Destination Area: Adaptive Brain and Behavior (ABB)

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https://hdl.handle.net/10919/78791

This destination area focuses broadly on how brains change and adapt over the life course, how they change following traumatic events or diseases, and how social and societal forces are affected by and affect brains and individuals. ABB brings together humanities, social sciences, and neuroscience to analyze adaptive changes across multiple levels of inquiry from molecules to individuals, families, and communities. This destination area has three organizational sub-themes: • Healthy and Unhealthy Brain Development: Characterizing healthy brain development first – including cognition, stress, emotion, and decision-making – allows researchers to better identify and understand unhealthy brain development with wide-ranging complex and interactive effects for people and communities. Virginia Tech has recognized leaders in research on focused brain and behavioral development. • Brain Trauma: Damage occurs to the brain not only due to injury, but also genetics or psychological/emotional causes such as PTSD, abuse, or neglect. Virginia Tech is a recognized leader for research and education to help recognize, respond to, and recover from brain trauma. • Brain Cancer: Affecting more than 200,000 people each year in the U.S. alone, brain cancer is a major health crisis. Virginia Tech has a strong contingent of internationally recognized investigators whose research is informing society on cancer biology, etiology, disease mechanisms, and experimental treatments. [http://provost.vt.edu/destination-areas/da-brain.htm]

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Cognitive function following SARS-CoV-2 infection in a population-representative Canadian sample
Hall, Peter A.; Meng, Gang; Hudson, Anna; Sakib, Mohammed N.; Hitchman, Sara C.; MacKillop, James; Bickel, Warren K.; Fong, Geoffrey T. (Elsevier, 2022-05-01)
Background: SARS-CoV-2 infection is believed to adversely affect the brain, but the degree of impact on socially relevant cognitive functioning and decision-making is not well-studied, particularly among those less vulnerable to age-related mortality. The current study sought to determine whether infection status and COVID-19 symptom severity are associated with cognitive dysfunction among young and middled-aged adults in the general population, using self-reported lapses in executive control and a standardized decision-making task. Method: The survey sample comprised 1958 adults with a mean age of 37 years (SD = 10.4); 60.8% were female. Participants reported SARS-CoV-2 infection history and, among those reporting a prior infection, COVID-19 symptom severity. Primary outcomes were self-reported symptoms of cognitive dysfunction assessed via an abbreviated form of the Barkley Deficits in Executive Functioning Scale (BDEFS) and performance on a validated delay-discounting task. Results: Young and middle-aged adults with a positive SARS-CoV-2 infection history reported a significantly higher number of cognitive dysfunction symptoms (Madj = 1.89, SE = 0.08, CI: 1.74, 2.04; n = 175) than their non-infected counterparts (Madj = 1.63, SE = 0.08, CI: 1.47,1.80; n = 1599; β = 0.26, p = .001). Among those infected, there was a dose-response relationship between COVID-19 symptom severity and level of cognitive dysfunction reported, with moderate (β = 0.23, CI: 0.003–0.46) and very/extremely severe (β = 0.69, CI: 0.22–1.16) COVID-19 symptoms being associated with significantly greater cognitive dysfunction. These effects remained reliable and of similar magnitude after controlling for demographics, vaccination status, mitigation behavior frequency, and geographic region, and after removal of those who had been intubated during hospitalization. Very similar—and comparatively larger—effects were found for the delay-discounting task, and when using only PCR confirmed SARS-CoV-2 cases. Conclusions: Positive SARS-CoV-2 infection history and moderate or higher COVID-19 symptom severity are associated with significant symptoms of cognitive dysfunction and amplified delay discounting among young and middle-aged adults with no history of medically induced coma.
