Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR Study.

PURPOSE: Radiation dose received by the neural stem cells of the hippocampus during whole-brain radiotherapy has been associated with neurocognitive decline. The key concern using hippocampal avoidance-prophylactic cranial irradiation (HA-PCI) in patients with small-cell lung cancer (SCLC) is the incidence of brain metastasis within the hippocampal avoidance zone. METHODS: This phase III trial enrolled 150 patients with SCLC (71.3% with limited disease) to standard prophylactic cranial irradiation (PCI; 25 Gy in 10 fractions) or HA-PCI. The primary objective was the delayed free recall (DFR) on the Free and Cued Selective Reminding Test (FCSRT) at 3 months; a decrease of 3 points or greater from baseline was considered a decline. Secondary end points included other FCSRT scores, quality of life (QoL), evaluation of the incidence and location of brain metastases, and overall survival (OS). Data were recorded at baseline, and 3, 6, 12, and 24 months after PCI. RESULTS: Participants' baseline characteristics were well balanced between the two groups. The median follow-up time for living patients was 40.4 months. Decline on DFR from baseline to 3 months was lower in the HA-PCI arm (5.8%) compared with the PCI arm (23.5%; odds ratio, 5; 95% CI, 1.57 to 15.86; P = .003). Analysis of all FCSRT scores showed a decline on the total recall (TR; 8.7% v 20.6%) at 3 months; DFR (11.1% v 33.3%), TR (20.3% v 38.9%), and total free recall (14.8% v 31.5%) at 6 months, and TR (14.2% v 47.6%) at 24 months. The incidence of brain metastases, OS, and QoL were not significantly different. CONCLUSION: Sparing the hippocampus during PCI better preserves cognitive function in patients with SCLC. No differences were observed with regard to brain failure, OS, and QoL compared with standard PCI.

Theta-modulated oscillatory transcranial direct current stimulation over posterior parietal cortex improves associative memory.

Associative memory (AM) reflects the ability to remember and retrieve multiple pieces of information bound together thus enabling complex episodic experiences. Despite growing interest in the use of transcranial direct current stimulation (tDCS) for the modulation of AM, there are inconsistent evidence regarding its benefits. An alternative to standard constant tDCS could be the application of frequency-modulated tDCS protocols, that mimic natural function-relevant brain rhythms. Here, we show the effects of anodal tDCS oscillating in theta rhythm (5 Hz; 1.5 ± 0.1 mA) versus constant anodal tDCS and sham over left posterior parietal cortex on cued recall of face-word associations. In a crossover design, each participant completed AM assessment immediately following 20-min theta-oscillatory, constant, and sham tDCS, as well as 1 and 5 days after. Theta oscillatory tDCS increased initial AM performance in comparison to sham, and so did constant tDCS. On the group level, no differences between oscillatory and constant tDCS were observed, but individual-level analysis revealed that some participants responded to theta-oscillatory but not to constant tDCS, and vice versa, which could be attributed to their different physiological modes of action. This study shows the potential of oscillatory tDCS protocols for memory enhancement to produce strong and reliable memory-modulating effects which deserve to be investigated further.

Red LED light treatment promotes cognitive learning through up-regulation of trpm4 in zebrafish.

Although light emitting diodes (LEDs) are widely used in our daily lives, there is little research regarding LED light's possible effects on biological functions. We used a zebrafish animal model to investigate the long-term effects of white, blue and red LED lights on cognitive learning and memory recall. Our data suggest that these treatments had not only an impact on learning but also surprisingly long-lasting effects, particularly with regard to individuals treated with red light. The qPCR results revealed that the expression levels of trpm4, trpa1b, grin2aa and dlg4 in the skin were increased after monochromatic light treatment. Furthermore, the up-regulation of trpm4 in the brain may correlate to enhanced learning and memory following red-light treatment. Our results identify a light-based stimulation system for enhancing zebrafish learning, which has the potential to provide important insights into the relationship between LED lighting and animal behaviour.

Quantitative Imaging Biomarkers of Damage to Critical Memory Regions Are Associated With Post-Radiation Therapy Memory Performance in Brain Tumor Patients.

