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1.
J Neurooncol ; 135(2): 403-411, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28828698

RESUMEN

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.


Asunto(s)
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/radioterapia , Recurrencia Local de Neoplasia/diagnóstico , Radiocirugia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Nomogramas , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia
2.
J Neurooncol ; 119(2): 429-35, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24990827

RESUMEN

We investigate the differences in molecular signature and clinical outcomes between multiple lesion glioblastoma (GBM) and single focus GBM in the modern treatment era. Between August 2000 and May 2010, 161 patients with GBM were treated with modern radiotherapy techniques. Of this group, 33 were considered to have multiple lesion GBM (25 multifocal and 8 multicentric). Patterns of failure, time to progression and overall survival were compared based on whether the tumor was considered a single focus or multiple lesion GBM. Genomic groupings and methylation status were also investigated as a possible predictor of multifocality in a cohort of 41 patients with available tissue for analysis. There was no statistically significant difference in overall survival (p < 0.3) between the multiple lesion tumors (8.2 months) and single focus GBM (11 months). Progression free survival was superior in the single focus tumors (7.1 months) as compared to multi-focal (5.6 months, p = 0.02). For patients with single focus, multifocal and multicentric GBM, 81, 76 and 88 % of treatment failures occurred in the 60 Gy volume (p < 0.5), while 54, 72, and 38 % of treatment failures occurred in the 46 Gy volume (p < 0.4). Out of field failures were rare in both single focus and multiple foci GBM (7 vs 3 %). Genomic groupings and methylation status were not found to predict for multifocality. Patterns of failure, survival and genomic signatures for multiple lesion GBM do not appreciably differ when compared to single focus tumors.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Glioblastoma/genética , Glioblastoma/radioterapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/patología , Estudios de Cohortes , Metilación de ADN , Supervivencia sin Enfermedad , Femenino , Glioblastoma/epidemiología , Glioblastoma/patología , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Prevalencia , Tomografía Computarizada por Rayos X , Adulto Joven
3.
Sci Eng Ethics ; 17(2): 289-97, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20213534

RESUMEN

The demand for science trainees to have appropriate responsible conduct of research instruction continues to increase the attention shown by federal agencies and graduate school programs to the development of effective ethics curriculums. However, it is important to consider that the main learning environment for science graduate students and post-doctoral research fellows is within a laboratory setting. Here we discuss an internal laboratory program of weekly 15-minute ethics discussions implemented and used over the last 3 years in addition to the graduate school's program of scientific integrity training. During this time, the environment and culture within our laboratory has changed to place greater emphasis on the ethical implications of our own research and the research we evaluate. We still struggle with how to accurately assess this behavioral change; although, we present preliminary survey results on the evaluation and impact of this style of curriculum for ethics instruction in our laboratory.


Asunto(s)
Curriculum , Ética en Investigación/educación , Investigación/educación , Ciencia/educación , Responsabilidad Social , Enseñanza/métodos , Educación de Postgrado , Humanos , Ciencia/ética , Estados Unidos
4.
J Med Ethics ; 36(10): 620-6, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20663754

RESUMEN

OBJECTIVE: We conducted a process evaluation to (a) assess the effectiveness of a new problem-based learning curriculum designed to teach professionalism and scientific integrity to biomedical graduate students and (b) modify the course to enhance its relevance and effectiveness. The content presented realistic cases and issues in the practice of science, to promote skill development and to acculturate students to professional norms of science. METHOD: We used 5-step Likert-scaled questions, open-ended questions, and interviews of students and facilitators to assess curricular effectiveness. RESULTS: Both facilitators and students perceived course objectives were achieved. For example, respondents preferred active learning over lectures; both faculty and students perceived that the curriculum increased their understanding of norms, role obligations and responsibilities of professional scientists. They also reported an increased ability to identify ethical situations and felt that they had developed skills in moral reasoning and effective group work. CONCLUSIONS: These data helped to improve course implementation and instructional material. For example, to correct a negative perception that this was an 'ethics' course, we redesigned case debriefing activities to reinforce learning objectives and important skills. We refined cases to be more engaging and relevant for students, and gave facilitators more specific training and resources for each case. The problem-based learning small group strategy can stimulate an environment whereby participants are more aware of ethical implications of science, and increase their socialisation and open communication about professional behaviour.