Imagining the Future to Reshape the Past: A Path to Combine Cue Extinction and Memory Reconsolidation With Episodic Foresight for Addiction Treatment
Rafei, Parnian; Rezapour, Tara; Bickel, Warren K.; Ekhtiari, Hamed (Frontiers, 2021-07-21)
Continuous maladaptive drug-related memories that are resistant to extinction and cause drug-seeking behaviors to be triggered are known to be one of the hallmarks of drug addiction (1). These drug-related memories are salient, strong, and persistent due to chronic maladaptive consolidation processes. Due to the salient content of drug-related memories formed during drug-taking behaviors, certain stimuli (e.g., peers, locations, paraphernalia) become encoded with reward contingencies associated with drugs. As a result of this learning processing, drug-paired stimuli acquire incentive motivational properties that change them into salient cues (2). According to Pavlovian conditioning, consequent exposure to these stimuli (Henceforth called drug cues) activates the original memories and evokes craving. This enhanced retrieval co-occurs with the activation of limbic cortico-striatal pathways involved in reward processing (3). A serious question in addiction neuroscience is whether these memories could be actively erased/reshaped in favor of the recovery process. Different research groups suggested various treatment strategies during the last decade to modulate these memories. Here in this short opinion paper, we propose a novel framework titled “Cue-induced Retrieval and Reconsolidation with Episodic Foresight” (CIREF) that aims to combine three different cognitive interventions, i.e., cue-exposure, memory reconsolidation, and episodic future thinking, to reshape these maladaptive drug-related memories toward more adaptive memories to support addiction recovery.
Neural cognitive control moderates the longitudinal link between hedonia and substance use across adolescence
Lindenmuth, Morgan; Herd, Toria; Brieant, Alexis; Lee, Jacob; Deater-Deckard, Kirby; Bickel, Warren K.; Casas, Brooks; Kim-Spoon, Jungmeen (Elsevier, 2022-06-01)
Hedonic dysregulation is evident in addiction and substance use disorders, but it is not clearly understood how hedonic processes may interact with brain development related to cognitive control to influence risky decision making and substance use during adolescence. The present study used prospective longitudinal data to clarify the role of cognitive control in the link between hedonic experiences and the development of substance use during adolescence. Participants included 167 adolescents (53% male) assessed at four time points, annually. Adolescents participated in a functional magnetic resonance imaging (fMRI) session where blood-oxygen level dependent (BOLD) response was monitored during the Multi-Source- Interference Task to assess cognitive control. Substance use and hedonia were assessed using self-report. A two-group growth curve model of substance use with hedonia as a time-varying covariate indicated that higher levels of hedonia predicted higher substance use, but only in adolescents with higher activation in the frontoparietal regions and in the rostral anterior cingulate cortex during cognitive control. Results elucidate the moderating effects of neural cognitive control on associations between hedonia and adolescent substance use, suggesting that lower cognitive control functioning in the brain may exacerbate risk for substance use promoted by hedonia.
Social Synchronization of Conditioned Fear in Mice Requires Ventral Hippocampus Input to Amygdala
Ito, Wataru; Palmer, Alexander J.; Morozov, Alexei (Elsevier, 2022-05-01)
Background: Social organisms synchronize behaviors as an evolutionary-conserved means for thriving. Synchronization under threat, in particular, benefits survival and occurs across species, including humans, but the underlying mechanisms remain unknown, due to the scarcity of the relevant animal models. Here, we developed a rodent paradigm in which mice synchronize classically conditioned fear response and identified an underlying neuronal circuit. Methods: Males and female mice were trained individually in an auditory fear conditioning and then tested 24 h later as dyads allowing unrestricted social interaction during exposure to the conditioned stimulus, under the visible or infrared illumination to eliminate visual cues. The synchronization of the immobility or freezing bouts was quantified by calculating the effect size Cohen’s D for the difference between the actual freezing time overlap and the overlap by chance. The inactivation of the dorsomedial prefrontal cortex, dorsal hippocampus, or ventral hippocampus was achieved by local infusions of muscimol. The chemogenetic disconnection of the hippocampus-amygdala pathway was performed by expressing hM4D(Gi) in the ventral hippocampal neurons and infusing CNO in the amygdala. Results: Mice synchronized cued but not contextual fear. It was higher in males than in females and attenuated in the absence of visible light. Inactivation of the ventral but not dorsal hippocampus or dorsomedial prefrontal cortex abolished fear synchronization. Finally, the disconnection of the hippocampal-amygdala pathway diminished fear synchronization. Conclusions: Mice synchronize expression of conditioned fear relying on the ventral hippocampus-amygdala pathway, suggesting that the hippocampus transmits social information to the amygdala to synchronize threat response.
