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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A 3-D Finite-Element Minipig Model to Assess Brain Biomechanical Responses to Blast Exposure
Sundaramurthy, Aravind; Kote, Vivek Bhaskar; Pearson, Noah; Boiczyk, Gregory M.; McNeil, Elizabeth M.; Nelson, Allison J.; Subramaniam, Dhananjay Radhakrishnan; Rubio, Jose E.; Monson, Kenneth; Hardy, Warren N.; VandeVord, Pamela J.; Unnikrishnan, Ginu; Reifman, Jaques (Frontiers, 2021-12-17)
Despite years of research, it is still unknown whether the interaction of explosion-induced blast waves with the head causes injury to the human brain. One way to fill this gap is to use animal models to establish “scaling laws” that project observed brain injuries in animals to humans. This requires laboratory experiments and high-fidelity mathematical models of the animal head to establish correlates between experimentally observed blast-induced brain injuries and model-predicted biomechanical responses. To this end, we performed laboratory experiments on Göttingen minipigs to develop and validate a three-dimensional (3-D) high-fidelity finite-element (FE) model of the minipig head. First, we performed laboratory experiments on Göttingen minipigs to obtain the geometry of the cerebral vasculature network and to characterize brain-tissue and vasculature material properties in response to high strain rates typical of blast exposures. Next, we used the detailed cerebral vasculature information and species-specific brain tissue and vasculature material properties to develop the 3-D high-fidelity FE model of the minipig head. Then, to validate the model predictions, we performed laboratory shock-tube experiments, where we exposed Göttingen minipigs to a blast overpressure of 210 kPa in a laboratory shock tube and compared brain pressures at two locations. We observed a good agreement between the model-predicted pressures and the experimental measurements, with differences in maximum pressure of less than 6%. Finally, to evaluate the influence of the cerebral vascular network on the biomechanical predictions, we performed simulations where we compared results of FE models with and without the vasculature. As expected, incorporation of the vasculature decreased brain strain but did not affect the predictions of brain pressure. However, we observed that inclusion of the cerebral vasculature in the model changed the strain distribution by as much as 100% in regions near the interface between the vasculature and the brain tissue, suggesting that the vasculature does not merely decrease the strain but causes drastic redistributions. This work will help establish correlates between observed brain injuries and predicted biomechanical responses in minipigs and facilitate the creation of scaling laws to infer potential injuries in the human brain due to exposure to blast waves.
A 4-year longitudinal neuroimaging study of cognitive control using latent growth modeling: developmental changes and brain-behavior associations
Kim-Spoon, Jungmeen; Herd, Toria; Brieant, Alexis; Elder, Jacob; Lee, Jacob; Deater-Deckard, Kirby; Casas, Brooks (2021-08-15)
Despite theoretical models suggesting developmental changes in neural substrates of cognitive control in adolescence, empirical research has rarely examined intraindividual changes in cognitive control-related brain activation using multi-wave multivariate longitudinal data. We used longitudinal repeated measures of brain activation and behavioral performance during the multi-source interference task (MSIT) from 167 adolescents (53% male) who were assessed annually over four years from ages 13 to 17 years. We applied latent growth modeling to delineate the pattern of brain activation changes over time and to examine longitudinal associations between brain activation and behavioral performance. We identified brain regions that showed differential change patterns: (1) the fronto-parietal regions that involved bilateral insula, bilateral middle frontal gyrus, left pre-supplementary motor area, left inferior parietal lobule, and right precuneus; and (2) the rostral anterior cingulate cortex (rACC) region. Longitudinal confirmatory factor analyses of the fronto-parietal regions revealed strong measurement invariance across time implying that multivariate functional magnetic resonance imaging data during cognitive control can be measured reliably over time. Latent basis growth models indicated that fronto-parietal activation decreased over time, whereas rACC activation increased over time. In addition, behavioral performance data, age-related improvement was indicated by a decreasing trajectory of intraindividual variability in response time across four years. Testing longitudinal brain-behavior associations using multivariate growth models revealed that better behavioral cognitive control was associated with lower fronto-parietal activation, but the change in behavioral performance was not related to the change in brain activation. The current findings suggest that reduced effects of cognitive interference indicated by fronto-parietal recruitment may be a marker of a maturing brain that underlies better cognitive control performance during adolescence.