Asunto(s)
Curriculum/normas , Educación de Postgrado en Medicina/métodos , Ética Médica/educación , Aprendizaje Basado en Problemas/métodos , Práctica Profesional/normas , Actitud del Personal de Salud , Investigación Biomédica/educación , Investigación Biomédica/ética , Comportamiento del Consumidor , Educación de Postgrado en Medicina/organización & administración , Competencia Profesional/normas , Encuestas y Cuestionarios
5.
J Med Ethics ; 36(10): 614-9, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20797979

RESUMEN

A multidisciplinary faculty committee designed a curriculum to shape biomedical graduate students into researchers with a high commitment to professionalism and social responsibility and to provide students with tools to navigate complex, rapidly evolving academic and societal environments with a strong ethical commitment. The curriculum used problem-based learning (PBL), because it is active and learner-centred and focuses on skill and process development. Two courses were developed: Scientific Professionalism: Scientific Integrity addressed discipline-specific and broad professional norms and obligations for the ethical practice of science and responsible conduct of research (RCR). Scientific Professionalism: Bioethics and Social Responsibility focused on current ethical and bioethical issues within the scientific profession, and implications of research for society. Each small-group session examined case scenarios that included: (1) learning objectives for professional norms and obligations; (2) key ethical issues and philosophies within each topic area; (3) one or more of the RCR instructional areas; and (4) at least one type of moral reflection. Cases emphasised professional standards, obligations and underlying philosophies for the ethical practice of science, competing interests of stakeholders and oversight of science (internal and external). To our knowledge, this is the first use of a longitudinal, multi-semester PBL course to teach scientific integrity and professionalism. Both faculty and students endorsed the active learning approach for these topics, in contrast to a compliance-based approach that emphasises learning rules and regulations.


Asunto(s)
Curriculum , Educación de Postgrado en Medicina/métodos , Ética Médica/educación , Principios Morales , Aprendizaje Basado en Problemas/métodos , Práctica Profesional , Discusiones Bioéticas , Investigación Biomédica/educación , Investigación Biomédica/ética , Humanos , Aprendizaje Basado en Problemas/organización & administración , Práctica Profesional/normas
6.
Inf Fusion ; 11(1): 12-20, 2010 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-20161039

RESUMEN

Determining when, if, and how information from separate sensory channels has been combined is a fundamental goal of research on multisensory processing in the brain. This can be a particular challenge in psychophysical data, as there is no direct recording of neural output. The most common way to characterize multisensory interactions in behavioral data is to compare responses to multisensory stimulation with the race model, a model of parallel, independent processing constructed from the probability of responses to the two unisensory stimuli which make up the multisensory stimulus. If observed multisensory reaction times are faster than those predicted by the model, it is inferred that information from the two channels is being combined rather than processed independently. Recently, behavioral research has been published employing capacity analyses where comparisons between two conditions are carried out at the level of the integrated hazard function. Capacity analyses seem to be particularly appealing technique for evaluating multisensory functioning, as they describe relationships between conditions across the entire distribution curve, are relatively easy and intuitive to interpret. The current paper presents capacity analysis of a behavioral data set previously analyzed using the race model. While applications of capacity analyses are still somewhat limited due to their novelty, it is hoped that this exploration of capacity and race model analyses will encourage the use of this promising new technique both in multisensory research and other applicable fields.

