Kim Edelstein

Cycle of period gene expression in a diurnal mammal (Spermophilus tridecemlineatus): implications for nonphotic phase shifting.

Ground squirrels, Spermophilus tridecemlineatus, were kept in a 12:12 h light-dark cycle. As expected for a diurnal species, their locomotor activity occurred almost entirely in the daytime. Expression of mPer1 and mPer2 in the suprachiasmatic nucleus was studied at six time points by in situ hybridization. For both these genes, mRNA was highest in the first part of the subjective day (about zeitgeber time 5). This is close to the time when mPer1 and mPer2 expression is maximal in nocturnal rodents. These results have implications for under- standing nonphotic phase response curves in diurnal species and thereby for guiding research on nonphotic phase shifting in people

Early aging in adult survivors of childhood medulloblastoma: long-term neurocognitive, functional, and physical outcomes.

Treatment for medulloblastoma during childhood impairs neurocognitive function in survivors. While those diagnosed at younger ages are most vulnerable, little is known about the long-term neurocognitive, functional, and physical outcomes in survivors as they approach middle age. In this retrospective cohort study, we assessed 20 adults who were treated with surgery and radiotherapy for medulloblastoma during childhood (median age at assessment, 21.9 years [range, 18-47 years]; median time since diagnosis, 15.5 years [range, 6.5-42.2 years]). Nine patients also underwent chemotherapy. Cross-sectional analyses of current neurocognitive, functional, and physical status were conducted. Data from prior neuropsychological assessments were available for 18 subjects; longitudinal analyses were used to model individual change over time for those subjects. The group was well below average across multiple neurocognitive domains, and 90% had required accommodations at school for learning disorders. Longer time since diagnosis, but not age at diagnosis, was associated with continued decline in working memory, a common sign of aging. Younger age at diagnosis was associated with lower intelligence quotient and academic achievement scores, even many years after treatment had been completed. The most common health complications in survivors were hearing impairment, second cancers, diabetes, hypertension, and endocrine deficiencies. Adult survivors of childhood medulloblastoma exhibit signs of early aging regardless of how young they were at diagnosis. As survival rates for brain tumors continue to improve, these neurocognitive and physical sequelae may become evident in survivors diagnosed at different ages across the lifespan. It will become increasingly important to identify factors that contribute to risk and resilience in this growing population.

Long-term neurocognitive outcomes in young adult survivors of childhood acute lymphoblastic leukemia.

Five-year survival rates of childhood acute lymphoblastic leukemia (ALL) exceed 80% due to central nervous system-directed treatment including cranial radiation (CRT) and chemotherapy. However, these treatments are associated with neurocognitive compromise, the extent of which is correlated with higher dose and younger age at treatment. The aims of this study were to explore long-term neurocognitive outcomes in adult survivors of childhood ALL, and to identify measures sensitive to neurotoxicity in long-term survivors. We examined 24 adults who received 18 Gy CRT and chemotherapy for treatment of ALL between ages 2 and 15 years (median, 5.5). Time since diagnosis ranged from 6 to 26 years (median, 16.6). Younger age at diagnosis and longer time since diagnosis were associated with lower scores on a computerized battery that requires speed and accuracy across a number of domains (MicroCog), and other standardized neurocognitive tests. When compared with population norms, MicroCog indices were below average in survivors diagnosed with ALL before age 5, but only the reasoning/calculation index was below average in survivors diagnosed with ALL after age 5. In contrast, intelligence quotient (IQ) scores were average. In addition to confirming earlier studies showing that younger children are more vulnerable to treatment-related neurotoxicity, here we show that deficits exist many years post treatment even with a relatively lower dose of CRT, and that these deficits are especially evident on tasks involving rapid processing of information.

Motor learning in children with spina bifida: Dissociation between performance level and acquisition rate

The cerebellum is part of a neural circuit involved in procedural motor learning. We examined how congenital cerebellar malformations affect mirror drawing performance, a procedural learning task that involves learning to trace the outline of a star while looking at the reflection of the star in a mirror. Participants were 88 children with spina bifida myelomeningocele, a neural tube defect that results in lesions of the spinal cord, dysmorphology of the cerebellum, and requires shunt treatment for hydrocephalus, and 35 typically developing controls. Participants completed 10 trials in the morning and 10 trials following a 3-hr delay. Although children with spina bifida myelomeningocele were initially slower at tracing and made more errors than controls, all participants improved their performance of the task, as demonstrated by increased speed and accuracy across trials. Moreover, degree of cerebellar dysmorphology was not correlated with level of performance, rate of acquisition, or retention of mirror drawing. The results suggest that congenital cerebellar dysmorphology in spina bifida does not impair motor skill learning as measured by acquisition and retention of the mirror drawing task.

