NIH Music-Based Intervention Toolkit: Music-Based Interventions for Brain Disorders of Aging.

Music-based interventions (MBIs) show promise for managing symptoms of various brain disorders. To fully realize the potential of MBIs and dispel the outdated misconception that MBIs are rooted in soft science, the NIH is promoting rigorously designed, well-powered MBI clinical trials. The pressing need of guidelines for scientifically rigorous studies with enhanced data collection brought together the Renée Fleming Foundation, the Foundation for the NIH, the Trans-NIH Music and Health Working Group, and an interdisciplinary scientific expert panel to create the NIH MBI Toolkit for research on music and health across the lifespan. The Toolkit defines the building blocks of MBIs, including a consolidated set of common data elements for MBI protocols, and core datasets of outcome measures and biomarkers for brain disorders of aging that researchers may select for their studies. Utilization of the guiding principles in this Toolkit will be strongly recommended for NIH-funded studies of MBIs.

The Emerging Science of Interoception: Sensing, Integrating, Interpreting, and Regulating Signals within the Self.

Interoception refers to the representation of the internal states of an organism, and includes the processes by which it senses, interprets, integrates, and regulates signals from within itself. This review presents a unified research framework and attempts to offer definitions for key terms to describe the processes involved in interoception. We elaborate on these definitions through illustrative research findings, and provide brief overviews of central aspects of interoception, including the anatomy and function of neural and non-neural pathways, diseases and disorders, manipulations and interventions, and predictive modeling. We conclude with discussions about major research gaps and challenges.

Cellular response of the rat brain to single doses of (137)Cs γ rays does not predict its response to prolonged 'biologically equivalent' fractionated doses.

PURPOSE: To determine if the brain's response to single doses predicts its response to 'biologically equivalent' fractionated doses. METHODS: Young adult male Fischer 344 rats were whole-brain irradiated with either single 11, 14, or 16.5 Gy doses of (137)Cs γ rays or their 'biologically equivalent' 20, 30, or 40 Gy fractionated doses (fWBI) delivered in 5 Gy fractions, twice/week for 2, 3, or 4 weeks, respectively. At 2 months post-irradiation, cellular markers of inflammation (total, activated, and newborn microglia) and neurogenesis (newborn neurons) were measured in 40 µm sections of the dentate gyrus (DG). RESULTS: Although the total number of microglia in the DG/hilus was not significantly different (p > 0.7) in unirradiated, single dose, and fWBI rats, single doses produced a significant (p < 0.003) increase in the percent-activated microglia; fWBI did not (p > 0.1). Additionally, single doses produced a significant (p < 0.002) dose-dependent increase in surviving newborn microglia; fWBI did not (p < 0.8). Although total proliferation in the DG was reduced equally by single and fWBI doses, single doses produced a significant dose-dependent (p < 0.02) decrease in surviving newborn neurons; fWBI did not (p > 0.6). CONCLUSIONS: These data demonstrate that the rat brain's cellular response to single doses often does not predict its cellular response to 'biologically equivalent' fWBI doses.

The peroxisomal proliferator-activated receptor (PPAR) α agonist, fenofibrate, prevents fractionated whole-brain irradiation-induced cognitive impairment.

We hypothesized that dietary administration of the peroxisomal proliferator-activated receptor α agonist, fenofibrate, to young adult male rats would prevent the fractionated whole-brain irradiation (fWBI)-induced reduction in cognitive function and neurogenesis and prevent the fWBI-induced increase in the total number of activated microglia. Eighty 12-14-week-old young adult male Fischer 344 × Brown Norway rats received either: (1) sham irradiation, (2) 40 Gy of fWBI delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation + dietary fenofibrate (0.2% w/w) starting 7 days prior to irradiation, or (4) fWBI + fenofibrate. Cognitive function was measured 26-29 weeks after irradiation using: (1) the perirhinal cortex (PRh)-dependent novel object recognition task; (2) the hippocampal-dependent standard Morris water maze (MWM) task; (3) the hippocampal-dependent delayed match-to-place version of the MWM task; and (4) a cue strategy preference version of the MWM to distinguish hippocampal from striatal task performance. Neurogenesis was assessed 29 weeks after fWBI in the granular cell layer and subgranular zone of the dentate gyrus using a doublecortin antibody. Microglial activation was assessed using an ED1 antibody in the dentate gyrus and hilus of the hippocampus. A significant impairment in perirhinal cortex-dependent cognitive function was measured after fWBI. In contrast, fWBI failed to alter hippocampal-dependent cognitive function, despite a significant reduction in hippocampal neurogenesis. Continuous administration of fenofibrate prevented the fWBI-induced reduction in perirhinal cortex-dependent cognitive function, but did not prevent the radiation-induced reduction in neurogenesis or the radiation-induced increase in activated microglia. These data suggest that fenofibrate may be a promising therapeutic for the prevention of some modalities of radiation-induced cognitive impairment in brain cancer patients.