7.0-T Magnetic Resonance Imaging Characterization of Acute Blood-Brain-Barrier Disruption Achieved with Intracranial Irreversible Electroporation
Garcia, Paulo A.; Rossmeisl, John H. Jr.; Robertson, John L.; Olson, JohnD.; Johnson, Annette J.; Ellis, Thomas L.; Davalos, Rafael V. (PLOS, 2012-11-30)
The blood-brain-barrier (BBB) presents a significant obstacle to the delivery of systemically administered chemotherapeutics for the treatment of brain cancer. Irreversible electroporation (IRE) is an emerging technology that uses pulsed electric fields for the non-thermal ablation of tumors. We hypothesized that there is a minimal electric field at which BBB disruption occurs surrounding an IRE-induced zone of ablation and that this transient response can be measured using gadolinium (Gd) uptake as a surrogate marker for BBB disruption. The study was performed in a Good Laboratory Practices (GLP) compliant facility and had Institutional Animal Care and Use Committee (IACUC) approval. IRE ablations were performed in vivo in normal rat brain (n = 21) with 1-mm electrodes (0.45 mm diameter) separated by an edge-to-edge distance of 4 mm. We used an ECM830 pulse generator to deliver ninety 50-ms pulse treatments (0, 200, 400, 600, 800, and 1000 V/cm) at 1 Hz. The effects of applied electric fields and timing of Gd administration (25, +5, +15, and +30 min) was assessed by systematically characterizing IRE-induced regions of cell death and BBB disruption with 7.0-T magnetic resonance imaging (MRI) and histopathologic evaluations. Statistical analysis on the effect of applied electric field and Gd timing was conducted via Fit of Least Squares with a = 0.05 and linear regression analysis. The focal nature of IRE treatment was confirmed with 3D MRI reconstructions with linear correlations between volume of ablation and electric field. Our results also demonstrated that IRE is an ablation technique that kills brain tissue in a focal manner depicted by MRI (n = 16) and transiently disrupts the BBB adjacent to the ablated area in a voltage-dependent manner as seen with Evan’s Blue (n = 5) and Gd administration.
Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model
Mizuno, Grace O.; Wang, Yinxue; Shi, Guilai; Wang, Yizhi; Sun, Junqing; Papadopoulos, Stelios; Broussard, Gerard J.; Unger, Elizabeth K.; Deng, Wenbin; Weick, Jason; Bhattacharyya, Anita; Chen, Chao-Yin; Yu, Guoqiang; Looger, Loren L.; Tian, Lin (Elsevier, 2018-07-10)
Down syndrome (DS) is a genetic disorder that causes cognitive impairment. The staggering effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We examined the neuronastrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patientderived induced pluripotent stem cells (iPSCs). By combining calciumimaging with genetic approaches, we discovered the functional defects of DS astroglia and their effects on neuronal excitability. Compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. Furthermore, suppressed neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100B, a calcium binding protein coded on HSA21. Our results suggest a mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability.
Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome
Motahari, Zahra; Maynard, Thomas M.; Popratiloff, Anastas; Moody, Sally A.; LaMantia, Anthony-Samuel (2020-09-15)
We identified divergent modes of initial axon growth that prefigure disrupted differentiation of the trigeminal nerve (CN V), a cranial nerve essential for suckling, feeding and swallowing (S/F/S), a key innate behavior compromised in multiple genetic developmental disorders including DiGeorge/22q11.2 Deletion Syndrome (22q11.2 DS). We combined rapid in vivo labeling of single CN V axons in LgDel(+/-) mouse embryos, a genomically accurate 22q11.2DS model, and 3D imaging to identify and quantify phenotypes that could not be resolved using existing methods. We assessed these phenotypes in three 22q11.2-related genotypes to determine whether individual CN V motor and sensory axons wander, branch and sprout aberrantly in register with altered anterior-posterior hindbrain patterning and gross morphological disruption of CN V seen in LgDel(+/-). In the additional 22q11.2-related genotypes: Tbx1(+/-), Ranbp1(+/-), Ranbp1(+/-) and LgDel(+/-):Raldh2(+/-); axon phenotypes are seen when hindbrain patterning and CN V gross morphology is altered, but not when it is normal or restored toward WT. This disordered growth of CN V sensory and motor axons, whose appropriate targeting is critical for optimal S/F/S, may be an early, critical determinant of imprecise innervation leading to inefficient oropharyngeal function associated with 22q11.2 deletion from birth onward.
Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments
Greer, Kisha; Gudenschwager-Basso, Erwin K.; Kelly, Colin; Cash, Alison; Kowalski, Elizabeth A.; Cerna, Steven; Ocampo, Collin Tanchanco; Wang, Xia; Theus, Michelle H. (2020-09-21)
Brain injury resulting from repeated mild traumatic insult is associated with cognitive dysfunction and other chronic co-morbidities. The current study tested the effects of aberrant neurogenesis in a mouse model of repeated mild traumatic brain injury (rmTBI). Using Barnes Maze analysis, we found a significant reduction in spatial learning and memory at 24 days post-rmTBI compared to repeated sham (rSham) injury. Cell fate analysis showed a greater number of BrdU-labeled cells which co-expressed Prox-1 in the DG of rmTBI-injured mice which coincided with enhanced cFos expression for neuronal activity. We then selectively ablated dividing neural progenitor cells using a 7-day continuous infusion of Ara-C prior to rSham or rmTBI. This resulted in attenuation of cFos and BrdU-labeled cell changes and prevented associated learning and memory deficits. We further showed this phenotype was ameliorated in EphA4f.(/f)/Tie2-Cre knockout compared to EphA4f.(/f) wild type mice, which coincided with altered mRNA transcript levels of MCP-1, Cx43 and TGF beta. These findings demonstrate that cognitive decline is associated with an increased presence of immature neurons and gene expression changes in the DG following rmTBI. Our data also suggests that vascular EphA4-mediated neurogenic remodeling adversely affects learning and memory behavior in response to repeated insult.
Acetylcholine Receptor Activation as a Modulator of Glioblastoma Invasion
Thompson, Emily G.; Sontheimer, Harald (MDPI, 2019-10-05)
Grade IV astrocytomas, or glioblastomas (GBMs), are the most common malignant primary brain tumor in adults. The median GBM patient survival of 12–15 months has remained stagnant, in spite of treatment strategies, making GBMs a tremendous challenge clinically. This is at least in part due to the complex interaction of GBM cells with the brain microenvironment and their tendency to aggressively infiltrate normal brain tissue. GBMs frequently invade supratentorial brain regions that are richly innervated by neurotransmitter projections, most notably acetylcholine (ACh). Here, we asked whether ACh signaling influences the biology of GBMs. We examined the expression and function of known ACh receptors (AChRs) in large GBM datasets, as well as, human GBM cell lines and patient-derived xenograft lines. Using RNA-Seq data from the “The Cancer Genome Atlas” (TCGA), we confirmed the expression of AChRs and demonstrated the functionality of these receptors in GBM cells with time-lapse calcium imaging. AChR activation did not alter cell proliferation or migration, however, it significantly increased cell invasion through complex extracellular matrices. This was due to the enhanced activity of matrix metalloproteinase-9 (MMP-9) from GBM cells, which we found to be dependent on an intracellular calcium-dependent mechanism. Consistent with these findings, AChRs were significantly upregulated in regions of GBM infiltration in situ (Ivy Glioblastoma Atlas Project) and elevated expression of muscarinic AChR M₃ correlated with reduced patient survival (TCGA). Data from the Repository for Molecular Brain Neoplasia Data (REMBRANDT) dataset also showed the co-expression of choline transporters, choline acetyltransferase, and vesicular acetylcholine transporters, suggesting that GBMs express all the proteins required for ACh synthesis and release. These findings identify ACh as a modulator of GBM behavior and posit that GBMs may utilize ACh as an autocrine signaling molecule.
