Prevalence of psychosocial distress in cancer patients across 55 North American cancer centers.

Routine distress screening in United States oncology clinics has been mandatory since 2015. OBJECTIVE: This study was the first to assess distress in a geographically diverse sample of cancer patients following mandated distress screening implementation by oncology social workers. METHODS: Sites were self-selected via social workers who applied to participate in the Association of Oncology Social Work's Project to Assure Quality Cancer Care, advertised through their social media outlets and conference. Electronic screening records were collected from 55 cancer treatment centers in the United States and Canada. Cases required cancer diagnoses and Distress Thermometer (DT) scores to be included. Distress rates and rates by age, sex, cancer type, and ethnicity were examined. RESULTS: Of 4664 cases, 46% (2157) experienced significant distress (DT score ≥ 4). Being female, age 40-59, and having diagnoses of pancreatic or lung cancer was associated with increased likelihood of distress. Half of cases experience clinically-significant distress, though this need was not evenly distributed across patient or cancer types. CONCLUSION: Identifying those at risk for distress may help inform optimal resource allocation. Methods to address needs of distressed patients in cases of limited resources are discussed.

Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment.

Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12-18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery-standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning. Both humans and mice had large increases in chemokines for myeloid cell recruitment. Intravital imaging of the brains of septic mice revealed increased neutrophil and CCR2+ inflammatory monocyte recruitment (the latter being far more robust), accompanied by subtle microglial activation. Prevention of CCR2+ inflammatory monocyte recruitment, but not neutrophil recruitment, reduced microglial activation and other signs of neuroinflammation and prevented all signs of cognitive impairment after infection. Therefore, therapeutically targeting CCR2+ inflammatory monocytes at the time of sepsis may provide a novel neuroprotective clinical intervention to prevent the development of persistent cognitive impairments.

Protocol for the MATCH study (Mindfulness and Tai Chi for cancer health): A preference-based multi-site randomized comparative effectiveness trial (CET) of Mindfulness-Based Cancer Recovery (MBCR) vs. Tai Chi/Qigong (TCQ) for cancer survivors.

PURPOSE: A growing number of cancer survivors suffer high levels of distress, depression and stress, as well as sleep disturbance, pain and fatigue. Two different mind-body interventions helpful for treating these problems are Mindfulness-Based Cancer Recovery (MBCR) and Tai Chi/Qigong (TCQ). However, while both interventions show efficacy compared to usual care, they have never been evaluated in the same study or directly compared. This study will be the first to incorporate innovative design features including patient choice while evaluating two interventions to treat distressed cancer survivors. It will also allow for secondary analyses of which program best targets specific symptoms in particular groups of survivors, based on preferences and baseline characteristics. METHODS AND SIGNIFICANCE: The design is a preference-based multi-site randomized comparative effectiveness trial. Participants (N=600) with a preference for either MBCR or TCQ will receive their preferred intervention; while those without a preference will be randomized into either intervention. Further, within the preference and non-preference groups, participants will be randomized into immediate intervention or wait-list control. Total mood disturbance on the Profile of mood states (POMS) post-intervention is the primary outcome. Other measures taken pre- and post-intervention and at 6-month follow-up include quality of life, psychological functioning, cancer-related symptoms and physical functioning. Exploratory analyses investigate biomarkers (cortisol, cytokines, blood pressure/Heart Rate Variability, telomere length, gene expression), which may uncover potentially important effects on key biological regulatory and antineoplastic functions. Health economic measures will determine potential savings to the health system.

Heterarchic reinstatement of long-term memory: A concept on hippocampal amnesia in rodent memory research.

