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1.  The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy 
Cancers  2014;6(4):1953-1985.
The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.
PMCID: PMC4276952  PMID: 25268164
glioblastoma; temozolomide; vaccine; immunotherapy
2.  Assessing Recollection and Familiarity of Similar Lures in a Behavioral Pattern Separation Task 
Hippocampus  2013;23(4):287-294.
The relationship between recollection-mediated recognition memory and behavioral pattern separation is poorly understood. In two separate experiments, we modified a well-validated object discrimination task with previously demonstrated sensitivity to neural pattern separation with instructions to assess recollection and familiarity. In the first experiment, we included a Remember/Know (R/K) judgment, and in the second we included a source memory judgment. We found that both “Remember” and correct source judgments were higher for lures labeled “similar” (where pattern separation is engaged) but also higher on lures called “old” (where pattern separation is absent), suggesting that false alarms in pattern separation tasks are frequently mediated by recollection. As one might expect, “Remember” judgments and correct source decisions increased with greater dissimilarity for “similar” responses and increased with greater similarity for “old” responses. This suggests that recollection can occur in the presence and in the absence of pattern separation and that false alarms to similar lures are not simply driven by familiarity.
PMCID: PMC4172605  PMID: 23401187
recollection; familiarity; pattern separation; pattern completion; recognition memory
3.  Regulation of KLF4 turnover reveals an unexpected tissue specific role of pVHL in tumorigenesis 
Molecular cell  2012;45(2):233-243.
The transcription factor Krüppel-like factor 4 (KLF4) is an important regulator of cell fate decision, including cell cycle regulation, apoptosis, and stem cell renewal, and plays an ambivalent role in tumorigenesis as a tissue specific tumor suppressor or oncogene. Here we report that the Von Hippel-Lindau gene product, pVHL, physically interacts with KLF4 and regulates its rapid turnover observed in both differentiated and stem cells. We provide mechanistic insights into KLF4 degradation and show that pVHL depletion in colorectal cancer cells leads to cell cycle arrest concomitant with increased transcription of the KLF4-dependent p21 gene. Finally, immunohistochemical staining revealed elevated pVHL and reduced KLF4 levels in colon cancer tissues. We therefore propose that unexpectedly pVHL, via the degradation of KLF4, is a facilitating factor in colorectal tumorigenesis.
PMCID: PMC3982234  PMID: 22284679
4.  A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children 
Brain research  2010;1358:172-183.
Because children are becoming overweight, unhealthy, and unfit, understanding the neurocognitive benefits of an active lifestyle in childhood has important public health and educational implications. Animal research has indicated that aerobic exercise is related to increased cell proliferation and survival in the hippocampus as well as enhanced hippocampal-dependent learning and memory. Recent evidence extends this relationship to elderly humans by suggesting that high aerobic fitness levels in older adults are associated with increased hippocampal volume and superior memory performance. The present study aimed to further extend the link between fitness, hippocampal volume, and memory to a sample of preadolescent children. To this end, magnetic resonance imaging was employed to investigate whether higher- and lower-fit 9- and 10-year-old children showed differences in hippocampal volume and if the differences were related to performance on an item and relational memory task. Relational but not item memory is primarily supported by the hippocampus. Consistent with predictions, higher-fit children showed greater bilateral hippocampal volumes and superior relational memory task performance compared to lower-fit children. Hippocampal volume was also positively associated with performance on the relational but not the item memory task. Furthermore, bilateral hippocampal volume was found to mediate the relationship between fitness level (VO2 max) and relational memory. No relationship between aerobic fitness, nucleus accumbens volume, and memory was reported, which strengthens the hypothesized specific effect of fitness on the hippocampus. The findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.
PMCID: PMC3953557  PMID: 20735996
Brain; Children; Exercise; Hippocampus; MRI; Physical activity
5.  STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications 
Cancers  2014;6(1):376-395.