Acoustic differences between healthy and depressed people: a cross-situation study
Wang, Jingying; Zhang, Lei; Liu, Tianli; Pan, Wei; Hu, Bin; Zhu, Tingshao (2019-10-15)
Background Abnormalities in vocal expression during a depressed episode have frequently been reported in people with depression, but less is known about if these abnormalities only exist in special situations. In addition, the impacts of irrelevant demographic variables on voice were uncontrolled in previous studies. Therefore, this study compares the vocal differences between depressed and healthy people under various situations with irrelevant variables being regarded as covariates. Methods To examine whether the vocal abnormalities in people with depression only exist in special situations, this study compared the vocal differences between healthy people and patients with unipolar depression in 12 situations (speech scenarios). Positive, negative and neutral voice expressions between depressed and healthy people were compared in four tasks. Multiple analysis of covariance (MANCOVA) was used for evaluating the main effects of variable group (depressed vs. healthy) on acoustic features. The significances of acoustic features were evaluated by both statistical significance and magnitude of effect size. Results The results of multivariate analysis of covariance showed that significant differences between the two groups were observed in all 12 speech scenarios. Although significant acoustic features were not the same in different scenarios, we found that three acoustic features (loudness, MFCC5 and MFCC7) were consistently different between people with and without depression with large effect magnitude. Conclusions Vocal differences between depressed and healthy people exist in 12 scenarios. Acoustic features including loudness, MFCC5 and MFCC7 have potentials to be indicators for identifying depression via voice analysis. These findings support that depressed people’s voices include both situation-specific and cross-situational patterns of acoustic features.
Active inference and agency: optimal control without cost functions
Friston, Karl J.; Samothrakis, Spyridon; Montague, P. Read (Springer, 2012-08-03)
This paper describes a variational free-energy formulation of (partially observable) Markov decision problems in decision making under uncertainty. We show that optimal control can be cast as active inference. In active inference, both action and posterior beliefs about hidden states minimise a free energy bound on the negative log-likelihood of observed states, under a generative model. In this setting, reward or cost functions are absorbed into prior beliefs about state transitions and terminal states. Effectively, this converts optimal control into a pure inference problem, enabling the application of standard Bayesian filtering techniques.We then consider optimal trajectories that rest on posterior beliefs about hidden states in the future. Crucially, this entails modelling control as a hidden state that endows the generative model with a representation of agency. This leads to a distinction between models with and without inference on hidden control states; namely, agency-free and agency-based models, respectively.
Activity Dependent Protein Degradation Is Critical for the Formation and Stability of Fear Memory in the Amygdala
Jarome, Timothy J.; Werner, Craig T.; Kwapis, Janine L.; Helmstetter, Fred J. (PLOS, 2011-09)
Protein degradation through the ubiquitin-proteasome system [UPS] plays a critical role in some forms of synaptic plasticity. However, its role in memory formation in the amygdala, a site critical for the formation of fear memories, currently remains unknown. Here we provide the first evidence that protein degradation through the UPS is critically engaged at amygdala synapses during memory formation and retrieval. Fear conditioning results in NMDA-dependent increases in degradationspecific polyubiquitination in the amygdala, targeting proteins involved in translational control and synaptic structure and blocking the degradation of these proteins significantly impairs long-term memory. Furthermore, retrieval of fear memory results in a second wave of NMDA-dependent polyubiquitination that targets proteins involved in translational silencing and synaptic structure and is critical for memory updating following recall. These results indicate that UPS-mediated protein degradation is a major regulator of synaptic plasticity necessary for the formation and stability of long-term memories at amygdala synapses.
Adaptive Brain and Behavior Across the Lifespan
(Virginia Tech, 2016-05)
Our aim is to understand adaptation and improve human lives in various contexts. Inequalities and environments in which people live affect their health and behavior — and their success of remaining healthy for a lifetime. Virginia Tech has embraced the idea of understanding how the brain is linked to human experiences, constraints, and behavioral choices that not only affect neural wellbeing, but overall health. The effort is aided by new, sophisticated technologies (e.g., ones that map the brain in real time or allow clearer diagnosis of disease). Individuals must continue to function in the world in terms of addictions or life consequences from poor decision-making, developmental disabilities such as cerebral palsy, brain cancer, and other health challenges. Pursuit of innovative science to cure diseases is an important thrust of this Destination Area, in concert with evidence-based treatments and interdisciplinary training of individuals who work with people who are affected for the long-term by diseases and atypical disorders and conditions. Virginia Tech is mobilizing all emerging tools to improve people’s lives. Today, neuroscientists understand our brain in action, at the level of molecules, cells, circuits, systems, and behavior — but more remains to be understood. Likewise, brain diseases and traumatic brain injuries, which can result from diverse causes that range from drug addiction to physical impact, have been difficult for society to grasp. Our current knowledge and research in both the human and animal domain will provide substantial opportunities for “brain exploration” with an intention to solve human health issues and address societal issues and behaviors across the lifespan. A vital humanities and social science approach connected to neuroscience and medical approaches promises to move solutions to brain and behavior problems forward. We will also focus on social aspects of human development as people live longer, through the creation and application of new technologies.