Behavioral responses to light in mice with dorsal lateral geniculate lesions

Light has rapid direct effects on behavior and physiology that may be distinguished from its indirect effects that occur via synchronization of the biological clock. In nocturnal animals, light at night acutely suppresses the wheel running activity usually observed at that time of day. This is known as masking because light masks the overt expression of the circadian activity rhythm. In the present study, we compared the effects of light on wheel running in mice with bilateral electrolytic lesions of the dorsal lateral geniculate nucleus (DLG) to those in sham-operated animals. DLG-lesioned animals exhibited greater suppression of wheel running in response to bright light than did the controls, but failed to exhibit the increased activity in response to dim light observed in intact animals. These findings support the view that masking effects of light on behavior comprise two opposing processes, one that increases activity and is mediated by the classical visual system, and another that suppresses activity and is mediated by a non image-forming irradiance detection system.

Space-based inhibition of return in children with spina bifida

Inhibition of return (IOR) refers to an increase in time to react to a target in a previously attended location. Children with spina bifida meningomyelocele (SBM) and hydrocephalus have congenital dysmorphology of the midbrain, a brain region associated with the control of covert orienting in general and with IOR in particular. The authors studied exogenously cued covert orienting in 8- to 19-year-old children and adolescents (84 with SBM and 37 age-matched, typically developing controls). The exogenous cue was a luminance change in a peripheral box that was 50% valid for the upcoming target location. Compared with controls, children with SBM showed attenuated IOR in the vertical plane, a deficit that was associated with midbrain dysmorphology in the form of tectal beaking but not with posterior brain volume loss. The data add to the emerging evidence for SBM deficits in attentional orienting to salient information.

Motor learning in children with spina bifida: intact learning and performance on a ballistic task.

Learning and performance on a ballistic task were investigated in children with spina bifida meningomyelocele (SBM), with either upper level spinal lesions (n = 21) or lower level spinal lesions (n = 81), and in typically developing controls (n = 35). Participants completed three phases (20 trials each) of an elbow goniometer task that required a ballistic arm movement to move a cursor to one of two target positions on a screen, including (1) an initial learning phase, (2) an adaptation phase with a gain change such that recalibration of the ballistic arm movement was required, and (3) a learning reactivation phase under the original gain condition. Initial error rate, asymptotic error rate, and learning rate did not differ significantly between the SBM and control groups. Relative to controls, the SBM group had reduced volumes in the cerebellar hemispheres and pericallosal gray matter (the region including the basal ganglia), although only the pericallosal gray matter was significantly correlated with motor adaptation. Congenital cerebellar dysmorphology is associated with preserved motor skill learning on voluntary, nonreflexive tasks in children with SBM, in whom the relative roles of the cerebellum and basal ganglia may differ from those in the adult brain.

