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Wolfgang A Tome - One of the best experts on this subject based on the ideXlab platform.
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hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low grade Adult Brain tumors
International Journal of Radiation Oncology Biology Physics, 2012Co-Authors: Vinai Gondi, Minesh P Mehta, Bruce P Hermann, Wolfgang A TomeAbstract:Purpose To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade Adult Brain tumors treated with fractionated stereotactic radiotherapy (FSRT). Methods and Materials Adult patients with benign or low-grade Adult Brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test–retest interval. NCF impairment was defined as a z score ≤−1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose–volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD 2 ) assuming an α/β ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose–response data were fit to a nonlinear model. Results Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD 2 to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD 2 to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). Conclusion EQD 2 to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade Adult Brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results.
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hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low grade Adult Brain tumors
International Journal of Radiation Oncology Biology Physics, 2012Co-Authors: Vinai Gondi, Minesh P Mehta, Bruce P Hermann, Wolfgang A TomeAbstract:Summary Equivalent dose in 2-Gy fractions to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term memory impairment. Modern intensity-modulated radiation therapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold. Purpose: To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade Adult Brain tumors treated with fractionated stereotactic radiotherapy (FSRT). Methods and Materials: Adult patients with benign or low-grade Adult Brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same testeretest interval. NCF impairment was defined as a z score �� 1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, doseevolume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD2) assuming an a/b ratio of 2 Gy were computed. Fisher’s exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Doseeresponse data were fit to a nonlinear model. Results: Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD2 to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p Z 0.043). The association between WMS-WL delayed recall and EQD2 to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p Z 0.068). Conclusion: EQD2 to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade Adult Brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled
Vinai Gondi - One of the best experts on this subject based on the ideXlab platform.
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hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low grade Adult Brain tumors
International Journal of Radiation Oncology Biology Physics, 2012Co-Authors: Vinai Gondi, Minesh P Mehta, Bruce P Hermann, Wolfgang A TomeAbstract:Purpose To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade Adult Brain tumors treated with fractionated stereotactic radiotherapy (FSRT). Methods and Materials Adult patients with benign or low-grade Adult Brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test–retest interval. NCF impairment was defined as a z score ≤−1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose–volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD 2 ) assuming an α/β ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose–response data were fit to a nonlinear model. Results Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD 2 to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD 2 to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). Conclusion EQD 2 to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade Adult Brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results.
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hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low grade Adult Brain tumors
International Journal of Radiation Oncology Biology Physics, 2012Co-Authors: Vinai Gondi, Minesh P Mehta, Bruce P Hermann, Wolfgang A TomeAbstract:Summary Equivalent dose in 2-Gy fractions to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term memory impairment. Modern intensity-modulated radiation therapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold. Purpose: To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade Adult Brain tumors treated with fractionated stereotactic radiotherapy (FSRT). Methods and Materials: Adult patients with benign or low-grade Adult Brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same testeretest interval. NCF impairment was defined as a z score �� 1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, doseevolume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD2) assuming an a/b ratio of 2 Gy were computed. Fisher’s exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Doseeresponse data were fit to a nonlinear model. Results: Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD2 to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p Z 0.043). The association between WMS-WL delayed recall and EQD2 to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p Z 0.068). Conclusion: EQD2 to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade Adult Brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled
Hongjun Song - One of the best experts on this subject based on the ideXlab platform.
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development of hippocampal mossy fiber synaptic outputs by new neurons in the Adult Brain
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Regina L Faulkner, Mi Hyeon Jang, Xiaobo Liu, Xin Duan, Kurt A Sailor, Ju Young Kim, Edward G Jones, Guo Li Ming, Hongjun Song, Hwaijong ChengAbstract:New neurons are continuously generated in restricted regions of the Adult mammalian Brain. Although these Adult-born neurons have been shown to receive synaptic inputs, little is known about their synaptic outputs. Using retrovirus-mediated birth-dating and labeling in combination with serial section electron microscopic reconstruction, we report that mossy fiber en passant boutons of Adult-born dentate granule cells form initial synaptic contacts with CA3 pyramidal cells within 2 weeks after their birth and reach morphologic maturity within 8 weeks in the Adult hippocampus. Knockdown of Disrupted-in-Schizophrenia-1 (DISC1) in newborn granule cells leads to defects in axonal targeting and development of synaptic outputs in the Adult Brain. Together with previous reports of synaptic inputs, these results demonstrate that Adult-born neurons are fully integrated into the existing neuronal circuitry. Our results also indicate a role for DISC1 in presynaptic development and may have implications for the etiology of schizophrenia and related mental disorders.