Graph auto-encoding brain networks with applications to analyzing large-scale brain imaging datasets
Liu, Meimei; Zhang, Zhengwu; Dunson, David B. (Academic Press-Elsevier, 2021-12-15)
There has been a huge interest in studying human brain connectomes inferred from different imaging modalities and exploring their relationships with human traits, such as cognition. Brain connectomes are usually represented as networks, with nodes corresponding to different regions of interest (ROIs) and edges to connection strengths between ROIs. Due to the high-dimensionality and non-Euclidean nature of networks, it is challenging to depict their population distribution and relate them to human traits. Current approaches focus on summarizing the network using either pre-specified topological features or principal components analysis (PCA). In this paper, building on recent advances in deep learning, we develop a nonlinear latent factor model to characterize the population distribution of brain graphs and infer their relationships to human traits. We refer to our method as Graph AuTo-Encoding (GATE). We applied GATE to two large-scale brain imaging datasets, the Adolescent Brain Cognitive Development (ABCD) study and the Human Connectome Project (HCP) for adults, to study the structural brain connectome and its relationship with cognition. Numerical results demonstrate huge advantages of GATE over competitors in terms of prediction accuracy, statistical inference, and computing efficiency. We found that the structural connectome has a stronger association with a wide range of human cognitive traits than was apparent using previous approaches.
Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme
Umans, Robyn A.; Martin, Joelle; Harrigan, Megan E.; Patel, Dipan C.; Chaunsali, Lata; Roshandel, Aarash; Iyer, Kavya; Powell, Michael D.; Oestreich, Ken; Sontheimer, Harald (MDPI, 2021-12)
Glioblastoma multiforme (GBM) is a highly invasive brain tumor that typically has poor patient outcomes. This is due in part to aggressive tumor expansion within the brain parenchyma. This process is aided by assiduous glutamate release via the System xc- (SXC) cystine-glutamate antiporter. SXC is over-expressed in roughly half of GBM tumors where it is responsible for glutamate-mediated neuronal cell death and provides excess glutamate to fuel tumor-associated epilepsy. Available pharmacological inhibitors have some promise, although they lack specificity and have poor bioavailability. Therefore, identifying regulators of SXC may provide a superior avenue to target GBM. In this study, we identify tumor protein 53 (TP53) as a molecular regulator of SXC in GBM. Glioblastoma multiforme (GBM) is a deadly brain tumor with a large unmet therapeutic need. Here, we tested the hypothesis that wild-type p53 is a negative transcriptional regulator of SLC7A11, the gene encoding the System xc- (SXC) catalytic subunit, xCT, in GBM. We demonstrate that xCT expression is inversely correlated with p53 expression in patient tissue. Using representative patient derived (PDX) tumor xenolines with wild-type, null, and mutant p53 we show that p53 expression negatively correlates with xCT expression. Using chromatin immunoprecipitation studies, we present a molecular interaction whereby p53 binds to the SLC7A11 promoter, suppressing gene expression in PDX GBM cells. Accordingly, genetic knockdown of p53 increases SLC7A11 transcript levels; conversely, over-expressing p53 in p53-null GBM cells downregulates xCT expression and glutamate release. Proof of principal studies in mice with flank gliomas demonstrate that daily treatment with the mutant p53 reactivator, PRIMA-1(Met), results in reduced tumor growth associated with reduced xCT expression. These findings suggest that p53 is a molecular switch for GBM glutamate biology, with potential therapeutic utility.
Characterization and structure-property relationships of an injectable thiol-Michael addition hydrogel toward compatibility with glioblastoma therapy
Khan, Zerin Mahzabin; Wilts, Emily; Vlaisavljevich, Eli; Long, Timothy E.; Verbridge, Scott S. (Elsevier, 2022-05-01)
Glioblastoma multiforme (GBM) is an aggressive primary brain cancer and although patients undergo surgery and chemoradiotherapy, residual cancer cells still migrate to healthy brain tissue and lead to tumor relapse after treatment. New therapeutic strategies are therefore urgently needed to better mitigate this tumor recurrence. To address this need, we envision after surgical removal of the tumor, implantable biomaterials in the resection cavity can treat or collect residual GBM cells for their subsequent eradication. To this end, we systematically characterized a poly(ethylene glycol)-based injectable hydrogel crosslinked via a thiol-Michael addition reaction by tuning its hydration level and aqueous NaHCO3 concentration. The physical and chemical properties of the different formulations were investigated by assessing the strength and stability of the polymer networks and their swelling behavior. The hydrogel biocompatibility was assessed by performing in vitro cytotoxicity assays, immunoassays, and immunocytochemistry to monitor the reactivity of astrocytes cultured on the hydrogel surface over time. These characterization studies revealed key structure-property relationships. Furthermore, the results indicated hydrogels synthesized with 0.175 M NaHCO3 and 50 wt% water content swelled the least, possessed a storage modulus that can withstand high intracranial pressures while avoiding a mechanical mismatch, had a sufficiently crosslinked polymer network, and did not degrade rapidly. This formulation was not cytotoxic to astrocytes and produced minimal immunogenic responses in vitro. These properties suggest this hydrogel formulation is the most optimal for implantation in the resection cavity and compatible toward GBM therapy. Statement of significance: Survival times for glioblastoma patients have not improved significantly over the last several decades, as cancer cells remain after conventional therapies and form secondary tumors. We characterized a biodegradable, injectable hydrogel to reveal structure-property relationships that can be tuned to conform the hydrogel toward glioblastoma therapy. Nine formulations were systematically characterized to optimize the hydrogel based on physical, chemical, and biological compatibility with the glioblastoma microenvironment. This hydrogel can potentially be used for adjuvant therapy to glioblastoma treatment, such as by providing a source of molecular release for therapeutic agents, which will be investigated in future work. The optimized formulation will be developed further to capture and eradicate glioblastoma cells with chemical and physical stimuli in future research.
Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior
Dudok, Barna; Szoboszlay, Miklos; Paul, Anirban; Klein, Peter M.; Liao, Zhenrui; Hwaun, Ernie; Szabo, Gergely G.; Geiller, Tristan; Vancura, Bert; Wang, Bor-Shuen; McKenzie, Sam; Homidan, Jesslyn; Klaver, Lianne M. F.; English, Daniel F.; Huang, Z. Josh; Buzsaki, Gyorgy; Losonczy, Attila; Soltesz, Ivan (Cell Press, 2021-12-01)
The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the "chandelier"or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their in vivo activity patterns and influence over pyramidal cell dynamics are not well understood. We achieved cell-type-specific genetic access to AACs in mice and show that AACs in the hippocampal area CA1 are synchronously activated by episodes of locomotion or whisking during rest. Bidirectional intervention experiments in head-restrained mice performing a random foraging task revealed that AACs inhibit CA1 pyramidal cells, indicating that the effect of GABA on the initial segments in the hippocampus is inhibitory in vivo. Finally, optogenetic inhibition of AACs at specific track locations induced remapping of pyramidal cell place fields. These results demonstrate brain-state -specific dynamics of a critical inhibitory controller of cortical circuits.
The early childhood inhibitory touchscreen task: A new measure of response inhibition in toddlerhood and across the lifespan
Holmboe, Karla; Larkman, Charlotte; de Klerk, Carina; Simpson, Andrew; Bell, Martha Ann; Patton, Leslie; Christodoulou, Charis; Dvergsdal, Henrik (PLOS, 2021-12-02)
Research into the earliest development of inhibitory control is limited by a lack of suitable tasks. In particular, commonly used inhibitory control tasks frequently have too high language and working memory demands for children under 3 years of age. Furthermore, researchers currently tend to shift to a new set of inhibitory control tasks between infancy, toddlerhood, and early childhood, raising doubts about whether the same function is being measured. Tasks that are structurally equivalent across age could potentially help resolve this issue. In the current report, a new response inhibition task, the Early Childhood Inhibitory Touchscreen Task (ECITT), was developed. This task can be minimally modified to suit different ages, whilst remaining structurally equivalent. In the new task, participants have to overcome a tendency to respond to a frequently rewarded location on a touchscreen and instead make an alternative response. The ECITT was validated in three independent studies (with additional data, N = 166, reported in Supporting Information). In Study 1 (N = 81), cross-sectional data indicated that inhibitory performance on the task improved significantly between 24 and 30 months of age. In Study 2 (N = 38), longitudinal data indicated steady improvement in inhibitory control between 18, 21 and 24 months, with significant stability in individual performance differences between each consecutive age in terms of accuracy (but not in terms of reaction time). Finally, in Study 3 (N = 64), inhibitory performance on a faster-paced version of the same task showed a similar developmental course across the lifespan (4-84 years) to other response inhibition tasks and was significantly correlated with Stop-signal performance. The ECITT extends the assessment of response inhibition earlier than previous tasks-into early toddlerhood. Because the task is simple and structurally equivalent across age, future longitudinal studies should benefit from using the ECITT to investigate the development of inhibitory control in a consistent manner across the toddler years and beyond.