Signal transducer and activator of transcription 3 (STAT3) is a potent regulator of gliomagenesis through its induction of angiogenesis, host immunosuppression, and tumor invasion. Gain of function mutations result in constitutive activation of STAT3 in glioma cells, making STAT3 an attractive target for inhibition in cancer therapy. Nevertheless, some studies show that STAT3 also participates in terminal differentiation and apoptosis of various cell lines and in glioma with phosphatase and tensin homolog (PTEN)-deficient genetic backgrounds. In light of these findings, the utility of STAT3 as a prognostic indicator and as a target of drug therapies will be contingent on a more nuanced understanding of its pro- and anti-tumorigenic effects.
PMCID: PMC3980601  PMID: 24518612
glioblastoma; STAT3; immunotherapy
6.  Neurobiological markers of exercise-related brain plasticity in older adults 
The current study examined how a randomized one-year aerobic exercise program for healthy older adults would affect serum levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor type 1 (IGF-1), and vascular endothelial growth factor (VEGF) - putative markers of exercise-induced benefits on brain function. The study also examined whether (a) change in the concentration of these growth factors was associated with alterations in functional connectivity following exercise, and (b) the extent to which pre-intervention growth factor levels were associated with training-related changes in functional connectivity. In 65 participants (mean age = 66.4), we found that although there were no group-level changes in growth factors as a function of the intervention, increased temporal lobe connectivity between the bilateral parahippocampus and the bilateral middle temporal gyrus was associated with increased BDNF, IGF-1, and VEGF for an aerobic walking group but not for a non-aerobic control group, and greater pre-intervention VEGF was associated with greater training-related increases in this functional connection. Results are consistent with animal models of exercise and the brain, but are the first to show in humans that exercise-induced increases in temporal lobe functional connectivity are associated with changes in growth factors and may be augmented by greater baseline VEGF.
PMCID: PMC3544982  PMID: 23123199
exercise; aging; functional connectivity; fMRI; default mode network; aerobic fitness; growth factors
7.  Immediate and follow-up results for 44 consecutive cases of small (<10 mm) internal carotid artery aneurysms treated with the pipeline embolization device 
The pipeline embolization device (PED) provides effective, durable and safe endovascular reconstruction of large and giant intracranial aneurysms. However, 80% of all cerebral aneurysms found in the general population are less than 10 mm in size. Treatment of small aneurysms (<10 mm) with flow diverters may be advantageous over endosaccular modalities that carry risks of procedural rupture during aneurysm access or coil placement.
We retrospectively reviewed a prospective, single-center aneurysm database to identify all patients with small (<10 mm) internal carotid artery (ICA) aneurysms who underwent endovascular treatment using the PED. Patient demographics, aneurysm characteristics, procedural details, complications, and technical and clinical outcomes were analyzed.
Forty-four cases were performed in 41 patients (age range 31-78 years). PED was successfully implanted in 42 cases. A single PED was used in 37/42 (88%) cases. Mean postprocedure hospital stay was 1.7 ± 0.3 days and 98% of patients were discharged home. Major complication occurred in one patient (2.3%), who died of early subarachnoid hemorrhage. Transient neurological deficit, delayed intracerebral hemorrhage (asymptomatic), and delayed groin infection occurred in one patient each. Follow-up rate was 91.8% (45 aneurysms in 35 patients) with a mean follow-up of 4.0 ± 1.9 months. By 6 months post-PED implantation, angiographic success (complete or near complete aneurysm occlusion) was observed in 80%. Mild (<50%), asymptomatic, nonflow limiting in-stent stenosis was observed in 5.4% (2/37 cases). All the 35 patients with follow-up remained at preprocedure neurological baseline.
Small (<10 mm) ICA aneurysm treatment with PED implantation is safe and carries a high rate of early angiographic success.
PMCID: PMC3779399  PMID: 24083050
Cerebral aneurysms; flow diverter; pipeline embolization device
8.  Functional connectivity: a source of variance in the association between cardiorespiratory fitness and cognition? 
Neuropsychologia  2010;48(5):1394-1406.