7.
Hum Brain Mapp ; 30(10): 3102-14, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19219847

RESUMEN

Caffeine is a commonly used neurostimulant that also produces cerebral vasoconstriction by antagonizing adenosine receptors. Chronic caffeine use results in an adaptation of the vascular adenosine receptor system presumably to compensate for the vasoconstrictive effects of caffeine. We investigated the effects of caffeine on cerebral blood flow (CBF) in increasing levels of chronic caffeine use. Low (mean = 45 mg/day), moderate (mean = 405 mg/day), and high (mean = 950 mg/day) caffeine users underwent quantitative perfusion magnetic resonance imaging on four separate occasions: twice in a caffeine abstinent state (abstained state) and twice in a caffeinated state following their normal caffeine use (native state). In each state, there were two drug conditions: participants received either caffeine (250 mg) or placebo. Gray matter CBF was tested with repeated-measures analysis of variance using caffeine use as a between-subjects factor, and correlational analyses were conducted between CBF and caffeine use. Caffeine reduced CBF by an average of 27% across both caffeine states. In the abstained placebo condition, moderate and high users had similarly greater CBF than low users; but in the native placebo condition, the high users had a trend towards less CBF than the low and moderate users. Our results suggest a limited ability of the cerebrovascular adenosine system to compensate for high amounts of daily caffeine use.


Asunto(s)
Encéfalo/metabolismo , Cafeína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Circulación Cerebrovascular/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Análisis de Varianza , Mapeo Encefálico , Cafeína/administración & dosificación , Cafeína/metabolismo , Estimulantes del Sistema Nervioso Central/administración & dosificación , Circulación Cerebrovascular/fisiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Imagen Eco-Planar/métodos , Femenino , Humanos , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Saliva/metabolismo , Estadística como Asunto , Adulto Joven
8.
Hum Brain Mapp ; 30(1): 228-40, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18072271

RESUMEN

Even the healthiest older adults experience changes in cognitive and sensory function. Studies show that older adults have reduced neural responses to sensory information. However, it is well known that sensory systems do not act in isolation but function cooperatively to either enhance or suppress neural responses to individual environmental stimuli. Very little research has been dedicated to understanding how aging affects the interactions between sensory systems, especially cross-modal deactivations or the ability of one sensory system (e.g., audition) to suppress the neural responses in another sensory system cortex (e.g., vision). Such cross-modal interactions have been implicated in attentional shifts between sensory modalities and could account for increased distractibility in older adults. To assess age-related changes in cross-modal deactivations, functional MRI studies were performed in 61 adults between 18 and 80 years old during simple auditory and visual discrimination tasks. Results within visual cortex confirmed previous findings of decreased responses to visual stimuli for older adults. Age-related changes in the visual cortical response to auditory stimuli were, however, much more complex and suggested an alteration with age in the functional interactions between the senses. Ventral visual cortical regions exhibited cross-modal deactivations in younger but not older adults, whereas more dorsal aspects of visual cortex were suppressed in older but not younger adults. These differences in deactivation also remained after adjusting for age-related reductions in brain volume of sensory cortex. Thus, functional differences in cortical activity between older and younger adults cannot solely be accounted for by differences in gray matter volume.


Asunto(s)
Envejecimiento/fisiología , Corteza Auditiva/fisiopatología , Percepción Auditiva/fisiología , Trastornos de la Percepción/fisiopatología , Corteza Visual/fisiopatología , Percepción Visual/fisiología , Estimulación Acústica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Atención/fisiología , Corteza Auditiva/patología , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Trastornos de la Percepción/etiología , Trastornos de la Percepción/patología , Estimulación Luminosa , Corteza Visual/patología , Adulto Joven
9.
Exp Brain Res ; 198(2-3): 273-85, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19404621

RESUMEN

The goal of the present study was to determine if older adults benefited from attention to a specific sensory modality in a voluntary attention task and evidenced changes in voluntary or involuntary attention when compared to younger adults. Suppressing and enhancing effects of voluntary attention were assessed using two cued forced-choice tasks, one that asked participants to localize and one that asked them to categorize visual and auditory targets. Involuntary attention was assessed using the same tasks, but with no attentional cues. The effects of attention were evaluated using traditional comparisons of means and Cox proportional hazards models. All analyses showed that older adults benefited behaviorally from selective attention in both visual and auditory conditions, including robust suppressive effects of attention. Of note, the performance of the older adults was commensurate with that of younger adults in almost all analyses, suggesting that older adults can successfully engage crossmodal attention processes. Thus, age-related increases in distractibility across sensory modalities are likely due to mechanisms other than deficits in attentional processing.