From gratitude to injustice: Neurocomputational mechanisms of gratitude-induced injustice
Zhu, Ruida; Xu, Zhenhua; Su, Song; Feng, Chunliang; Luo, Yi; Tang, Honghong; Zhang, Shen; Wu, Xiaoyan; Mai, Xiaoqin; Liu, Chao (Academic Press-Elsevier, 2021-12-15)
Gratitude shapes individuals' behaviours and impacts the harmony of society. Many previous studies focused on its association with prosocial behaviours. A possibility that gratitude can lead to moral violation has been overlooked until recently. Nevertheless, the neurocognitive mechanisms of gratitude-induced moral violation are still unclear. On the other hand, though neural correlates of the gratitude's formation have been examined, the neural underpinnings of gratitude-induced behaviour remain unknown. For addressing these two overlapped research gaps, we developed novel tasks to investigate how participants who had received voluntary (Gratitude group) or involuntary help (Control group) punished their benefactors' unfairness with functional magnetic resonance imaging (fMRI). The Gratitude group punished their benefactors less than the Control group. The self-report and computational modelling results demonstrated a crucial role of the boosted protection tendency on behalf of benefactors in the gratitude-induced injustice. The fMRI results showed that activities in the regions associated with mentalizing (temporoparietal junction) and reward processing (ventral medial prefrontal cortex) differed between the groups and were related to the gratitude-induced injustice. They suggest that grateful individuals concern for benefactors' benefits, value chances to interact with benefactors, and refrain from action that perturbs relationship-building (i.e., exert less punishment on benefactors' unfairness), which reveal a dark side of gratitude and enrich the gratitude theory (i.e., the find-bind-remind theory). Our findings provide psychological, computational, and neural accounts of the gratitude-induced behaviour and further the understanding of the nature of gratitude.
Cranial manipulation affects cholinergic pathway gene expression in aged rats
Anandakrishnan, Ramu; Tobey, Hope; Nguyen, Steven; Sandoval, Osscar; Klein, Bradley G.; Costa, Blaise M. (De Gruyter, 2022-01-10)
Context: Age-dependent dementia is a devastating disorder afflicting a growing older population. Although pharmacological agents improve symptoms of dementia, age-related comorbidities combined with adverse effects often outweigh their clinical benefits. Therefore, nonpharmacological therapies are being investigated as an alternative. In a previous pilot study, aged rats demonstrated improved spatial memory after osteopathic cranial manipulative medicine (OCMM) treatment. Objectives: In this continuation of the pilot study, we examine the effect of OCMM on gene expression to elicit possible explanations for the improvement in spatialmemory. Methods: OCMM was performed on six of 12 elderly rats every day for 7 days. Rats were then euthanized to obtain the brain tissue, from which RNA samples were extracted. RNA from three treated and three controls were of sufficient quality for sequencing. These samples were sequenced utilizing next-generation sequencing from Illumina NextSeq. The Cufflinks software suite was utilized to assemble transcriptomes and quantify the RNA expression level for each sample. Results: Transcriptome analysis revealed that OCMM significantly affected the expression of 36 genes in the neuronal pathway (false discovery rate [FDR] <0.004). The top five neuronal genes with the largest-fold change were part of the cholinergic neurotransmission mechanism, which is known to affect cognitive function. In addition, 39.9% of 426 significant differentially expressed (SDE) genes (FDR<0.004) have been previously implicated in neurological disorders. Overall, changes in SDE genes combined with their role in central nervous system signaling pathways suggest a connection to previously reported OCMM-induced behavioral and biochemical changes in aged rats. Conclusions: Results from this pilot study provide sufficient evidence to support a more extensive study with a larger sample size. Further investigation in this direction will provide a better understanding of the molecular mechanisms of OCMM and its potential in clinical applications. With clinical validation, OCMM could represent a much-needed low-risk adjunct treatment for age-related dementia including Alzheimer's disease.