Over the next twenty years the number of Americans diagnosed with dementia is expected to more than double (CDC 2007). It is, therefore, an important public health initiative to understand what factors contribute to the longevity of a healthy mind. Both default mode network (DMN) function and increased aerobic fitness have been associated with better cognitive performance and reduced incidence of Alzheimer’s disease among older adults. Here we examine the association between aerobic fitness, functional connectivity in the DMN, and cognitive performance. Results showed significant age-related deficits in functional connectivity in both local and distributed DMN pathways. However, in a group of healthy elderly adults, almost half of the age-related disconnections showed increased functional connectivity as a function of aerobic fitness level. Finally, we examine the hypothesis that functional connectivity in the DMN is one source of variance in the relationship between aerobic fitness and cognition. Results demonstrate instances of both specific and global DMN connectivity mediating the relationship between fitness and cognition. We provide the first evidence for functional connectivity as a source of variance in the association between aerobic fitness and cognition, and discuss results in the context of neurobiological theories of cognitive aging and disease.
PMCID: PMC3708614  PMID: 20079755
cognitive aging; fMRI; functional connectivity; aerobic exercise; executive function; spatial memory
9.  Draft Genome Sequence of the Xylan-Degrading Marine Bacterium Strain S124, Representing a Novel Species of the Genus Oceanicola 
Journal of Bacteriology  2012;194(22):6325.
We isolated a xylan-degrading bacterium from seawater of Micronesia and identified it as Oceanicola sp. strain S124. We sequenced the Oceanicola sp. S124 genome using GSFLX 454 pyrosequencing and predicted 4,433 open reading frames (ORFs) including putative saccharification and phage-related genes.
PMCID: PMC3486357  PMID: 23105065
10.  CASE REPORT Spontaneous Forearm Compartment Syndrome in a Boy With Hemophilia A: A Therapeutic Dilemma 
Eplasty  2013;13:e16.
Objective: We present the case of a 14-year-old Factor VIII-deficient patient with no history of trauma, who developed acute spontaneous compartment syndrome of the volar forearm. We also suggest a treatment strategy. Methods: Fasciotomy with hematoma evacuation and ipsilateral carpal tunnel release was performed, and the wound was closed with vascular loops in “Jacob's ladder” fashion. Factor infusions were continued overnight. Results: The volar forearm compartment was successfully decompressed, and the patient's coagulopathy was managed with appropriate clotting factors. Conclusions: Hemophilic patients warrant special consideration and multispecialty care; with replenished coagulation factors and timely surgical decompression, they can expect satisfactory recovery of muscular and neurological function.
PMCID: PMC3601454  PMID: 23573336
11.  TcyR regulates L-cystine uptake via the TcyABC transporter in Streptococcus mutans 
Fems Microbiology Letters  2012;328(2):114-121.
Streptococcus mutans, a primary dental pathogen, has a remarkable capacity to scavenge nutrients from the oral biofilm for its survival. Cystine is an amino acid dimer formed by the oxidation of two cysteine residues that is required for optimal growth, whereas S. mutans modulates l-cystine uptake via two recently identified transporters designated TcyABC and TcyDEFGH, which have not been fully characterized. Using a non-polar tcyABC-deficient mutant (SmTcyABC), here we report that L-cystine uptake is drastically diminished in the mutant, whereas its ability to grow is severely impaired under l-cystine starvation conditions, relative to wild type. A substrate competition assay showed that l-cystine uptake by the TcyABC transporter was strongly inhibited by dl-cystathionine and l-djenkolic acid and moderately inhibited by S-methyl-l-cysteine and l-cysteine. Using gene expression analysis, we observed that the tcyABC operon was up-regulated under cystine starvation. TcyABC has been shown to be positively regulated by the LysR-type transcriptional regulator CysR. We identified another LysR-type transcriptional regulator that negatively regulates TcyABC with homology to the B. subtilis YtlI regulator, which we termed TcyR. Our study enhances the understanding of l-cystine uptake in S. mutans which allows survival and persistence of this pathogen in the oral biofilm.