Evidence from clinical and animal research highlights the role of the hippocampus in long-term memory (LTM). Decades of experimental work have produced numerous theoretical accounts of the hippocampus in LTM, and each suggests that hippocampal disruption produces amnesia for specific categories of memory. These accounts also imply that hippocampal disruption before or soon after a learning episode should have equivalent amnestic effects. Recent evidence from lesion and inactivation experiments in rodents illustrates that hippocampal disruption after a learning episode causes memory impairment in a wider range of memory tasks than if the same disruption occurs before learning. Although this finding supports that multiple circuits can acquire and retrieve similar information, it also suggests they do not do so independently. In addition, damage after learning produces amnesia for simple elements of a task as well as complex, conjunctive features. Here we develop an explanation for why anterograde and retrograde hippocampal effects differ. This explanation, the heterarchic reinstatement view, also generates novel predictions.

Epigenetic alterations in the suprachiasmatic nucleus and hippocampus contribute to age-related cognitive decline.

Circadian rhythm dysfunction and cognitive decline, specifically memory loss, frequently accompany natural aging. Circadian rhythms and memory are intertwined, as circadian rhythms influence memory formation and recall in young and old rodents. Although, the precise relationship between circadian rhythms and memory is still largely unknown, it is hypothesized that circadian rhythm disruption, which occurs during aging, contributes to age-associated cognitive decline, specifically memory loss. While there are a variety of mechanisms that could mediate this effect, changes in the epigenome that occur during aging has been proposed as a potential candidate. Interestingly, epigenetic mechanisms, such as DNA methylation and sirtuin1 (SIRT1) are necessary for both circadian rhythms and memory. During aging, similar alterations of epigenetic mechanisms occur in the suprachiasmatic nucleus (SCN) and hippocampus, which are necessary for circadian rhythm generation and memory, respectively. Recently, circadian rhythms have been linked to epigenetic function in the hippocampus, as some of these epigenetic mechanisms oscillate in the hippocampus and are disrupted by clock gene deletion. The current paper will review how circadian rhythms and memory change with age, and will suggest how epigenetic changes in these processes might contribute to age-related cognitive decline.

The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body.

This review consolidates research employing human correlational and experimental work across brain and body with experimental animal models to provide a more complete representation of how circadian rhythms influence almost all aspects of life. In doing so, we will cover the morphological and biochemical pathways responsible for rhythm generation as well as interactions between these systems and others (e.g., stress, feeding, reproduction). The effects of circadian disruption on the health of humans, including time of day effects, cognitive sequelae, dementia, Alzheimer's disease, diet, obesity, food preferences, mood disorders, and cancer will also be discussed. Subsequently, experimental support for these largely correlational human studies conducted in non-human animal models will be described.

Persistent impairments in hippocampal function following a brief series of photoperiod shifts in rats.

The impact of an acute circadian disruption on learning and memory in male and female rats was examined. Circadian disruption was elicited using a brief series of photoperiod shifts. Previous research using male rats showed that acute circadian disruption during acquisition of a spatial navigation task impaired long-term retention and that chronic circadian disruption impaired acquisition of the same task. However, the long-term effects of acute circadian disruption following circadian re-entrainment and whether sex differences in response to circadian disruption exist are still unknown. For the present study, rats were trained on the standard, spatial version of the Morris water task (MWT) and a visual discrimination task developed for the eight-arm radial maze. After reaching asymptotic performance, behavioural training was terminated and the experimental group experienced a series of photoperiod shifts followed by circadian re-entrainment. Following circadian re-entrainment, the subjects were given retention tests on the MWT and visual discrimination task. Following retention testing, an extra-dimensional shift using the eight-arm radial maze was also performed. An acute episode of circadian disruption elicited via photoperiod shifts negatively impacted retention of spatial memory in male and female rats. Retention of the visual discrimination task and the ability to detect extra-dimensional shifts were not impaired. The observed impairments on the MWT indicate that hippocampal representations are susceptible to a small number of photoperiod shifts even if the association is acquired prior to rhythm manipulation and retention is assessed following rhythm stabilization. Effects were limited to a hippocampus-dependent task, indicating that impairments are specific, not global.