Choice Bundling Increases Valuation of Delayed Losses More Than Gains in Cigarette Smokers
Stein, Jeffrey S.; Brown, Jeremiah M.; Tegge, Allison N.; Freitas-Lemos, Roberta; Koffarnus, Mikhail N.; Bickel, Warren K.; Madden, Gregory J. (Frontiers, 2022-01-13)
Choice bundling, in which a single choice produces a series of repeating consequences over time, increases valuation of delayed monetary and non-monetary gains. Interventions derived from this manipulation may be an effective method for mitigating the elevated delay discounting rates observed in cigarette smokers. No prior work, however, has investigated whether the effects of choice bundling generalize to reward losses. In the present study, an online panel of cigarette smokers (N = 302), recruited using survey firms Ipsos and InnovateMR, completed assessments for either monetary gains or losses (randomly assigned). In Step 1, participants completed a delay-discounting task to establish Effective Delay 50 (ED50), or the delay required for an outcome to lose half of its value. In Step 2, participants completed three conditions of an adjusting-amount task, choosing between a smaller, sooner (SS) adjusting amount and a larger, later (LL) fixed amount. The bundle size (i.e., number of consequences) was manipulated across conditions, where a single choice produced either 1 (control), 3, or 9 consequences over time (ascending/descending order counterbalanced). The delay to the first LL amount in each condition, as well as the intervals between all additional SS and LL amounts (where applicable), were set to individual participants' ED50 values from Step 1 to control for differences in discounting of gains and losses. Results from Step 1 showed significantly higher ED50 values (i.e., less discounting) for losses compared to gains (p < 0.001). Results from Step 2 showed that choice bundling significantly increased valuation of both LL gains and losses (p < 0.001), although effects were significantly greater for losses (p < 0.01). Sensitivity analyses replicated these conclusions. Future research should examine the potential clinical utility of choice bundling, such as development of motivational interventions that emphasize both the bundled health gains associated with smoking cessation and the health losses associated with continued smoking.
Editorial: Similarities and Discrepancies Across Family Members at Multiple Levels: Insights From Behavior, Psychophysiology, and Neuroimaging
Rogers, Christy Rae; Qu, Yang; Lee, Tae-Ho; Liu, Siwei; Kim, Sun Hyung (Frontiers, 2022-01-28)
Preconception maternal posttraumatic stress and child negative affectivity: Prospectively evaluating the intergenerational impact of trauma
Swales, Danielle A.; Davis, Elysia Poggi; Mahrer, Nicole E.; Guardino, Christine M.; Shalowitz, Madeleine U.; Ramey, Sharon L.; Schetter, Chris Dunkel (Cambridge University Press, 2022-01-25)
The developmental origins of psychopathology begin before birth and perhaps even prior to conception. Understanding the intergenerational transmission of psychopathological risk is critical to identify sensitive windows for prevention and early intervention. Prior research demonstrates that maternal trauma history, typically assessed retrospectively, has adverse consequences for child socioemotional development. However, very few prospective studies of preconception trauma exist, and the role of preconception symptoms of posttraumatic stress disorder (PTSD) remains unknown. The current study prospectively evaluates whether maternal preconception PTSD symptoms predict early childhood negative affectivity, a key dimension of temperament and predictor of later psychopathology. One hundred and eighteen women were recruited following a birth and prior to conception of the study child and were followed until the study child was 3-5 years old. Higher maternal PTSD symptoms prior to conception predicted greater child negative affectivity, adjusting for concurrent maternal depressive symptoms and sociodemographic covariates. In exploratory analyses, we found that neither maternal prenatal nor postpartum depressive symptoms or perceived stress mediated this association. These findings add to a limited prospective literature, highlighting the importance of assessing the mental health of women prior to conception and providing interventions that can disrupt the intergenerational sequelae of trauma.
Efficacy of D-cycloserine augmented brief intensive cognitive-behavioural therapy for paediatric obsessive-compulsive disorder: A randomised clinical trial
Farrell, Lara J.; Waters, Allison M.; Tiralongo, Evelin; Mathieu, Sharna; McKenzie, Matthew; Garbharran, Vinay; Ware, Robert S.; Zimmer-Gembeck, Melanie J.; McConnell, Harry; Lavell, Cassie; Cadman, Jacinda; Ollendick, Thomas H.; Hudson, Jennifer L.; Rapee, Ronald M.; McDermott, Brett; Geller, Daniel; Storch, Eric A. (Wiley, 2022-01)
Objective To examine the efficacy of weight-adjusted D-cycloserine (DCS) (35 or 70 mg) relative to placebo augmentation of intensive exposure therapy for youth with obsessive-compulsive disorder (OCD) in a double-blind, randomised controlled trial, and examine whether antidepressant medication or patient age moderated outcomes. Methods Youth (n = 100, 7-17 years) with OCD were randomised in a 1:1 ratio to either DCS + exposure (n = 49) or placebo + exposure (n = 51). Assessments occurred posttreatment, 1 month later, and at 3 and 6 months. Pills were ingested immediately before sessions. Results Significant improvements on all outcomes were observed at posttreatment, and to 6-month follow-up. Treatment arms did not differ across time, with no significant time-by-medication interactions on symptom severity (T1 to T2 estimate: 9.3, 95% confidence interval [CI]: -11.2 to -7.4, and estimate -10.7, 95% CI: -12.6 to -8.7), diagnostic severity (T1 to T2 estimate: -2.0, 95% CI: -2.4 to -1.5 and estimate -2.5, 95% CI: -3.0 to -2.0) or global functioning (T1 to T2 estimate: 13.8, 95% CI: 10.6 to 17.0, and estimate 16.6, 95% CI: 13.2 to 19.9). Neither antidepressants at baseline nor age moderated primary outcomes. There were significantly fewer responders/remitters at 1- and 6-month follow-up among youth in the DCS condition stabilised on SSRIs, relative to youth not taking SSRIs. Conclusions DCS augmented intensive exposure therapy did not result in overall additional benefits relative to placebo. Intensive exposure proved effective in reducing symptoms for the overall sample.