Asunto(s)
Envejecimiento , Atención , Percepción Auditiva , Percepción Visual , Estimulación Acústica , Adulto , Anciano , Análisis de Varianza , Señales (Psicología) , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Estimulación Luminosa , Modelos de Riesgos Proporcionales , Tiempo de Reacción , Percepción Espacial , Análisis y Desempeño de Tareas
10.
Cereb Cortex ; 18(2): 433-42, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17575289

RESUMEN

Age-related alterations in white matter have the potential to profoundly affect cognitive functioning. In fact, magnetic resonance imaging (MRI) studies using fractional anisotropy (FA) to measure white matter integrity reveal a positive correlation between FA and behavioral performance in older adults. Confounding these results are imaging studies demonstrating age-related white matter atrophy in some areas displaying altered FA, suggesting changes in diffusion may be simply an epiphenomenon of tissue loss. In the current study, structural MRI techniques were used to identify the relationship between white matter integrity and decreased volume in healthy aging adults. The data demonstrated that white matter atrophy did in fact account for differences in some areas, but significant FA decreases remained across much of the white matter after adjusting for atrophy. Results suggest a complex relationship between changes in white matter integrity and volume. FA appears to be more sensitive than volume loss to changes in normal appearing tissue, and these FA changes may actually precede white matter atrophy in some brain areas. As such, the ability to detect early white matter alterations may facilitate development of targeted treatments that prevent or slow age-related white matter degradation and associated cognitive sequelae.


Asunto(s)
Envejecimiento/patología , Encéfalo/citología , Interpretación de Imagen Asistida por Computador/métodos , Imagenología Tridimensional/métodos , Fibras Nerviosas Mielínicas/ultraestructura , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Tamaño de los Órganos
11.
Radiat Res ; 191(3): 217-231, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30694733

RESUMEN

Fractionated whole-brain irradiation for the treatment of intracranial neoplasia causes progressive neurodegeneration and neuroinflammation. The long-term consequences of single-fraction high-dose irradiation to the brain are unknown. To assess the late effects of brain irradiation we compared transcriptomic gene expression profiles from nonhuman primates (NHP; rhesus macaques Macaca mulatta) receiving single-fraction total-body irradiation (TBI; n = 5, 6.75-8.05 Gy, 6-9 years prior to necropsy) to those receiving fractionated whole-brain irradiation (fWBI; n = 5, 40 Gy, 8 × 5 Gy fractions; 12 months prior to necropsy) and control comparators (n = 5). Gene expression profiles from the dorsolateral prefrontal cortex (DLPFC), hippocampus (HC) and deep white matter (WM; centrum semiovale) were compared. Stratified analyses by treatment and region revealed that radiation-induced transcriptomic alterations were most prominent in animals receiving fWBI, and primarily affected white matter in both TBI and fWBI groups. Unsupervised canonical and ontologic analysis revealed that TBI or fWBI animals demonstrated shared patterns of injury, including white matter neuroinflammation, increased expression of complement factors and T-cell activation. Both irradiated groups also showed evidence of impaired glutamatergic neurotransmission and signal transduction within white matter, but not within the dorsolateral prefrontal cortex or hippocampus. Signaling pathways and structural elements involved in extracellular matrix (ECM) deposition and remodeling were noted within the white matter of animals receiving fWBI, but not of those receiving TBI. These findings indicate that those animals receiving TBI are susceptible to neurological injury similar to that observed after fWBI, and these changes persist for years postirradiation. Transcriptomic profiling reaffirmed that macrophage/microglial-mediated neuroinflammation is present in radiation-induced brain injury (RIBI), and our data provide novel evidence that the complement system may contribute to the pathogenesis of RIBI. Finally, these data challenge the assumption that the hippocampus is the predilection site of injury in RIBI, and indicate that impaired glutamatergic neurotransmission may occur in white matter injury.