The PPARδ agonist GW0742 inhibits neuroinflammation, but does not restore neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after whole-brain irradiation.

Brain tumor patients often develop cognitive impairment months to years after partial or fractionated whole-brain irradiation (WBI). Studies suggest that neuroinflammation and decreased hippocampal neurogenesis contribute to the pathogenesis of radiation-induced brain injury. In this study, we determined if the peroxisomal proliferator-activated receptor (PPAR) δ agonist GW0742 can prevent radiation-induced brain injury in C57Bl/6 wild-type (WT) and PPARδ knockout (KO) mice. Dietary GW0742 prevented the acute increase in IL-1ß mRNA and ERK phosphorylation measured at 3h after a single 10-Gy dose of WBI; it also prevented the increase in the number of activated hippocampal microglia 1 week after WBI. In contrast, dietary GW074 failed to prevent the radiation-induced decrease in hippocampal neurogenesis determined 2 months after WBI in WT mice or to mitigate their hippocampal-dependent spatial memory impairment measured 3 months after WBI using the Barnes maze task. PPARδ KO mice exhibited defects including decreased numbers of astrocytes in the dentate gyrus/hilus of the hippocampus and a failure to exhibit a radiation-induced increase in activated hippocampal microglia. Interestingly, the number of astrocytes in the dentate gyrus/hilus was reduced in WT mice, but not in PPARδ KO mice 2 months after WBI. These results demonstrate that, although dietary GW0742 prevents the increase in inflammatory markers and hippocampal microglial activation in WT mice after WBI, it does not restore hippocampal neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after WBI. Thus, the exact relationship between radiation-induced neuroinflammation, neurogenesis, and cognitive impairment remains elusive.

Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline.

OBJECTIVE: In a retrospective review to assess neuroanatomical targets of radiation-induced cognitive decline, dose volume histogram (DVH) analyses of specific brain regions of interest (ROI) are correlated to neurocognitive performance in 57 primary brain tumor survivors. METHODS: Neurocognitive assessment at baseline included Trail Making Tests A/B, a modified Rey-Osterreith Complex Figure, California or Hopkins Verbal Learning Test, Digit Span, and Controlled Oral Word Association. DVH analysis was performed for multiple neuroanatomical targets considered to be involved in cognition. The %v10 (percent of ROI receiving 10 Gy), %v40, and %v60 were calculated for each ROI. Factor analysis was used to estimate global cognition based on a summary of performance on individual cognitive tests. Stepwise regression was used to determine which dose volume predicted performance on global factors and individual neurocognitive tests for each ROI. RESULTS: Regions that predicted global cognitive outcomes at doses <60 Gy included the corpus callosum, left frontal white matter, right temporal lobe, bilateral hippocampi, subventricular zone, and cerebellum. Regions of adult neurogenesis primarily predicted cognition at %v40 except for the right hippocampus which predicted at %v10. Regions that did not predict global cognitive outcomes at any dose include total brain volume, frontal pole, anterior cingulate, right frontal white matter, and the right precentral gyrus. CONCLUSIONS: Modeling of radiation-induced cognitive decline using neuroanatomical target theory appears to be feasible. A prospective trial is necessary to validate these data.

Molecular pathways: radiation-induced cognitive impairment.