Adolescent Emotionality and Emotion Regulation in the Context of Parent Emotion Socialization Among Adolescents with Neurodevelopmental Disorders: A Call to Action with Pilot Data
Breaux, Rosanna; Eadeh, Hana-May; Swanson, Courtney S.; McQuade, Julia D. (Springer, 2021-06-30)
To date, only three studies have examined the role of emotion socialization in the emotional functioning of youth with neurodevelopmental disorders. As such, this review article with pilot data sought to provide a call to action and first step in addressing this limited research body. Pilot data was collected with 18 adolescents (Mage = 13.5, SD = 1.6; 70% male) with a neurodevelopmental disorder and their primary caregiver. All adolescents were diagnosed with attention-deficit/hyperactivity disorder and displayed a range of comorbid disorders: autism spectrum disorder (27.8%), anxiety (66.7%), depression (44.4%), and disruptive behavior disorders (50%). Adolescents and caregivers completed a conflict discussion task while physiological, observational, and self-report measures of emotion socialization and emotional functioning were measured. Observed supportive parent emotion socialization behaviors were significantly associated with more observed adaptive emotion regulation strategies, and decreased observed and adolescent-reported negative affect, whereas non-supportive emotion socialization behaviors were associated with more observed negative affect and less observed adaptive emotion regulation strategies. Our pilot findings support growing research suggesting that adaptive parent emotion socialization practices can help foster less negative emotionality and better emotion regulation in youth with neurodevelopment disorders. We make a call to action for more emotion socialization research focused on youth with neurodevelopmental disorders, and propose four important directions for future research: 1) Research examining emotion socialization behaviors during daily life, 2) Understanding the nuanced role of emotion socialization practices, 3) Considering diversity in emotion socialization practices with clinical populations, and 4) Longitudinal and intervention research studies.
Age differences in functional network reconfiguration with working memory training
Iordan, Alexandru D.; Moored, Kyle D.; Katz, Benjamin; Cooke, Katherine A.; Buschkuehl, Martin; Jaeggi, Susanne M.; Polk, Thad A.; Peltier, Scott J.; Jonides, John; Reuter-Lorenz, Patricia A. (2021-04-15)
Demanding cognitive functions like working memory (WM) depend on functional brain networks being able to communicate efficiently while also maintaining some degree of modularity. Evidence suggests that aging can disrupt this balance between integration and modularity. In this study, we examined how cognitive training affects the integration and modularity of functional networks in older and younger adults. Twenty three younger and 23 older adults participated in 10 days of verbal WM training, leading to performance gains in both age groups. Older adults exhibited lower modularity overall and a greater decrement when switching from rest to task, compared to younger adults. Interestingly, younger but not older adults showed increased task-related modularity with training. Furthermore, whereas training increased efficiency within, and decreased participation of, the default-mode network for younger adults, it enhanced efficiency within a task-specific salience/sensorimotor network for older adults. Finally, training increased segregation of the default-mode from frontoparietal/salience and visual networks in younger adults, while it diffusely increased between-network connectivity in older adults. Thus, while younger adults increase network segregation with training, suggesting more automated processing, older adults persist in, and potentially amplify, a more integrated and costly global workspace, suggesting different age-related trajectories in functional network reorganization with WM training.