Asunto(s)
Traumatismos Experimentales por Radiación/etiología , Traumatismos Experimentales por Radiación/genética , Sustancia Blanca/efectos de la radiación , Animales , Relación Dosis-Respuesta en la Radiación , Ontología de Genes , Macaca mulatta , Masculino , Traumatismos Experimentales por Radiación/patología , Factores de Tiempo , Transcriptoma/efectos de la radiación , Sustancia Blanca/metabolismo , Sustancia Blanca/patología
12.
J Cancer Res Clin Oncol ; 145(2): 337-344, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30417218

RESUMEN

INTRODUCTION: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30-50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. METHODS: We enrolled patients > 18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (≤ 3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. RESULTS: 18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade ≥ 3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered "possible." In the dose-expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. CONCLUSION: Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Pioglitazona/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundario , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Seguridad del Paciente , Pronóstico , Radioterapia Conformacional , Tasa de Supervivencia
13.
BMC Neurol ; 8: 35, 2008 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-18817554

RESUMEN

BACKGROUND: Processing stimuli in one sensory modality is known to result in suppression of other sensory-specific cortices. Additionally, behavioral experiments suggest that the primary consequence of paying attention to a specific sensory modality is poorer task performance in the unattended sensory modality. This study was designed to determine how focusing attention on the auditory or visual modality impacts neural activity in cortical regions responsible for processing stimuli in the unattended modality. METHODS: Functional MRI data were collected in 15 participants who completed a cued detection paradigm. This task allowed us to assess the effects of modality-specific attention both during the presence and the absence of targets in the attended modality. RESULTS: The results of this experiment demonstrate that attention to a single sensory modality can result in decreased activity in cortical regions that process information from an unattended sensory modality (cross-modal deactivations). The effects of attention are likely additive with stimulus-driven effects with the largest deactivations being observed during modality-specific selective attention, in the presence of a stimulus in that modality. CONCLUSION: Modality-specific selective attention results in behavioral decrements in unattended sensory modalities. The imaging results presented here provide a neural signature (cross-modal deactivation) for modality-specific selective attention.


Asunto(s)
Atención/fisiología , Conducta/fisiología , Corteza Cerebral/fisiología , Señales (Psicología) , Desempeño Psicomotor/fisiología , Estimulación Acústica/métodos , Adulto , Corteza Auditiva/anatomía & histología , Corteza Auditiva/fisiología , Percepción Auditiva/fisiología , Corteza Cerebral/anatomía & histología , Cognición/fisiología , Discriminación en Psicología/fisiología , Femenino , Lateralidad Funcional/fisiología , Humanos , Imagen por Resonancia Magnética , Masculino , Estimulación Luminosa/métodos , Tiempo de Reacción/fisiología , Análisis de Regresión , Corteza Visual/anatomía & histología , Corteza Visual/fisiología , Percepción Visual/fisiología
14.
Exp Brain Res ; 184(1): 39-52, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17684735

RESUMEN

Stimuli occurring in multiple sensory modalities that are temporally synchronous or spatially coincident can be integrated together to enhance perception. Additionally, the semantic content or meaning of a stimulus can influence cross-modal interactions, improving task performance when these stimuli convey semantically congruent or matching information, but impairing performance when they contain non-matching or distracting information. Attention is one mechanism that is known to alter processing of sensory stimuli by enhancing perception of task-relevant information and suppressing perception of task-irrelevant stimuli. It is not known, however, to what extent attention to a single sensory modality can minimize the impact of stimuli in the unattended sensory modality and reduce the integration of stimuli across multiple sensory modalities. Our hypothesis was that modality-specific selective attention would limit processing of stimuli in the unattended sensory modality, resulting in a reduction of performance enhancements produced by semantically matching multisensory stimuli, and a reduction in performance decrements produced by semantically non-matching multisensory stimuli. The results from two experiments utilizing a cued discrimination task demonstrate that selective attention to a single sensory modality prevents the integration of matching multisensory stimuli that is normally observed when attention is divided between sensory modalities. Attention did not reliably alter the amount of distraction caused by non-matching multisensory stimuli on this task; however, these findings highlight a critical role for modality-specific selective attention in modulating multisensory integration.