Each year, approximately 200,000 patients in the United States will receive partial- or whole-brain irradiation for the treatment of primary or metastatic brain cancer. Early and delayed radiation effects are transient and reversible with modern therapeutic standards; yet, late radiation effects (≥6 months postirradiation) remain a significant risk, resulting in progressive cognitive impairment. These risks include functional deficits in memory, attention, and executive function that severely affect the patient's quality of life. The mechanisms underlying radiation-induced cognitive impairment remain ill defined. Classically, radiation-induced alterations in vascular and neuroinflammatory glial cell clonogenic populations were hypothesized to be responsible for radiation-induced brain injury. Recently, preclinical studies have focused on the hippocampus, one of two sites of adult neurogenesis within the brain, which plays an important role in learning and memory. Radiation ablates hippocampal neurogenesis, alters neuronal function, and induces neuroinflammation. Neuronal stem cells implanted into the hippocampus prevent the decrease in neurogenesis and improve cognition after irradiation. Clinically prescribed drugs, including PPARα and PPARγ agonists, as well as RAS blockers, prevent radiation-induced neuroinflammation and cognitive impairment independent of improved neurogenesis. Translating these exciting findings to the clinic offers the promise of improving the quality of life of brain tumor patients who receive radiotherapy.

Behavioral paradigms to evaluate PPAR modulation in animal models of brain injury.

The use of behavioral testing has become an invaluable tool for assessing the efficacy of therapeutics for a variety of disorders of the central nervous system. This chapter will describe in detail several behavioral paradigms to evaluate the efficacy of PPAR agonists to modulate cognitive impairments in rodent models. When used together as a battery these procedures allow for a global assessment of cognition. These tests are explained in detail below, and include: (1) Novel Object Recognition (NOR), (2) Morris Water Maze (MWM), (3) Delay Match to Place (DMP), and (4) Cue Strategy.

Radiation-induced cognitive impairment--from bench to bedside.

Approximately 100,000 patients per year in the United States with primary and metastatic brain tumor survive long enough (>6 months) to develop radiation-induced brain injury. Before 1970, the human brain was thought to be radioresistant; the acute central nervous system (CNS) syndrome occurs after single doses of ≥ 30 Gy, and white matter necrosis can occur at fractionated doses of ≥ 60 Gy. Although white matter necrosis is uncommon with modern radiation therapy techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become increasingly important, having profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenic mechanisms involved in radiation-induced cognitive impairment. Although reductions in hippocampal neurogenesis and hippocampal-dependent cognitive function have been observed in rodent models, it is important to recognize that other brain regions are affected; non-hippocampal-dependent reductions in cognitive function occur. Neuroinflammation is viewed as playing a major role in radiation-induced cognitive impairment. During the past 5 years, several preclinical studies have demonstrated that interventional therapies aimed at modulating neuroinflammation can prevent/ameliorate radiation-induced cognitive impairment independent of changes in neurogenesis. Translating these exciting preclinical findings to the clinic offers the promise of improving the quality of life in patients with brain tumors who receive radiation therapy.

Radiation-induced brain injury: A review.

Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their integration at clinically relevant doses and schedules. Recently developed techniques in neuroscience and neuroimaging provide not only an opportunity to accomplish this, but they also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects.

Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment.

We hypothesized that chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, to young adult male rats would prevent/ameliorate fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Eighty 12-14-week-old young adult male Fischer 344 rats received either: (1) sham irradiation, (2) 40 Gy of fractionated whole-brain irradiation delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation plus continuous administration of 15 mg/L of ramipril in the drinking water starting 3 days before irradiation, or (4) fractionated whole-brain irradiation plus ramipril. Cognitive function was assessed using a perirhinal cortex-dependent version of the novel object recognition task 26 weeks after irradiation. Microglial activation was determined in the perirhinal cortex and the dentate gyrus of the hippocampus 28 weeks after irradiation using the ED1 antibody. Neurogenesis was assessed in the granular cell layer and subgranular zones of the dentate gyrus using a doublecortin antibody. Fractionated whole-brain irradiation led to: (1) a significant impairment in perirhinal cortex-dependent cognitive function, (2) a significant increase in activated microglia in the dentate gyrus but not in the perirhinal cortex, and (3) a significant decrease in neurogenesis. Continuous administration of ramipril before, during, and after irradiation prevented the fractionated whole-brain irradiation-induced changes in perirhinal cortex-dependent cognitive function, as well as in microglial activation in the dentate gyrus. Thus, as hypothesized, continuous administration of the angiotensin-converting enzyme inhibitor, ramipril, can prevent the fractionated whole-brain irradiation-induced impairment in perirhinal cortex-dependent cognitive function.