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1.  Elevated prefrontal myo-inositol and choline following breast cancer chemotherapy 
Brain imaging and behavior  2013;7(4):10.1007/s11682-013-9228-1.
Breast cancer survivors are at increased risk for cognitive dysfunction, which reduces quality of life. Neuroimaging studies provide critical insights regarding the mechanisms underlying these cognitive deficits as well as potential biologic targets for interventions. We measured several metabolite concentrations using 1H magnetic resonance spectroscopy as well as cognitive performance in 19 female breast cancer survivors and 17 age-matched female controls. Women with breast cancer were all treated with chemotherapy. Results indicated significantly increased choline (Cho) and myo-inositol (mI) with correspondingly decreased N-acetylaspartate (NAA)/Cho and NAA/mI ratios in the breast cancer group compared to controls. The breast cancer group reported reduced executive function and memory, and subjective memory ability was correlated with mI and Cho levels in both groups. These findings provide preliminary evidence of an altered metabolic profile that increases our understanding of neurobiologic status post-breast cancer and chemotherapy.
PMCID: PMC3731420  PMID: 23536015
MR Spectroscopy; Breast Cancer; Cognition; Prefrontal Cortex; Chemotherapy
2.  Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors 
Brain, behavior, and immunity  2012;30(0):S109-S116.
Many survivors of breast cancer show significant cognitive impairments, including memory deficits. Inflammation induced by chemotherapy may contribute to hippocampal changes that underlie these deficits. In this cross-sectional study, we measured bilateral hippocampal volumes from high-resolution magnetic resonance images in 42 chemotherapy-treated breast cancer survivors and 35 healthy female controls. Patients with breast cancer were, on average, 4.8 ± 3.4 years off-therapy. In a subset of these participants (20 breast cancer, 23 controls), we quantified serum cytokine levels. Left hippocampal volumes and memory performance were significantly reduced and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα) concentrations were significantly elevated in the breast cancer group compared to controls. In the breast cancer group, lower left hippocampal volume was associated with higher levels of TNFα and lower levels of IL-6 with a significant interaction between these two cytokines suggesting a potential modulatory effect of IL-6 on TNFα. Verbal memory performance was associated with cytokine levels and left hippocampal volume in both groups. These findings provide evidence of altered hippocampal volume and verbal memory difficulties following breast cancer chemotherapy that may be mediated by TNFα and IL-6.
PMCID: PMC3665606  PMID: 22698992
Breast cancer; Chemotherapy; Interleukin-6; Tumor necrosis factor-alpha; Memory; Hippocampus; MRI
3.  Changes in frontal-parietal activation and math skills performance following adaptive number sense training: Preliminary results from a pilot study 
Neuropsychological rehabilitation  2011;21(4):433-454.
Number sense is believed to be critical for math development. It is putatively an implicitly learned skill and may therefore have limitations in terms of being explicitly trained, particularly in individuals with altered neurodevelopment. A case series study was conducted using an adaptive, computerized program that focused on number sense and general problem solving skills was designed to investigate training effects on performance as well as brain function in a group of children with Turner syndrome who are at risk for math difficulties and altered development of math-related brain networks. Standardized measurements of math and math-related cognitive skills as well as functional magnetic resonance imaging (fMRI) were used to assess behavioral and neurobiologic outcomes following training. Participants demonstrated significantly increased basic math skills, including number sense, and calculation as well as processing speed, cognitive flexibility and visual-spatial processing skills. With the exception of calculation, increased scores also were clinically significant (i.e. recovered) based on reliable change analysis. Participants additionally demonstrated significantly increased bilateral parietal lobe activation and decreased frontal-striatal and mesial temporal activation following the training program. These findings show proof of concept for an accessible training approach that may be potentially associated with improved number sense, math and related skills, as well as functional changes in math-related neural systems, even among individuals at risk for altered brain development.
PMCID: PMC3152634  PMID: 21714745
number sense; math skills training; fMRI; frontoparietal network
4.  Altered small-world properties of gray matter networks in breast cancer 
BMC Neurology  2012;12:28.