Asunto(s)
Atención , Señales (Psicología) , Discriminación en Psicología/fisiología , Percepción , Umbral Sensorial/fisiología , Estimulación Acústica , Adulto , Percepción Auditiva , Cognición , Percepción de Color , Femenino , Humanos , Masculino , Estimulación Luminosa , Tiempo de Reacción , Valores de Referencia , Percepción Visual
15.
Radiat Res ; 190(4): 361-373, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30016219

RESUMEN

Late-delayed radiation-induced brain injury (RIBI) is a major adverse effect of fractionated whole-brain irradiation (fWBI). Characterized by progressive cognitive dysfunction, and associated cerebrovascular and white matter injury, RIBI deleteriously affects quality of life for cancer patients. Despite extensive morphological characterization of the injury, the pathogenesis is unclear, thus limiting the development of effective therapeutics. We previously reported that RIBI is associated with increased gene expression of the extracellular matrix (ECM) protein fibronectin (FN1). We hypothesized that fibronectin contributes to perivascular ECM, which may impair diffusion to the dependent parenchyma, thus contributing to the observed cognitive decline. The goal of this study was to determine the localization of fibronectin in RIBI and further characterize the composition of perivascular ECM, as well as identify the cell of origin for FN1 by in situ hybridization. Briefly, fibronectin localized to the vascular basement membrane of morphologically normal blood vessels from control comparators and animals receiving fWBI, and to the perivascular space of edematous and fibrotic vascular phenotypes of animals receiving fWBI. Additional mild diffuse parenchymal staining in areas of vascular injury suggested blood-brain-barrier disruption and plasma fibronectin extravasation. Perivascular ECM lacked amyloid and contained lesser amounts of collagens I and IV, which localized to the basement membrane. These changes occurred in the absence of alterations in microvascular area fraction or microvessel density. Fibronectin transcripts were rarely expressed in control comparators, and were most strongly induced within cerebrovascular endothelial and vascular smooth muscle cells after fWBI. Our results demonstrate that fibronectin is produced by cerebrovascular endothelial and smooth muscle cells in late-delayed RIBI and contributes to perivascular ECM, which we postulate may contribute to diffusion barrier formation. We propose that pathways that antagonize fibronectin deposition and matrix assembly or enhance degradation may serve as potential therapeutic targets in RIBI.


Asunto(s)
Lesiones Encefálicas/metabolismo , Circulación Cerebrovascular , Endotelio Vascular/metabolismo , Matriz Extracelular/metabolismo , Fibronectinas/fisiología , Músculo Liso Vascular/metabolismo , Traumatismos Experimentales por Radiación/metabolismo , Animales , Encéfalo/irrigación sanguínea , Encéfalo/efectos de la radiación , Lesiones Encefálicas/etiología , Lesiones Encefálicas/patología , Fibronectinas/biosíntesis , Expresión Génica , Macaca mulatta , Masculino , Traumatismos Experimentales por Radiación/patología
16.
Neuroreport ; 18(10): 1077-81, 2007 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-17558300

RESUMEN

Older adults are known to gain more than younger adults from the simultaneous presentation of semantically congruent sensory stimuli. Although these findings are quite exciting, they may not solely be due to age-related differences in multisensory processing. Rather, enhanced integration may be explained by alterations associated with general cognitive slowing. This study utilized a task that eliminated most high-order cognitive processing. As such, no significant differences in unisensory response times were seen; however, older adults actually showed faster multisensory responses than younger adults. Older adults continued to show significantly greater multisensory enhancement than younger adults. Data support the conclusion that differences in multisensory processing for older adults cannot be explained solely by the effects of general cognitive slowing.