PMCID: PMC3288405  PMID: 22212096
Cystine; cysteine; transport; TcyABC; Streptococcus mutans
12.  Mandible Reconstruction 
Eplasty  2013;13:ic19.
PMCID: PMC3558846  PMID: 23409210
13.  Breast Reconstruction 
Eplasty  2013;13:ic22.
PMCID: PMC3558845  PMID: 23409213
14.  Aerobic fitness is associated with greater efficiency of the network underlying cognitive control in preadolescent children 
Neuroscience  2011;199:166-176.
This study examined whether individual differences in aerobic fitness are associated with differences in activation of cognitive control brain networks in preadolescent children. As expected, children performed worse on a measure of cognitive control compared to a group of young adults. However, individual differences in aerobic fitness were associated with cognitive control performance among children. Lower-fit children had disproportionate performance cost in accuracy with increasing task difficulty, relative to higher-fit children. Brain activation was compared between performance-matched groups of lower- and higher-fit children. Fitness groups differed in brain activity for regions associated with response execution and inhibition, task set maintenance, and top-down regulation. Overall, differing activation patterns coupled with different patterns of brain-behavior correlations suggest an important role of aerobic fitness in modulating task strategy and the efficiency of neural networks that implement cognitive control in preadolescent children.
PMCID: PMC3237764  PMID: 22027235
exercise; physical activity; aerobic fitness; executive control; fMRI; development
15.  Dietary baked-milk accelerates resolution of cow's milk allergy in children 
The majority (∼75%) of cow's milk-allergic children tolerate extensively heated-(baked-) milk products. Long-term effects of inclusion of dietary baked-milk have not been reported.
We report on the outcomes of children who incorporated baked-milk products into their diets.
Children evaluated for tolerance to baked-milk (muffin) underwent sequential food challenges to baked-cheese (pizza) followed by unheated-milk. Immunologic parameters were measured at challenge visits. The comparison group were matched to active subjects (using age, sex, and baseline milk-specific IgE) to evaluate the natural history of tolerance development.
Over a median of 37 months (range 8-75 months), 88 children underwent challenges at varying intervals (range 6-54 months). Among 65 subjects initially tolerant to baked-milk, 39 (60%) now tolerate unheated-milk, 18 (28%) tolerate baked-milk/baked-cheese and 8 (12%) chose to avoid milk strictly. Among the baked-milk-reactive subgroup (n=23), 2 (9%) tolerate unheated-milk, 3 (13%) tolerate baked-milk/baked-cheese, while the majority (78%) avoid milk strictly. Subjects who were initially tolerant to baked-milk were 28 times more likely to become unheated-milk-tolerant compared to baked-milk-reactive subjects (P<.001). Subjects who incorporated dietary baked-milk were 16 times more likely than the comparison group to become unheated-milk-tolerant (P<.001). Median casein IgG4 levels in the baked-milk-tolerant group increased significantly (P<.001); median milk IgE values did not change significantly.
Tolerance of baked-milk is a marker of transient IgE-mediated cow's milk allergy whereas reactivity to baked-milk portends a more persistent phenotype. The addition of baked-milk to the diet of children tolerating such foods appears to accelerate development of unheated-milk tolerance compared to strict avoidance.
Clinical implications
Addition of dietary baked-milk is safe, convenient, and well-accepted by patients. Prescribing baked-milk products to milk-allergic children represents an important shift in the treatment paradigm for milk allergy.
Capsule summary
The majority of cow's milk-allergic children tolerate extensively baked-milk products, which is a marker of transient IgE-mediated cow's milk allergy. Dietary baked-milk appears to accelerate development of unheated-milk tolerance compared to strict avoidance.