PURPOSE: We used quantitative magnetic resonance imaging to prospectively analyze the association between microstructural damage to memory-associated structures within the medial temporal lobe and longitudinal memory performance after brain radiation therapy (RT). METHODS AND MATERIALS: Patients with a primary brain tumor receiving fractionated brain RT were enrolled on a prospective trial (n = 27). Patients underwent high-resolution volumetric brain magnetic resonance imaging, diffusion-weighted imaging, and neurocognitive testing before and 3, 6, and 12 months post-RT. Medial temporal lobe regions (hippocampus; entorhinal, parahippocampal, and temporal pole white matter [WM]) were autosegmented, quantifying volume and diffusion biomarkers of WM integrity (mean diffusivity [MD]; fractional anisotropy [FA]). Reliable change indices measured changes in verbal (Hopkins Verbal Learning Test-Revised) and visuospatial (Brief Visuospatial Memory Test-Revised [BVMT-R]) memory. Linear mixed-effects models assessed longitudinal associations between imaging parameters and memory. RESULTS: Visuospatial memory significantly declined at 6 months post-RT (mean reliable change indices, -1.3; P = .012). Concurrent chemotherapy and seizures trended toward a significant association with greater decline in visuospatial memory (P = .053 and P = .054, respectively). Higher mean dose to the left temporal pole WM was significantly associated with decreased FA (r = -0.667; P = .002). Over all time points, smaller right hippocampal volume (P = .021), lower right entorhinal FA (P = .023), greater right entorhinal MD (P = .047), and greater temporal pole MD (BVMT-R total recall, P = .003; BVMT-R delayed recall, P = .042) were associated with worse visuospatial memory. The interaction between right entorhinal MD (BVMT-R total recall, P = .021; BVMT-R delayed recall, P = .004) and temporal pole FA (BVMT-R delayed recall, P = .024) significantly predicted visuospatial memory performance. CONCLUSIONS: Brain tumor patients exhibited visuospatial memory decline post-RT. Microstructural damage to critical memory regions, including the hippocampus and medial temporal lobe WM, were associated with post-RT memory decline. The integrity of medial temporal lobe structures is critical to memory performance post-RT, representing possible avoidance targets for memory preservation.

Association between hippocampal dose and memory in survivors of childhood or adolescent low-grade glioma: a 10-year neurocognitive longitudinal study.

BACKGROUND: Hippocampal avoidance has been suggested as a strategy to reduce short-term memory decline in adults receiving whole-brain radiation therapy (RT). The purpose of this study was to determine whether the hippocampal dose in children and adolescents undergoing RT for low-grade glioma was associated with memory, as measured by verbal recall. METHODS: Eighty patients aged at least 6 years but less than 21 years with low-grade glioma were treated with RT to 54 Gy on a phase II protocol. Patients underwent age-appropriate cognitive testing at baseline, 6 months posttreatment, yearly through 5 years posttreatment, year 7 or 8, and year 10 posttreatment. Random coefficient models were used to estimate the longitudinal trends in cognitive assessment scores. RESULTS: Median neurocognitive follow-up was 9.8 years. There was a significant decline in short-delay recall (slope = -0.01 standard deviation [SD]/year, P < 0.001), total recall (slope = -0.09 SD/y, P = 0.005), and long-delay recall (slope = -0.01 SD/y, P = 0.002). On multivariate regression, after accounting for hydrocephalus, decline in short-delay recall was associated with the volume of right (slope = -0.001 SD/y, P = 0.019) or left hippocampus (slope = -0.001 SD/y, P = 0.025) receiving 40 Gy (V40 Gy). On univariate regression, decline in total recall was only associated with right hippocampal dosimetry (V40 Gy slope = -0.002, P = 0.025). In children <12 years, on univariate regression, decline in long-delay recall was only associated with right (V40 Gy slope = -0.002, P = 0.013) and left (V40 Gy slope = -0.002, P = 0.014) hippocampal dosimetry. CONCLUSION: In this 10-year longitudinal study, greater hippocampal dose was associated with a greater decline in delayed recall. Such findings might be informative for radiation therapy planning, warranting prospective evaluation.

Impaired Recent, but Preserved Remote, Autobiographical Memory in Pediatric Brain Tumor Patients.