A patient-designed tissue-engineered model of the infiltrative glioblastoma microenvironment
Cornelison, R. Chase; Yuan, J. X.; Tate, Kinsley M.; Petrosky, A.; Beeghly, G. F.; Bloomfield, Mathew; Schwager, S. C.; Berr, A. L.; Stine, Caleb A.; Cimini, Daniela; Bafakih, F. F.; Mandell, J. W.; Purow, B. W.; Horton, B. J.; Munson, Jennifer M. (Nature Portfolio, 2022-07-29)
Glioblastoma is an aggressive brain cancer characterized by diffuse infiltration. Infiltrated glioma cells persist in the brain post-resection where they interact with glial cells and experience interstitial fluid flow. We use patient-derived glioma stem cells and human glial cells (i.e., astrocytes and microglia) to create a four-component 3D model of this environment informed by resected patient tumors. We examine metrics for invasion, proliferation, and putative stemness in the context of glial cells, fluid forces, and chemotherapies. While the responses are heterogeneous across seven patient-derived lines, interstitial flow significantly increases glioma cell proliferation and stemness while glial cells affect invasion and stemness, potentially related to CCL2 expression and differential activation. In a screen of six drugs, we find in vitro expression of putative stemness marker CD71, but not viability at drug IC50, to predict murine xenograft survival. We posit this patient-informed, infiltrative tumor model as a novel advance toward precision medicine in glioblastoma treatment.
Sulfasalazine decreases astrogliosis-mediated seizure burden
Alcoreza, Oscar; Jagarlamudi, Sai; Savoia, Andrew; Campbell, Susan L.; Sontheimer, Harald (Wiley, 2022-04)
Objective Previously, we reported that inhibition of the astrocytic cystine/glutamate antiporter system xc- (SXC), using sulfasalazine (SAS), decreased evoked excitatory signaling in three distinct hyperexcitability models ex vivo. The current study expands on this work by evaluating the in vivo efficacy of SAS in decreasing astrogliosis-mediated seizure burden seen in the beta-1 integrin knockout (B1KO) model. Methods Video-EEG (electroencephalography) monitoring (24/7) was obtained using Biopac EEG acquisition hardware and software. EEG spectral analysis was performed using MATLAB. SAS was used at an equivalence of doses taken by Crohn's disease patients. Whole-cell patch-clamp recordings were made from cortical layer 2/3 pyramidal neurons. Results We report that 100% of B1KO mice that underwent 24/7 video-EEG monitoring developed spontaneous recurrent seizures and that intraperitoneal administration of SAS significantly reduced seizure frequency in B1KOs compared to B1KOs receiving sham saline. Spectral analysis found an acute reduction in EEG power following SAS treatment in B1KOs; however, this effect was not observed in nonepileptic control mice receiving SAS. Finally, whole-cell recordings from SXC knockout mice had hyperpolarized neurons and SXC-B1 double knockouts fired significantly less action potentials in response to current injection compared to B1KOs with SXC. Significance To devise effective strategies in finding relief for one-in-three patients with epilepsy who experience drug-resistant epilepsy we must continue to explore the mechanisms regulating glutamate homeostasis. This study explored the efficacy of targeting an astrocytic glutamate antiporter, SXC, as a novel antiepileptic drug (AED) target and further characterized a unique mouse model in which chronic astrogliosis is sufficient to induce spontaneous seizures and epilepsy. These findings may serve as a foundation to further assess the potential for SAS or inform the development of more potent and specific compounds that target SXC as a novel treatment for epilepsy.