PMCID: PMC3151608  PMID: 21601913
cow's milk allergy; milk allergy; tolerance; extensively heated; baked; immunotherapy; immunomodulation
16.  Association between Short Sleep Duration and the Risk of Sensitization to Food and Aero Allergens in Rural Chinese Adolescents 
Both long and short sleep duration have been associated with obesity, cardiovascular disease, and diabetes. However, there have been no previous studies investigating the potential relationship between altered sleep duration and allergen sensitization.
To explore the association between sleep duration and sensitization to food and aeroallergens.
This study includes 1534 rural Chinese adolescent twins aged 12 to 21 years who completed standard sleep questionnaires and skin prick tests (SPTs) to 9 food and 5 aeroallergens. Total sleep time was defined as the interval from bedtime to wake-up time minus sleep latency. Sensitization was defined as having at least one positive SPT.
Compared to individuals with the highest (3rd) tertile of sleep duration, those who slept less were more likely to be sensitized to any food allergen with odds ratios (ORs) of 1.9 (95% confidence interval(CI):1.3–2.7) and 1.4 (95%CI:1.0–1.9) for the 1st and 2nd tertiles (trend test Ptrend=3×10−4), respectively. The corresponding ORs for sensitization to any aeroallergen were 1.5 (95%CI: 1.1–2.0) and 1.3 (95%CI:1.0–1.7) (Ptrend=8×10−3). These associations were independent of percent body fat. In addition, we observed a significant dose-response association between the number of positive SPTs and percentage of shortest sleep duration (1st tertile) (Ptrend=1×10−3).
Conclusions and Clinical Relevance
In this sample of relatively lean rural Chinese adolescents, we found that short sleep duration was associated with increased risk of sensitization to food and aeroallergens, independent of percent body fat. Longitudinal studies are needed to further determine the temporal and causal relationships. If short sleep duration indeed is one of the risk factors for allergic sensitization, the global burden of allergic diseases could be dramatically reduced by providing appropriate guidance on sleep duration for youth.
PMCID: PMC3056931  PMID: 21255141
sleep duration; skin prick test; allergen; sensitization; adolescent
17.  High temperatures alter physiological properties of pyramidal cells and inhibitory interneurons in hippocampus 
Temperature has multiple effects on neurons, yet little is known about the effects of high temperature on the physiology of mammalian central neurons. Hyperthermia can influence behavior and cause febrile seizures. We studied the effects of acute hyperthermia on the immature hippocampus in vitro by recording from pyramidal neurons and inhibitory oriens-lacunosum moleculare (O-LM) interneurons (identified by green fluorescent protein (GFP) expression in the GIN mouse line). Warming to 41°C caused depolarization, spontaneous action potentials, reduced input resistance and membrane time constant, and increased spontaneous synaptic activity of most pyramidal cells and O-LM interneurons. Pyramidal neurons of area CA3 were more strongly excited by hyperthermia than those of area CA1. About 90% of O-LM interneurons in both CA1 and CA3 increased their firing rates at hyperthermic temperatures; interneurons in CA3 fired faster than those in CA1 on average. Blockade of fast synaptic transmission did not abolish the effect of hyperthermia on neuronal excitability. Our results suggest that hyperthermia increases hippocampal excitability, particularly in seizure-prone area CA3, by altering the intrinsic membrane properties of pyramidal cells and interneurons.
PMCID: PMC3390787  PMID: 22783167
febrile seizures; hippocampal neurons; hyperthermia; inhibition
18.  Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone Acetate Demonstrating Clinical Activity in Patients With Castration-Resistant Prostate Cancer Who Received Prior Ketoconazole Therapy 
Journal of Clinical Oncology  2010;28(9):1481-1488.
Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy.
Patients and Methods
Thirty-three men with chemotherapy-naïve progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing.
Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed ≥ 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses.
Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted.
PMCID: PMC2849769  PMID: 20159824
19.  Age-related differences in the involvement of the prefrontal cortex in attentional control 
Brain and cognition  2009;71(3):328-335.