Breast cancer survivors, particularly those treated with chemotherapy, are at significantly increased risk for long-term cognitive and neurobiologic impairments. These deficits tend to involve skills that are subserved by distributed brain networks. Additionally, neuroimaging studies have shown a diffuse pattern of brain structure changes in chemotherapy-treated breast cancer survivors that might impact large-scale brain networks.
We therefore applied graph theoretical analysis to compare the gray matter structural networks of female breast cancer survivors with a history of chemotherapy treatment and healthy age and education matched female controls.
Results revealed reduced clustering coefficient and small-world index in the brain network of the breast cancer patients across a range of network densities. In addition, the network of the breast cancer group had less highly interactive nodes and reduced degree/centrality in the frontotemporal regions compared to controls, which may help explain the common impairments of memory and executive functioning among these patients.
These results suggest that breast cancer and chemotherapy may decrease regional connectivity as well as global network organization and integration, reducing efficiency of the network. To our knowledge, this is the first report of altered large-scale brain networks associated with breast cancer and chemotherapy.
PMCID: PMC3404945  PMID: 22632066
5.  Cognitive reserve and brain volumes in pediatric acute lymphoblastic leukemia 
Brain imaging and behavior  2010;4(3-4):256-269.
Acute lymphoblastic leukemia (ALL) is associated with long-term, progressive cognitive deficits and white matter injury. We measured global and regional white and gray matter as well as cognitive function and examined relationships between these variables and cognitive reserve, as indicated by maternal education level, in 28 young survivors of ALL and 31 healthy controls. Results indicated significantly reduced white matter volumes and cognitive testing scores in the ALL group compared to controls. Maternal education was inversely related to both global and regional white matter and directly related to gray matter in ALL and was directly related to both gray and white matter in controls, consistent with the cognitive reserve hypothesis. Cognitive performance was associated with different brain regions in ALL compared to controls. Maternal education was significantly positively correlated with working and verbal memory in ALL as well as processing speed and verbal memory in controls, improving models of cognitive outcome over medical and/or demographic predictors. Our findings suggest that cognitive reserve may be an important factor in brain injury and cognitive outcome in ALL. Additionally, children with ALL may experience some neural reorganization related to cognitive outcome.
PMCID: PMC3049995  PMID: 20814845
Leukemia; Neuroimaging; MRI; Brain volumetrics; Cognitive reserve; Maternal education
6.  Regulation of Hippocampal and Behavioral Excitability by Cyclin-Dependent Kinase 5 
PLoS ONE  2009;4(6):e5808.
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that has been implicated in learning, synaptic plasticity, neurotransmission, and numerous neurological disorders. We previously showed that conditional loss of Cdk5 in adult mice enhanced hippocampal learning and plasticity via modulation of calpain-mediated N-methyl-D-aspartic acid receptor (NMDAR) degradation. In the present study, we characterize the enhanced synaptic plasticity and examine the effects of long-term Cdk5 loss on hippocampal excitability in adult mice. Field excitatory post-synaptic potentials (fEPSPs) from the Schaffer collateral CA1 subregion of the hippocampus (SC/CA1) reveal that loss of Cdk5 altered theta burst topography and enhanced post-tetanic potentiation. Since Cdk5 governs NMDAR NR2B subunit levels, we investigated the effects of long-term Cdk5 knockout on hippocampal neuronal excitability by measuring NMDAR-mediated fEPSP magnitudes and population-spike thresholds. Long-term loss of Cdk5 led to increased Mg2+-sensitive potentials and a lower threshold for epileptiform activity and seizures. Biochemical analyses were performed to better understand the role of Cdk5 in seizures. Induced-seizures in wild-type animals led to elevated amounts of p25, the Cdk5-activating cofactor. Long-term, but not acute, loss of Cdk5 led to decreased p25 levels, suggesting that Cdk5/p25 may be activated as a homeostatic mechanism to attenuate epileptiform activity. These findings indicate that Cdk5 regulates synaptic plasticity, controls neuronal and behavioral stimulus-induced excitability and may be a novel pharmacological target for cognitive and anticonvulsant therapies.
PMCID: PMC2695674  PMID: 19529798

Results 1-6 (6)