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development of neural stem cell in the Adult Brain
Current Opinion in Neurobiology, 2008Co-Authors: Xin Duan, Guo Li Ming, Eunchai Kang, Cindy Y Liu, Hongjun SongAbstract:New neurons are continuously generated in the dentate gyrus of the mammalian hippocampus and in the subventricular zone of the lateral ventricles throughout life. The origin of these new neurons is believed to be from multipotent Adult neural stem cells. Aided by new methodologies, significant progress has been made in the characterization of neural stem cells and their development in the Adult Brain. Recent studies have also begun to reveal essential extrinsic and intrinsic molecular mechanisms that govern sequential steps of Adult neurogenesis in the hippocampus and subventricular zone/olfactory bulb, from proliferation and fate specification of neural progenitors to maturation, navigation, and synaptic integration of the neuronal progeny. Future identification of molecular mechanisms and physiological functions of Adult neurogenesis will provide further insight into the plasticity and regenerative capacity of the mature central nervous system.
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gaba regulates synaptic integration of newly generated neurons in the Adult Brain
Nature, 2006Co-Authors: Eyleen L K Goh, Kurt A Sailor, Guo Li Ming, Yasuji Kitabatake, Hongjun SongAbstract:Adult neurogenesis, the birth and integration of new neurons from Adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the Adult mammalian Brain. Accumulating evidence suggests that neuronal activity regulates Adult neurogenesis and that new neurons contribute to specific Brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the Adult Brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the Adult hippocampus are tonically activated by ambient GABA (gamma-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the Adult Brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the Adult Brain, and suggests an unexpected mechanism for activity-dependent regulation of Adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.
Edmund J S Sonugabarke - One of the best experts on this subject based on the ideXlab platform.
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early childhood deprivation is associated with alterations in Adult Brain structure despite subsequent environmental enrichment
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Nuria K Mackes, Dennis Golm, Sagari Sarkar, Robert Kumsta, Michael Rutter, Graeme Fairchild, Mitul A Mehta, Edmund J S SonugabarkeAbstract:Early childhood deprivation is associated with higher rates of neurodevelopmental and mental disorders in Adulthood. The impact of childhood deprivation on the Adult Brain and the extent to which structural changes underpin these effects are currently unknown. To investigate these questions, we utilized MRI data collected from young Adults who were exposed to severe deprivation in early childhood in the Romanian orphanages of the Ceaușescu era and then, subsequently adopted by UK families; 67 Romanian adoptees (with between 3 and 41 mo of deprivation) were compared with 21 nondeprived UK adoptees. Romanian adoptees had substantially smaller total Brain volumes (TBVs) than nondeprived adoptees (8.6% reduction), and TBV was strongly negatively associated with deprivation duration. This effect persisted after covarying for potential environmental and genetic confounds. In whole-Brain analyses, deprived adoptees showed lower right inferior frontal surface area and volume but greater right inferior temporal lobe thickness, surface area, and volume than the nondeprived adoptees. Right medial prefrontal volume and surface area were positively associated with deprivation duration. No deprivation-related effects were observed in limbic regions. Global reductions in TBV statistically mediated the observed relationship between institutionalization and both lower intelligence quotient (IQ) and higher levels of attention deficit/hyperactivity disorder symptoms. The deprivation-related increase in right inferior temporal volume seemed to be compensatory, as it was associated with lower levels of attention deficit/hyperactivity disorder symptoms. We provide compelling evidence that time-limited severe deprivation in the first years of life is related to alterations in Adult Brain structure, despite extended enrichment in adoptive homes in the intervening years.
Fulton T Crews - One of the best experts on this subject based on the ideXlab platform.