Asunto(s)
Envejecimiento/fisiología , Percepción Auditiva/fisiología , Discriminación en Psicología/fisiología , Procesos Mentales/fisiología , Percepción Visual/fisiología , Estimulación Acústica/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Mapeo Encefálico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estimulación Luminosa/métodos , Tiempo de Reacción/fisiología
17.
Radiat Res ; 187(5): 599-611, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28398880

RESUMEN

Fractionated whole-brain irradiation (fWBI) is a mainstay of treatment for patients with intracranial neoplasia; however late-delayed radiation-induced normal tissue injury remains a major adverse consequence of treatment, with deleterious effects on quality of life for affected patients. We hypothesize that cerebrovascular injury and remodeling after fWBI results in ischemic injury to dependent white matter, which contributes to the observed cognitive dysfunction. To evaluate molecular effectors of radiation-induced brain injury (RIBI), real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46), hippocampus and temporal white matter of 4 male Rhesus macaques (age 6-11 years), which had received 40 Gray (Gy) fWBI (8 fractions of 5 Gy each, twice per week), and 3 control comparators. All fWBI animals developed neurologic impairment; humane euthanasia was elected at a median of 6 months. Radiation-induced brain injury was confirmed histopathologically in all animals, characterized by white matter degeneration and necrosis, and multifocal cerebrovascular injury consisting of perivascular edema, abnormal angiogenesis and perivascular extracellular matrix deposition. Herein we demonstrate that RIBI is associated with white matter-specific up-regulation of hypoxia-associated lactate dehydrogenase A (LDHA) and that increased gene expression of fibronectin 1 (FN1), SERPINE1 and matrix metalloprotease 2 (MMP2) may contribute to cerebrovascular remodeling in late-delayed RIBI. Additionally, vascular stability and maturation associated tumor necrosis super family member 15 (TNFSF15) and vascular endothelial growth factor beta (VEGFB) mRNAs were increased within temporal white matter. We also demonstrate that radiation-induced brain injury is associated with decreases in white matter-specific expression of neurotransmitter receptors SYP, GRIN2A and GRIA4. We additionally provide evidence that macrophage/microglial mediated neuroinflammation may contribute to RIBI through increased gene expression of the macrophage chemoattractant CCL2 and macrophage/microglia associated CD68. Global patterns in cerebral gene expression varied significantly between regions examined (P < 0.0001, Friedman's test), with effects most prominent within cerebral white matter.


Asunto(s)
Lesiones Encefálicas/fisiopatología , Trastornos Cerebrovasculares/etiología , Trastornos Cerebrovasculares/fisiopatología , Irradiación Craneana/efectos adversos , Epilepsia/fisiopatología , Traumatismos por Radiación/fisiopatología , Animales , Lesiones Encefálicas/etiología , Lesiones Encefálicas/patología , Trastornos Cerebrovasculares/patología , Epilepsia/etiología , Epilepsia/patología , Humanos , Macaca mulatta , Masculino , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/efectos de la radiación , Traumatismos por Radiación/etiología , Traumatismos por Radiación/patología , Dosificación Radioterapéutica , Sustancia Blanca/patología , Sustancia Blanca/fisiopatología , Sustancia Blanca/efectos de la radiación
18.
J Radiosurg SBRT ; 5(1): 35-42, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29296461

RESUMEN

OBJECTIVES: Recent trials have shown that whole brain radiotherapy (WBRT) can worsen performance status, particularly in the geriatric population. We reviewed our institutional experience with geriatric patients (> 70 years) with brain metastases treated with radiosurgery (SRS) to determine clinical and quality of life (QOL) outcomes. METHODS: Between 7/2000 and 1/2013, a retrospective review was performed on 467 patients treated with SRS (114 geriatric patients). Overall survival (OS), cause of death, and WBRT were evaluated. A retrospective review of geriatric patients was performed with assessments of Karnofsky performance score (KPS, N=69), mini-mental status examinations (MMSE, N=39), and Spitzer QOL (SQOL, N=39) at initial interview, 6, and 12 months after SRS. Repeated Measures ANOVA was used to evaluate differences in quality of life values. Kaplan-Meier analysis estimated survival and time to WBRT. RESULTS: Geriatric patients had a shorter OS compared to non-geriatric patients (p<0.035). Fewer patients in the geriatric cohort received whole brain (p<0.001) or subsequent Gamma Knife stereotactic radiosurgery (GKRS) (p<0.025). No difference was seen in neurologic death rates (p<0.4). In geriatric patients, SQOL declined from 0 to 6 months (mean 6.5 to 5.9, respectively, p<0.02) and 0 to 12 months (mean 6.5 and 5.6, respectively, p<0.03). KPS and MMSE scores did not change over time. Grade 3 or 4 toxicity was 9% in geriatric patients. There was no grade 5 toxicity. CONCLUSION: Geriatric patients tolerate GKRS without a significant decline in KPS or MMSE and with acceptable toxicity profile. SRS also spares a significant proportion of geriatric patients from WBRT, and its associated toxicities.