Electronic Cigarette Vaping Did Not Enhance the Neural Process of Working Memory for Regular Cigarette Smokers
Kim, Dong-Youl; Jang, Yujin; Heo, Da-Woon; Jo, Sungman; Kim, Hyun-Chul; Lee, Jong-Hwan (Frontiers, 2022-02-18)
BackgroundElectronic cigarettes (e-cigs) as substitute devices for regular tobacco cigarettes (r-cigs) have been increasing in recent times. We investigated neuronal substrates of vaping e-cigs and smoking r-cigs from r-cig smokers. MethodsTwenty-two r-cig smokers made two visits following overnight smoking cessation. Functional magnetic resonance imaging (fMRI) data were acquired while participants watched smoking images. Participants were then allowed to smoke either an e-cig or r-cig until satiated and fMRI data were acquired. Their craving levels and performance on the Montreal Imaging Stress Task and a 3-back alphabet/digit recognition task were obtained and analyzed using two-way repeated-measures analysis of variance. Regions-of-interest (ROIs) were identified by comparing the abstained and satiated conditions. Neuronal activation within ROIs was regressed on the craving and behavioral data separately. ResultsCraving was more substantially reduced by smoking r-cigs than by vaping e-cigs. The response time (RT) for the 3-back task was significantly shorter following smoking r-cigs than following vaping e-cigs (interaction: F (1, 17) = 5.3, p = 0.035). Neuronal activations of the right vermis (r = 0.43, p = 0.037, CI = [-0.05, 0.74]), right caudate (r = 0.51, p = 0.015, CI = [0.05, 0.79]), and right superior frontal gyrus (r = -0.70, p = 0.001, CI = [-0.88, -0.34]) were significantly correlated with the RT for the 3-back task only for smoking r-cigs. ConclusionOur findings suggest that insufficient satiety from vaping e-cigs for r-cigs smokers may be insignificant effect on working memory function.
Delayed Presentation of Posterior Reversible Encephalopathy Syndrome in the Setting of Serotonin-Norepinephrine Reuptake Inhibitors
Bhutada, Abhishek S.; Kodankandath, Thomas V. (Cureus, 2022-02-21)
Posterior reversible encephalopathy syndrome (PRES) is a complex process that has been implicated in the setting of many chronic diseases (i.e., hypertension, chronic kidney disease, autoimmune diseases, infections, transplant treatments, etc.). The exact pathogenesis of PRES is still unclear; however, it has been suggested to involve endothelial injury leading to immune system activation and cytokine release. This case report examines an atypical presentation of PRES caused by serotonin-norepinephrine reuptake inhibitors (SNRIs).
Biocompatibility of the fiberoptic microneedle device chronically implanted in the rat brain
Kani, Yukitaka; Hinckley, Jonathan; Robertson, John L.; Mehta, Jason M.; Rylander, Christopher G.; Rossmeisl, John H. Jr. (Elsevier, 2022-03)
The fiberoptic microneedle device (FMD) is a fused-silica microcatheter capable of co-delivery of fluids and light that has been developed for convection-enhanced delivery and photothermal treatments of glioblastoma. Here we investigate the biocompatibility of FMD fragments chronically implanted in the rat brain in the context of evaluating potential mechanical device failure. Fischer rats underwent craniectomy procedures for sham control (n & nbsp;= 16) or FMD implantation (n = 16) within the brain. Rats were examined daily after implantation, and at 14, 30, 90, and 180 days after implantation were evaluated via computed tomography of the head, hematologic and blood biochemical profiling, and necropsy examinations. Clinical signs of illness and distant implant migration were not observed, and blood analyses were not different between control and FMD implanted groups at any time. Mild inflammatory and astrogliotic reactions localized to the treatment sites within the brain were observed in all groups, more robust in FMD implanted groups compared to controls at days 30 and 90, and decreased in severity over days 90-180 of the study. One rat developed a chronic, superficial surgical site pyogranuloma attributed to the FMD silica implant. Chronically implanted FMD fragments were well tolerated clinically and resulted in anticipated mild, localized brain tissue responses that were comparable with other implanted biomaterials in the brain.

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