We investigated the relative involvement of cortical regions supporting attentional control in older and younger adults during performance on a modified version of the Stroop task. Participants were exposed to two different types of incongruent trials. One of these, an incongruent-ineligible condition, produces conflict at the non-response level, while the second, an incongruent-eligible condition, produces conflict at both non-response and response levels of information processing. Greater attentional control is needed to perform the incongruent-eligible condition compared to other conditions. We examined the cortical recruitment associated with this task in an event-related functional magnetic resonance imaging paradigm in twenty-five older and twenty-five younger adults. Our results indicated that while younger adults demonstrated an increase in the activation of cortical regions responsible for maintaining attentional control in response to increased levels of conflict, such sensitivity and flexibility of the cortical regions to increased attentional control demands was absent in older adults. These results suggest a limitation in older adults’ capabilities for flexibly recruiting the attentional network in response to increasing attentional demands.
PMCID: PMC2783271  PMID: 19699019
attentional control; aging; fMRI; flexibility; Stroop task; interference; inhibition
20.  Early Life Eczema, Food Introduction, and Risk of Food Allergy in Children 
The effect of food introduction timing on the development of food allergy remains controversial. We sought to examine whether the presence of childhood eczema changes the relationship between timing of food introduction and food allergy. The analysis includes 960 children recruited as part of a family-based food allergy cohort. Food allergy was determined by objective symptoms developing within 2 hours of ingestion, corroborated by skin prick testing/specific IgE. Physician diagnosis of eczema and timing of formula and solid food introduction were obtained by standardized interview. Cox Regression analysis provided hazard ratios for the development of food allergy for the same subgroups. Logistic regression models estimated the association of eczema and formula/food introduction with the risk of food allergy, individually and jointly. Of the 960 children, 411 (42.8%) were allergic to 1 or more foods and 391 (40.7%) had eczema. Children with eczema had a 8.4-fold higher risk of food allergy (OR, 95% CI: 8.4, 5.9–12.1). Among all children, later (>6 months) formula and rice/wheat cereal introduction lowered the risk of food allergy. In joint analysis, children without eczema who had later formula (OR, 95% CI: 0.5, 0.3–0.9) and later (>1 year) solid food (OR, 95% CI: 0.5, 0.3–0.95) introduction had a lower risk of food allergy. Among children with eczema, timing of food or formula introduction did not modify the risk of developing food allergy. Later food introduction was protective for food allergy in children without eczema but did not alter the risk of developing food allergy in children with eczema.
PMCID: PMC3281290  PMID: 22375277
21.  Integrated device for optical stimulation and spatiotemporal electrical recording of neural activity in light-sensitized brain tissue 
Journal of neural engineering  2009;6(5):055007.
Neural stimulation with high spatial and temporal precision is desirable both for studying the real-time dynamics of neural networks and for prospective clinical treatment of neurological diseases. Optical stimulation of genetically targeted neurons expressing the light sensitive channel protein Channelrhodopsin (ChR2) has recently been reported as a means for millisecond temporal control of neuronal spiking activities with cell-type selectivity. This offers the prospect of enabling local delivery of optical stimulation and the simultaneous monitoring of the neural activity by electrophysiological means, both in the vicinity of and distant to the stimulation site. We report here a novel dual-modality hybrid device, which consists of a tapered coaxial optical waveguide (‘optrode’) integrated into a 100 element intra-cortical multi-electrode recording array. We first demonstrate the dual optical delivery and electrical recording capability of the single optrode in in vitro preparations of mouse retina, photo-stimulating the native retinal photoreceptors while recording light-responsive activities from ganglion cells. The dual-modality array device was then used in ChR2 transfected mouse brain slices. Specifically, epileptiform events were reliably optically triggered by the optrode and their spatiotemporal patterns were simultaneously recorded by the multi-electrode array.
PMCID: PMC2921864  PMID: 19721185
22.  Top-down attentional control in spatially coincident stimuli enhances activity in both task-relevant and task-irrelevant regions of cortex 
Behavioural brain research  2008;197(1):186-197.
