogies were impacted by semantic distance such that far analogies were solved slower and less accurately than near analogies. Correctly solving near analogies elicited more positive waveforms at the N400 and during later relational processing. However, valid analogies elicited more positive signals during only later relational processing and not during the N400. These results suggest that semantic information impacts both early semantic and late relational comparison stages, while relational properties exert more influence in later stages of analogical reasoning. The degree of semantic similarity shared between knowledge domains demonstrated a potent effect throughout the time course of analogy that affected not only semantic access, but also the mapping of relational structures.