Multiple effects of circadian dysfunction induced by photoperiod shifts: alterations in context memory and food metabolism in the same subjects.

Humans exposed to shiftwork conditions have been reported to have increased susceptibility to various health problems including various forms of dementia, cancer, heart disease, and metabolic disorders related to obesity. The present experiments assessed the effects of circadian disruption on learning and memory function and various food related processes including diet consumption rates, food metabolism, and changes in body weight. These experiments utilized a novel variant of the conditioned place preference task (CPP) that is normally used to assess Pavlovian associative learning and memory processes produced via repeated context-reward pairings. For the present experiments, the standard CPP paradigm was modified in that both contexts were paired with food, but the dietary constituents of the food were different. In particular, we were interested in whether rats could differentiate between two types of carbohydrates, simple (dextrose) and complex (starch). Consumption rates for each type of carbohydrate were measured throughout training. A test of context preference without the food present was also conducted. At the end of behavioral testing, a fasting glucose test and a glucose challenge test were administered. Chronic photoperiod shifting resulted in impaired context learning and memory processes thought to be mediated by a neural circuit centered on the hippocampus. The results also showed that preferences for the different carbohydrate diets were altered in rats experiencing photoperiod shifting in that they maintained an initial preference for the simple carbohydrate throughout training. Lastly, photoperiod shifting resulted in changes in fasting blood glucose levels and elicited weight gain. These results show that chronic photoperiod shifting, which likely resulted in circadian dysfunction, impairs multiple functions of the brain and/or body in the same individual.

Persistent impairments in hippocampal, dorsal striatal, and prefrontal cortical function following repeated photoperiod shifts in rats.

Cognitive impairments are observed when learned associations are being acquired or retrieved during a period of circadian disruption. However, the extent of the functional impacts on previously acquired associations following circadian rhythm re-entrainment is unknown. The impacts of repeated photoperiod shifts on learning and memory in male and female rats were examined. For these experiments, rats were trained on a spatial version of the Morris water task (MWT) and a visual discrimination task designed for the 8-arm radial maze. Following asymptotic performance on these tasks, rats experienced a repeating photoperiod shift procedure and were then re-entrained. Following circadian re-entrainment, retention of pre-photoperiod-shift-acquired associations was tested. In addition, an extra-dimensional set shift was performed using the 8-arm radial maze. Impaired retention of the MWT platform location was observed in photoperiod-shifted subjects relative to subjects with stable, unmanipulated photoperiods. Repeated photoperiod shifts negatively impacted retention in males and females compared with subjects with stable photoperiods. Retention and the ability to detect extra-dimensional shifts on the visual discrimination task were also impaired, though not consistently by sex or photoperiod condition. Running wheel availability was also included in the analyses to determine whether exercise influenced the effects of photoperiod shifting. The absence of a running wheel produced significant declines in memory retention on both MWT and the visual discrimination task, but only for male rats. The observed impairments indicate that multiple neural systems supporting different learning and memory functions are susceptible to circadian disruption, even if the association is acquired prior to rhythm fragmentation and tested following rhythm re-entrainment.

Expression of a conditioned place preference or spatial navigation task following muscimol-induced inactivations of the amygdala or dorsal hippocampus: A double dissociation in the retrograde direction.

Previous work indicates an essential role of the basolateral amygdala in stimulus-reward learning and the dorsal hippocampus in spatial learning and memory. The goal of the present, experiments was to examine the involvement of the amygdala and hippocampus in performance of tasks requiring stimulus-reward and spatial/relational learning and memory processes in the retrograde direction. Accordingly, this series of experiments tested the effects of temporary, inactivations directed at the basolateral nucleus of the amygdala or dorsal hippocampus on the, expression of a conditioned place preference (CPP) task or a spatial navigation water task. The results, of Experiments 1a and b showed that inactivations of the amygdala impaired the expression of a, previously acquired CPP but did not impair the expression of a learned spatial response required for, accurate performance of a spatial navigation task. The results of Experiments 2a and b showed that, inactivations of the dorsal hippocampus impaired expression of a learned response required for the, accurate performance of a spatial navigation task but did not impair the learned response required for, the expression of a CPP. Taken together, the results showed a functional dissociation between the, effects of amygdala or hippocampal dysfunction on the expression of these different classes of tasks.