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adolescent binge ethanol treatment alters Adult Brain regional volumes cortical extracellular matrix protein and behavioral flexibility
Pharmacology Biochemistry and Behavior, 2014Co-Authors: Leon G Coleman, Martin Styner, Wen Liu, Ipek Oguz, Fulton T CrewsAbstract:Abstract Adolescents binge drink more than any other age group, increasing risk of disrupting the development of the frontal cortex. We hypothesized that adolescent binge drinking would lead to persistent alterations in Adulthood. In this study, we modeled adolescent weekend underage binge-drinking, using adolescent mice (post-natal days [P] 28–37). The adolescent intermittent binge ethanol (AIE) treatment includes 6 binge intragastric doses of ethanol in an intermittent pattern across adolescence. Assessments were conducted in Adulthood following extended abstinence to determine if there were persistent changes in Adults. Reversal learning, open field and other behavioral assessments as well as Brain structure using magnetic imaging and immunohistochemistry were determined. We found that AIE did not impact Adult Barnes Maze learning. However, AIE did cause reversal learning deficits in Adults. AIE also caused structural changes in the Adult Brain. AIE was associated with Adulthood volume enlargements in specific Brain regions without changes in total Brain volume. Enlarged regions included the orbitofrontal cortex (OFC, 4%), cerebellum (4.5%), thalamus (2%), internal capsule (10%) and genu of the corpus callosum (7%). The enlarged OFC volume in Adults after AIE is consistent with previous imaging studies in human adolescents. AIE treatment was associated with significant increases in the expression of several extracellular matrix (ECM) proteins in the Adult OFC including WFA (55%), Brevican (32%), Neurocan (105%), Tenacin-C (25%), and HABP (5%). These findings are consistent with AIE causing persistent changes in Brain structure that could contribute to a lack of behavioral flexibility.
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adolescent binge drinking alters Adult Brain neurotransmitter gene expression behavior Brain regional volumes and neurochemistry in mice
Alcoholism: Clinical and Experimental Research, 2011Co-Authors: Leon G Coleman, Joohwi Lee, Martin Styner, Fulton T CrewsAbstract:Background: Binge drinking is common in human adolescents. The adolescent Brain is undergoing structural maturation and has a unique sensitivity to alcohol neurotoxicity. Therefore, adolescent binge ethanol may have long-term effects on the Adult Brain that alter Brain structure and behaviors that are relevant to alcohol-use disorders. Methods: To determine whether adolescent ethanol (AE) binge drinking alters the Adult Brain, male C57BL/6 mice were treated with either water or ethanol during adolescence (5 g/kg/d, i.g., postnatal days P28 to P37) and assessed during Adulthood (P60 to P88). An array of neurotransmitter-specific genes, behavioral tests (i.e., reversal learning, prepulse inhibition, and open field), and postmortem Brain structure using magnetic resonance imaging (MRI) and immunohistochemistry, were employed to assess persistent alterations in Adult Brain. Results: At P38, 24 hours after AE binge, many neurotransmitter genes, particularly cholinergic and dopaminergic, were reduced by ethanol treatment. Interestingly, dopamine receptor type 4 mRNA was reduced and confirmed using immunohistochemistry. Normal control maturation (P38 to P88) resulted in decreased neurotransmitter mRNA, e.g., an average decrease of 56%. Following AE treatment, Adults showed greater gene expression reductions than controls, averaging 73%. Adult spatial learning assessed in the Morris water maze was not changed by AE treatment, but reversal learning experiments revealed deficits. Assessment of Adult Brain region volumes using MRI indicated that the olfactory bulb and basal foreBrain were smaller in Adults following AE. Immunohistochemical analyses found reduced basal foreBrain area and fewer basal foreBrain cholinergic neurons. Conclusions: Adolescent binge ethanol treatment reduces Adult neurotransmitter gene expression, particularly cholinergic genes, reduces basal foreBrain and olfactory bulb volumes, and causes a reduction in the density of basal foreBrain acetylcholine neurons. Loss of cholinergic neurons and foreBrain structure could underlie Adult reversal learning deficits following adolescent binge drinking. Language: en