Cognitive Dysfunction after Chemotherapy For Breast Cancer

Approximately 13 million adult cancer survivors live in the United States; about 2 million of them were diagnosed over 20 years ago (National Cancer Institute, 2012). Current 5-year survival rates are close to 70% and rising, so the number of people living with the physical and mental health consequences of cancer and cancer treatment will increase. One of these consequences is cognitive decline, popularly known as chemo-brain. The papers in this symposium reflect some of the approaches used to understand the nature and course of cognitive decline in women with breast cancer. Oncology research has long recognized that cognition may be affected by cancer. This was attributed to distress until 1978, when cognitive symptoms in breast cancer patients were attributed to ‘‘organic brain syndrome’’ (Levine, Silverfarb, & Lipowski, 1978). The first reports documenting greater cognitive deficits in cancer patients treated with chemotherapy than in patients who did not receive chemotherapy were published in the early 1980s (Greer and Silberfarb, 1982; Oxman and Silberfarb, 1980; Silberfarb, 1983). Following a lull, Wieneke and Dienst (1995) showed that breast cancer survivors treated with chemotherapy performed more than two standard deviations below test norms on tests of memory, mental flexibility, processing speed, attention, visuospatial ability, and/or motor function. Performance was correlated with length of treatment but not depression or time since treatment. Since then, studies examining cancer, chemotherapy, and cognition have increased exponentially. However, the field is relatively new and there is a great deal we do not understand. Although many studies using self-reported concerns distinguish people who received chemotherapy from those who have not (Pullens, De Vries, & Roukema, 2010), cohort studies using standardized neuropsychological measures often reveal ‘‘average’’ abilities relative to population norms (Anderson-Hanley, Sherman, Riggs, Agocha, Compas, 2003; Correa & Ahles, 2008; Stewart, Bielajew, Collins, Parkinson, & Tomiak, 2006; Wefel & Schagen, 2012). Discrepancies between patients’ complaints and objective test performance (Bender et al., 2008; Castellon et al., 2004; Cimprich, So, Ronis, & Trask, 2005; Hermelink et al., 2007) are frustrating for cancer survivors who express concerns about concentration, memory, processing speed, word-finding, decision making, and problem solving (Pullens et al., 2010). These changes hinder people from returning to work, school, or household obligations (Oberst, Bradley, Gardiner, Schenk, & Given, 2010), and affect psychological well-being (Boykoff, Moieni, & Subramanian, 2009) as well as relationships with the medical team, family and friends (Munir, Burrows, Yarker, Kalawsky, & Bains, 2010). In young adults with cancer, 27% fail to return to school or work 15–35 months after diagnosis and 30% report memory, attention and processing speed problems (Parsons et al., 2012). Although cognitive decline may be one factor contributing to these outcomes, other reasons may underlie the discrepancy between subjective concerns and performance. Wefel and Schagen (this issue) provide compelling evidence that quiets suspicions about motivation or secondary gain (e.g., perhaps due to return to work, disability support, or other issues). Their analysis of large samples of breast cancer patients showed no evidence of noncredible performance on performance validity testing. Another challenge is making sense of variable results across studies. The divergence between subjective and objective deficits indicates that they are not identical constructs; direct measurement of performance is important to characterize abilities rather than only relying on patient report. Yet across crosssectional and longitudinal studies that use neuropsychological tools, either no impairment is found, or there is variability in which cognitive domains are impaired and the magnitude of impairment (see Vardy & Tannock, 2007 for review). These discrepancies may result from methodological differences, including but not limited to:

Comorbid symptoms of emotional distress in adult survivors of childhood cancer.

Childhood cancer survivors are at risk for emotional distress symptoms, but symptom comorbidity has not been previously examined. This study examined distress profiles for adult survivors of childhood cancer diagnosed between 1970 and 1999.

Cognitive, behaviour, and academic functioning in adolescent and young adult survivors of childhood acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study.

BACKGROUND Survivors of childhood acute lymphoblastic leukaemia (ALL) are at risk for neurocognitive deficits that affect development in adolescence and young adulthood, and influence educational attainment and future independence. We examined a large and diverse cohort of survivors to identify risk predictors and modifiers of these outcomes. METHODS In this cohort study, cognitive and behaviour symptoms were assessed via a standardised parent questionnaire for 1560 adolescent survivors of ALL diagnosed between 1970 and 1999. Clinically significant symptoms (≥90th percentile) and learning problems were compared between survivors and a sibling cohort. Multivariable regression models were used to examine associations with demographic and treatment characteristics. Models were adjusted for inverse probability of sampling weights to reflect undersampling of ALL survivors in the expansion cohort. In a subset of survivors with longitudinal data (n=925), we examined associations between adolescent symptoms or problems and adult educational attainment. FINDINGS Compared with siblings, survivors treated with chemotherapy only were more likely to demonstrate headstrong behaviour (155 [19%] of 752 survivors vs 88 [14%] of 610 siblings, p=0·010), inattention-hyperactivity (15 [19%] vs 86 [14%], p<0·0001), social withdrawal (142 [18%] vs 75 [12%], p=0·002), and had higher rates of learning problems (191 [28%] vs 76 [14%], p<0·0001). In multivariable models among survivors, increased cumulative dose of intravenous methotrexate (ie, >4·3 g/m2) conferred increased risk of inattention-hyperactivity (relative risk [RR] 1·53, 95% CI 1·13-2·08). Adolescent survivors with cognitive or behaviour problems and those with learning problems were less likely to graduate from college as young adults than adolescent survivors without cognitive or behaviour problems. INTERPRETATION Although modern therapy for childhood ALL has eliminated the use of cranial radiation therapy, adolescent survivors treated with chemotherapy only remain at increased risk for cognitive, behaviour, and academic problems that adversely affect adult education outcomes. FUNDING National Cancer Institute, American Lebanese-Syrian Associated Charities.