Prefrontal cortical contributions during discriminative fear conditioning, extinction, and spontaneous recovery in rats.

This research examined the roles played by the ventromedial orbital prefrontal cortex (OPFC) and the infralimbic/prelimbic prefrontal cortex (I/P PFC) during discriminative fear conditioning. The first experiment included nine rats with bilateral lesions to the I/P PFC, an additional nine with OPFC lesions, and eight sham lesion controls. Behavioural analysis was conducted using a discriminative fear conditioning to context task 10 days after surgery. Results indicate that lesions to ventromedial orbital prefrontal cortex result in generalized fear and impaired extinction. In contrast, infralimbic/prelimbic cortical lesioned animals exhibit appropriate fear response patterns and extinction, but show a specific impairment in spontaneous recovery. To ascertain why I/P PFC lesion rats did not exhibit spontaneous recovery, a second experiment was conducted. All procedures in the second experiment were identical to the first except a decay period was employed in place of extinction training. Results from the second experiment indicate that the difficulty retrieving the extinguished association is related to extinction processes and not decay. Taken together, these findings suggest that OPFC and I/P PFC have distinct roles in associative processes necessary for discriminative fear conditioning, extinction, and spontaneous recovery. These results further implicate OPFC and I/P PFC in the pathology underlying generalized anxiety disorder.

A novel method for reliable nuclear antibody detection in tissue with high levels of pathology-induced autofluorescence.

Immunofluorescence is the basis for many techniques used to quantify phenomena in neuroscience research, in both normal and pathological tissue. Autofluorescence (non-specific, broad spectrum background fluorescence) is an unfortunate consequence of damage to brain tissue. Damage-induced autofluorescence potentially confounds analyses of tissue labeled with fluorescent markers in many experiments. This is especially problematic in protocols that utilize co-localization methods such as BrdU/NeuN in which autofluorescence might lead to overestimates of the number of double-labeled cells. Techniques to reduce autofluorescence are variable and relatively ineffective in damaged brain tissue. Here we show using confocal microscopy that damage-induced autofluorescence does not co-localize with the nuclear specific markers DAPI or Hoechst. Further co-localization of nuclear markers such as Ki67 or BrdU/NeuN with DAPI or Hoechst should serve to help discriminate between intended and spurious fluorescent signal.

A complex associative structure formed in the mammalian brain during acquisition of a simple visual discrimination task: dorsolateral striatum, amygdala, and hippocampus.

A review of empirical evidence supporting the multiple memory systems view of the organization of learning and memory in the mammalian brain is presented as a powerful component of a broader foundation of basic scientific information necessary for understanding human behavior. However, it is argued that there are significant gaps in our knowledge about these different learning and memory systems, how they interact with one another, and how they interact with the rest of the brain. To demonstrate how little we know about these complex processes, this article reviews recent evidence showing the complexity of associative structure formed during the acquisition of a simple visual discrimination task. The results show that the dorsolateral striatum is necessary for the acquisition of this task but that both the amygdala and hippocampus incidentally acquire and store information during this training period. A new experiment is also presented showing that rats with complete or partial (dorsal vs. ventral) hippocampal lesions show a retrograde amnesic effect on the simple visual discrimination task despite the fact that these same lesions produce no impairment in the anterograde direction. Evidence is presented in support of one interpretation of this effect suggesting that the retrograde amnesia occurs, at least in part, because the hippocampus acquires a context-specific inhibitory association during original training. Although this representation is not required for acquisition of the task in the anterograde direction, removal of this representation has a disruptive effect on expression of the task.