Medulloblastomas, the most common malignant brain tumor in children, are typically treated with radiotherapy. Refinement of this treatment has greatly improved survival rates in this patient population. However, radiotherapy also profoundly affects the developing brain and is associated with reduced hippocampal volume and blunted hippocampal neurogenesis. Such hippocampal (as well as extrahippocampal) abnormalities likely contribute to cognitive impairments in this population. While several aspects of memory have been examined in this population, the impact of radiotherapy on autobiographical memory has not previously been evaluated. Here we evaluated autobiographical memory in male and female patients who received radiotherapy for posterior fossa tumors (PFTs), including medulloblastoma, during childhood. Using the Children's Autobiographical Interview, we retrospectively assessed episodic and nonepisodic details for events that either preceded (i.e., remote) or followed (i.e., recent) treatment. For post-treatment events, PFT patients reported fewer episodic details compared with control subjects. For pretreatment events, PFT patients reported equivalent episodic details compared with control subjects. In a range of conditions associated with reduced hippocampal volume (including medial temporal lobe amnesia, mild cognitive impairment, Alzheimer's disease, temporal lobe epilepsy, transient epileptic amnesia, frontal temporal dementia, traumatic brain injury, encephalitis, and aging), loss of episodic details (even in remote memories) accompanies hippocampal volume loss. It is therefore surprising that pretreatment episodic memories in PFT patients with reduced hippocampal volume are retained. We discuss these findings in light of the anterograde and retrograde impact on memory of experimentally suppressing hippocampal neurogenesis in rodents.SIGNIFICANCE STATEMENT Pediatric medulloblastoma survivors develop cognitive dysfunction following cranial radiotherapy treatment. We report that radiotherapy treatment impairs the ability to form new autobiographical memories, but spares preoperatively acquired autobiographical memories. Reductions in hippocampal volume and cortical volume in regions of the recollection network appear to contribute to this pattern of preserved preoperative, but impaired postoperative, memory. These findings have significant implications for understanding disrupted mnemonic processing in the medial temporal lobe memory system and in the broader recollection network, which are inadvertently affected by standard treatment methods for medulloblastoma tumors in children.

Physical activity as an option to reduce adverse effect of EMF exposure during pregnancy.

The popularity of using wireless fidelity over the last decades increased apprehensions about impact of high frequency electromagnetic fields (EMF) on health. Most of previous studies mentioned adverse effect of EMF on cognitive processes, but so far, no study has provided a way to control adverse effects of EMF exposure. The purpose of this study was to examine the effect of Wi-Fi EMF and physical activity on spatial learning and motor function in pregnant rat's offspring. Forty Albino-Wistar pregnant rats divided randomly into four groups (EMF, physical activity, combined 2.4GHZ EMF and physical activity and control groups). For assessing spatial learning in 56 post-natal days' old (PND) male offspring, Morris Water Maze (MWM) was used and to examine motor function Open-field test was taken. Although results of MWM test revealed that Wi-Fi modem EMF caused impairment in spatial learning in rats exposed to EMF but physical activity could reduce negative effect of EMF in pregnant rat's offspring who exposed during pregnancy but performed swimming. In addition, results of open-field test showed that litter's motor function in EMF group significantly declined in comparison with physical activity and combined 2.4GHZ EMF and physical activity groups. According to our findings, it can be concluded that execution physical activity individually or along with wave-exposed pregnancy can significantly progressive effect on offspring' cognitive and motor functions.

Cortisol disrupts the neural correlates of extinction recall.

The renewal effect describes the recovery of extinguished responses that may occur after a change in context and indicates that extinction memory retrieval is sometimes prone to failure. Stress hormones have been implicated to modulate extinction processes, with mostly impairing effects on extinction retrieval. However, the neurobiological mechanisms mediating stress effects on extinction memory remain elusive. In this functional magnetic resonance imaging study, we investigated the effects of cortisol administration on the neural correlates of extinction memory retrieval in a predictive learning task. In this task, participants were required to predict whether certain food stimuli were associated with stomach trouble when presented in two different contexts. A two-day renewal paradigm was applied in which an association was acquired in context A and subsequently extinguished in context B. On the following day, participants received either cortisol or placebo 40min before extinction memory retrieval was tested in both contexts. Behaviorally, cortisol impaired the retrieval of extinguished associations when presented in the extinction context. On the neural level, this effect was characterized by a reduced context differentiation for the extinguished stimulus in the ventromedial prefrontal cortex, but only in men. In the placebo group, ventromedial prefrontal cortex was functionally connected to the left cerebellum, the anterior cingulate and the right anterior parahippocampal gyrus to express extinction memory. This functional crosstalk was reduced under cortisol. These findings illustrate that the stress hormone cortisol disrupts ventromedial prefrontal cortex functioning and its communication with other brain regions implicated in extinction memory.