Models of selective attention predict that focused attention to spatially contiguous stimuli may result in enhanced activity in areas of cortex specialized for processing task-relevant and task-irrelevant information. We examined this hypothesis by localizing color-sensitive areas (CSA) and word and letter sensitive areas of cortex and then examining modulation of these regions during performance of a modified version of the Stroop task in which target and distractors are spatially coincident. We report that only the incongruent condition with the highest cognitive demand showed increased activity in CSA relative to other conditions, indicating an attentional enhancement in target processing areas. We also found an enhancement of activity in one region sensitive to word/letter processing during the most cognitively demanding incongruent condition indicating greater processing of the distractor dimension. Correlations with performance revealed that top-down modulation during the task was critical for effective filtering of irrelevant information in conflict conditions. These results support predictions made by models of selective attention and suggest an important mechanism of top-down attentional control in spatially contiguous stimuli.
PMCID: PMC2845993  PMID: 18804123
Attentional control; Top-down modulation; Stroop task; Color-sensitive; Visual word form area
23.  Plasticity of Brain Networks in a Randomized Intervention Trial of Exercise Training in Older Adults 
Research has shown the human brain is organized into separable functional networks during rest and varied states of cognition, and that aging is associated with specific network dysfunctions. The present study used functional magnetic resonance imaging (fMRI) to examine low-frequency (0.008 < f < 0.08 Hz) coherence of cognitively relevant and sensory brain networks in older adults who participated in a 1-year intervention trial, comparing the effects of aerobic and non-aerobic fitness training on brain function and cognition. Results showed that aerobic training improved the aging brain's resting functional efficiency in higher-level cognitive networks. One year of walking increased functional connectivity between aspects of the frontal, posterior, and temporal cortices within the Default Mode Network and a Frontal Executive Network, two brain networks central to brain dysfunction in aging. Length of training was also an important factor. Effects in favor of the walking group were observed only after 12 months of training, compared to non-significant trends after 6 months. A non-aerobic stretching and toning group also showed increased functional connectivity in the DMN after 6 months and in a Frontal Parietal Network after 12 months, possibly reflecting experience-dependent plasticity. Finally, we found that changes in functional connectivity were behaviorally relevant. Increased functional connectivity was associated with greater improvement in executive function. Therefore the study provides the first evidence for exercise-induced functional plasticity in large-scale brain systems in the aging brain, using functional connectivity techniques, and offers new insight into the role of aerobic fitness in attenuating age-related brain dysfunction.
PMCID: PMC2947936  PMID: 20890449
exercise; aging; functional connectivity; fMRI; default mode network; executive function; aerobic fitness
24.  Cardiorespiratory Fitness and Attentional Control in the Aging Brain 
A growing body of literature provides evidence for the prophylactic influence of cardiorespiratory fitness on cognitive decline in older adults. This study examined the association between cardiorespiratory fitness and recruitment of the neural circuits involved in an attentional control task in a group of healthy older adults. Employing a version of the Stroop task, we examined whether higher levels of cardiorespiratory fitness were associated with an increase in activation in cortical regions responsible for imposing attentional control along with an up-regulation of activity in sensory brain regions that process task-relevant representations. Higher fitness levels were associated with better behavioral performance and an increase in the recruitment of prefrontal and parietal cortices in the most challenging condition, thus providing evidence that cardiorespiratory fitness is associated with an increase in the recruitment of the anterior processing regions. There was a top-down modulation of extrastriate visual areas that process both task-relevant and task-irrelevant attributes relative to the baseline. However, fitness was not associated with differential activation in the posterior processing regions, suggesting that fitness enhances attentional function by primarily influencing the neural circuitry of anterior cortical regions. This study provides novel evidence of a differential association of fitness with anterior and posterior brain regions, shedding further light onto the neural changes accompanying cardiorespiratory fitness.
PMCID: PMC3024830  PMID: 21267428
cardiorespiratory fitness; Stroop task; cognitive and attentional control

Résultats 1-25 (37)