Age, but Not Sex, Modulates Foxp3 Expression in the Rat Brain across Development
Taylor, Makenzlie R.; Roby, Clinton R.; Elziny, Soad; Duricy, Erin; Taylor, Tina M.; Bowers, J. Michael (Elsevier, 2020)
The interconnectivity between brain development and the immune system has become an area of interest for many neuroscientists. However, to date, a limited number of known immune mediators of the peripheral nervous system (PNS) have been found to influence the development of the central nervous system (CNS). FOXP3 is a well-established mediator of regulatory T-cells in the PNS. However, the expression pattern of FOXP3 in the CNS and the PNS throughout development is unknown. To fill this void, we have characterized, in several brain regions, the developmental profile of Foxp3 for both sexes using rats. We found different patterns of Foxp3 in the CNS and PNS. In the CNS, we found Foxp3 was ubiquitously expressed, with the levels of Foxp3 varying by brain region. We also found both Foxp3 mRNA and protein levels peak during embryonic development and then steadily decrease with a peak increase during adulthood. In adulthood, the protein but not mRNA increases to the equivalent levels found at the embryonic stage of life. In the PNS, Foxp3 protein levels were low embryonically and increased steadily over the life of the animal with maximal levels reached in adulthood. Patterns observed for both the PNS and CNS were similar in males and females across all developmental timepoints. Our novel findings have implications for understanding how the neural immune system impacts neurodevelopmental disorders such as autism and schizophrenia.
Age-Related Intrinsic Functional Connectivity Changes of Locus Coeruleus from Childhood to Older Adults
Song, Inuk; Neal, Joshua; Lee, Tae-Ho (MDPI, 2021-11-10)
The locus coeruleus is critical for selective information processing by modulating the brain’s connectivity configuration. Increasingly, studies have suggested that LC controls sensory inputs at the sensory gating stage. Furthermore, accumulating evidence has shown that young children and older adults are more prone to distraction and filter out irrelevant information less efficiently, possibly due to the unoptimized LC connectivity. However, the LC connectivity pattern across the life span is not fully examined yet, hampering our ability to understand the relationship between LC development and the distractibility. In this study, we examined the intrinsic network connectivity of the LC using a public fMRI dataset with wide-range age samples. Based on LC-seed functional connectivity maps, we examined the age-related variation in the LC connectivity with a quadratic model. The analyses revealed two connectivity patterns explicitly. The sensory-related brain regions showed a positive quadratic age effect (u-shape), and the frontal regions for the cognitive control showed a negative quadratic age effect (inverted u-shape). Our results imply that such age-related distractibility is possibly due to the impaired sensory gating by the LC and the insufficient top-down controls by the frontal regions. We discuss the underlying neural mechanisms and limitations of our study.
Aging and network properties: Stability over time and links with learning during working memory training
Iordan, Alexandru D.; Cooke, Katherine A.; Moored, Kyle D.; Katz, Benjamin; Buschkuehl, Martin; Jaeggi, Susanne M.; Jonides, John; Peltier, Scott J.; Polk, Thad A.; Reuter-Lorenz, Patricia A. (Frontiers Media S.A., 2018-01-04)
Growing evidence suggests that healthy aging affects the configuration of large-scale functional brain networks. This includes reducing network modularity and local efficiency. However, the stability of these effects over time and their potential role in learning remain poorly understood. The goal of the present study was to further clarify previously reported age effects on “resting-state” networks, to test their reliability over time, and to assess their relation to subsequent learning during training. Resting-state fMRI data from 23 young (YA) and 20 older adults (OA) were acquired in 2 sessions 2 weeks apart. Graph-theoretic analyses identified both consistencies in network structure and differences in module composition between YA and OA, suggesting topological changes and less stability of functional network configuration with aging. Brain-wide, OA showed lower modularity and local efficiency compared to YA, consistent with the idea of age-related functional dedifferentiation, and these effects were replicable over time. At the level of individual networks, OA consistently showed greater participation and lower local efficiency and within-network connectivity in the cingulo-opercular network, as well as lower intra-network connectivity in the default-mode network and greater participation of the somato-sensorimotor network, suggesting age-related differential effects at the level of specialized brain modules. Finally, brain-wide network properties showed associations, albeit limited, with learning rates, as assessed with 10 days of computerized working memory training administered after the resting-state sessions, suggesting that baseline network configuration may influence subsequent learning outcomes. Identification of neural mechanisms associated with learning-induced plasticity is important for further clarifying whether and how such changes predict the magnitude and maintenance of training gains, as well as the extent and limits of cognitive transfer in both younger and older adults.