19.
Adv Radiat Oncol ; 2(4): 624-629, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29204530

RESUMEN

PURPOSE: Radiation-induced cognitive decline is relatively common after treatment for primary and metastatic brain tumors; however, identifying dosimetric parameters that are predictive of radiation-induced cognitive decline is difficult due to the heterogeneity of patient characteristics. The memory function is especially susceptible to radiation effects after treatment. The objective of this study is to correlate volumetric radiation doses received by critical neuroanatomic structures to post-radiation therapy (RT) memory impairment. METHODS AND MATERIALS: Between 2008 and 2011, 53 patients with primary brain malignancies were treated with conventionally fractionated RT in prospectively accrued clinical trials performed at our institution. Dose-volume histogram analysis was performed for the hippocampus, parahippocampus, amygdala, and fusiform gyrus. Hopkins Verbal Learning Test-Revised scores were obtained at least 6 months after RT. Impairment was defined as an immediate recall score ≤15. For each anatomic region, serial regression was performed to correlate volume receiving a given dose (VD(Gy)) with memory impairment. RESULTS: Hippocampal V53.4Gy to V60.9Gy significantly predicted post-RT memory impairment (P < .05). Within this range, the hippocampal V55Gy was the most significant predictor (P = .004). Hippocampal V55Gy of 0%, 25%, and 50% was associated with tumor-induced impairment rates of 14.9% (95% confidence interval [CI], 7.2%-28.7%), 45.9% (95% CI, 24.7%-68.6%), and 80.6% (95% CI, 39.2%-96.4%), respectively. CONCLUSIONS: The hippocampal V55Gy is a significant predictor for impairment, and a limiting dose below 55 Gy may minimize radiation-induced cognitive impairment.

20.
Radiat Res ; 186(5): 447-454, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27740889

RESUMEN

In this study, the effects of a potentially lethal radiation exposure on the brain for long-term cognitive sequelae were investigated using Rhesus macaques ( Macaca mulatta ) adopted from other facilities after analysis of acute radiation response via the Centers for Medical Countermeasures against Radiation (CMCR) network. Fifty-nine animals were given the opportunity to participate in cognitive cage-side testing. The animals that received single-dose gamma irradiation were significantly less likely to engage in cognitive testing than the controls, suggesting that irradiated animals may have differences in cognitive ability. Five irradiated (6.75-8.05 Gy) and three naïve control animals self-selected, were extensively trained and administered a simple visual discrimination with reversal (SVD+R) task 2-3 times per week for 11-18 months. Each session consisted of 30 trials in which the animals were required to choose the correct visual stimulus for a food reward. After the initial presentation, the stimulus that signaled the presence of food was twice reversed once the animal reached criterion (90% accuracy across four consecutive sessions). While the limited sample size precluded definitive statistical analysis, irradiated animals took longer to reach the criterion subsequent to reversal than did control animals, suggesting a relative deficiency in cognitive flexibility. These results provide preliminary data supporting the potential use of a nonhuman primate model to study radiation-induced, late-delayed cognitive deficits.


Asunto(s)
Encéfalo/fisiología , Encéfalo/efectos de la radiación , Cognición/efectos de la radiación , Rayos gamma/efectos adversos , Animales , Discriminación en Psicología/efectos de la radiación , Femenino , Macaca mulatta , Masculino
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