Aging into Perceptual Control: A Dynamic Causal Modeling for fMRI Study of Bistable Perception
Dowlati, Ehsan; Adams, Sarah E.; Stiles, Alexandra; Moran, Rosalyn J. (Frontiers, 2016-03-31)
Aging is accompanied by stereotyped changes in functional brain activations, for example a cortical shift in activity patterns from posterior to anterior regions is one hallmark revealed by functional magnetic resonance imaging (fMRI) of aging cognition. Whether these neuronal effects of aging could potentially contribute to an amelioration of or resistance to the cognitive symptoms associated with psychopathology remains to be explored. We used a visual illusion paradigm to address whether aging affects the cortical control of perceptual beliefs and biases. Our aim was to understand the effective connectivity associated with volitional control of ambiguous visual stimuli and to test whether greater top-down control of early visual networks emerged with advancing age. Using a bias training paradigm for ambiguous images we found that older participants (n = 16) resisted experimenter-induced visual bias compared to a younger cohort (n = 14) and that this resistance was associated with greater activity in prefrontal and temporal cortices. By applying Dynamic Causal Models for fMRI we uncovered a selective recruitment of top-down connections from the middle temporal to Lingual gyrus (LIN) by the older cohort during the perceptual switch decision following bias training. In contrast, our younger cohort did not exhibit any consistent connectivity effects but instead showed a loss of driving inputs to orbitofrontal sources following training. These findings suggest that perceptual beliefs are more readily controlled by top-down strategies in older adults and introduce age-dependent neural mechanisms that may be important for understanding aberrant belief states associated with psychopathology.
Aging, resistance training, and diabetes prevention
Flack, Kyle D.; Davy, Kevin P.; Hulver, Matthew W.; Winett, Richard A.; Frisard, Madlyn I.; Davy, Brenda M. (2010-12-15)
With the aging of the baby-boom generation and increases in life expectancy, the American population is growing older. Aging is associated with adverse changes in glucose tolerance and increased risk of diabetes; the increasing prevalence of diabetes among older adults suggests a clear need for effective diabetes prevention approaches for this population. The purpose of paper is to review what is known about changes in glucose tolerance with advancing age and the potential utility of resistance training (RT) as an intervention to prevent diabetes among middle-aged and older adults. Age-related factors contributing to glucose intolerance, which may be improved with RT, include improvements in insulin signaling defects, reductions in tumor necrosis factor-α, increases in adiponectin and insulin-like growth factor-1 concentrations, and reductions in total and abdominal visceral fat. Current RT recommendations and future areas for investigation are presented.
Agrin and Synaptic Laminin Are Required to Maintain Adult Neuromuscular Junctions
Samuel, Melanie; Valdez, Gregorio; Tapia, Juan C.; Lichtman, Jeff W.; Sanes, Joshua R. (PLOS, 2012-10-03)
As synapses form and mature the synaptic partners produce organizing molecules that regulate each other’s differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ), these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-a4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.
Alexithymia as a Transdiagnostic Precursor to Empathy Abnormalities: The Functional Role of the Insula
Valdespino, Andrew; Antezana, Ligia; Ghane, Merage; Richey, John A. (Frontiers, 2017-12-21)
Distorted empathic processing has been observed across multiple psychiatric disorders. Simulation theory provides a theoretical framework that proposes a mechanism through which empathy difficulties may arise. Specifically, introspection-centric simulation theory (IST) predicts that an inability to accurately interpret and describe internal affective states may lead to empathy difficulties. The purpose of this review is to synthesize and summarize an empirical literature suggesting that simulation theory provides insights into a cognitive and neurobiological mechanism (i.e., alexithymia and insula pathology) that negatively impacts empathic processing, in addition to how disruptions in these processes manifest across psychiatric disorders. Specifically, we review an emerging non-clinical literature suggesting that consistent with IST, alexithymia and associated insula pathology leads to empathy deficits. Subsequently, we highlight clinical research suggesting that a large number of disorders characterized by empathy pathology also feature alexithymia. Collectively, these findings motivate the importance for future work to establish the role of alexithymia in contributing to empathy deficits across clinical symptoms and disorders. The current review suggests that simulation theory provides a tractable conceptual platform for identifying a potential common cognitive and neural marker that is associated with empathy deficits across a wide array of diagnostic classes.

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