Visual associations cued recall A Paradigm for Measuring Episodic Memory Decline in Alzheimer's Disease.

Repeated measurements of episodic memory are needed for monitoring amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD). Most episodic memory tests may pose a challenge to patients, even when they are in the milder stages of the disease. This cross-sectional study compared floor effects of the Visual Association Test (VAT) and the Rey Auditory Verbal Learning Test (RAVLT) in healthy elderly controls and in patients with aMCI or AD (N = 125). A hierarchical multiple regression analysis was used to examine whether linear or quadratic trends best fitted the data of cognitive test performance across global cognitive impairment. Results showed that VAT total scores decreased linearly across the range of global cognitive impairment, whereas RAVLT total scores showed a quadratic trend, with total scores levelling off for 90% of aMCI patients and 94% of AD patients. We conclude that the VAT shows few if any floor effects in patients with aMCI and mild AD and is therefore a potentially promising cognitive test for monitoring episodic memory impairment.

CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933.

Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests' completion rates were 52-53 % at 2 months and 34-42 % at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p ≤ 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p ≤ 0.01). At 4 months, mean relative decline was 7.0 % for HVLT-R Delayed Recall and 18.0 % for ISLT Delayed Recall. OCLT showed an 8.0 % increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z = -0.40, p = 0.34; z = -0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials.

Neuropsychological Testing in Interventional Cardiology Staff after Long-Term Exposure to Ionizing Radiation.

This study aimed at comparing neuropsychological test scores in 83 cardiologists and nurses (exposed group, EG) working in the cardiac catheterization laboratory, and 83 control participants (non exposed group, nEG), to explore possible cognitive impairments. The neuropsychological assessment was carried out by means of a battery called "Esame Neuropsicologico Breve." EG participants showed significantly lower scores on the delayed recall, visual short-term memory, and semantic lexical access ability than the nEG ones. No dose response could be detected. EG participants showed lower memory and verbal fluency performances, as compared with nEG. These reduced skills suggest alterations of some left hemisphere structures that are more exposed to IR in interventional cardiology staff. On the basis of these findings, therefore, head protection would be a mandatory good practice to reduce effects of head exposure to ionizing radiation among invasive cardiology personnel (and among other exposed professionals).

Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial.

PURPOSE: Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance. PATIENTS AND METHODS: Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function and quality-of-life (QOL) assessments were performed at baseline and 2, 4, and 6 months. The primary end point was the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) at 4 months. The historical control demonstrated a 30% mean relative decline in HVLT-R DR from baseline to 4 months. To detect a mean relative decline ≤ 15% in HVLT-R DR after HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with α = 0.05. RESULTS: Of 113 patients accrued from March 2011 through November 2012, 42 patients were analyzable at 4 months. Mean relative decline in HVLT-R DR from baseline to 4 months was 7.0% (95% CI, -4.7% to 18.7%), significantly lower in comparison with the historical control (P < .001). No decline in QOL scores was observed. Two grade 3 toxicities and no grade 4 to 5 toxicities were reported. Median survival was 6.8 months. CONCLUSION: Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series.

Please silence your cell phone: Your ringtone captures other people's attention.

Ringtones are designed to draw attention away from on-going activities. In the present study, it was investigated whether the disruptive effects of a ringing cell phone on short-term memory are inevitable or become smaller as a function of exposure and whether (self-) relevance plays a role. Participants performed a serial recall task either in silence or while task-irrelevant ringtones were presented. Performance was worse when a ringing phone had to be ignored, but gradually recovered compared with the quiet control condition with repeated presentation of the distractor sound. Whether the participant's own ringtone was played or that of a yoked-control partner did not affect performance and habituation rate. The results offer insight into auditory distraction by highly attention-demanding distractors and recovery therefrom. Implications for work environments and other applied settings are discussed.

Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors.

PURPOSE: To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT). METHODS AND MATERIALS: Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval. NCF impairment was defined as a z score ≤-1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose-volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD(2)) assuming an α/ß ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose-response data were fit to a nonlinear model. RESULTS: Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD(2) to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD(2) to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). CONCLUSION: EQD(2) to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results.

Transcranial infrared laser stimulation produces beneficial cognitive and emotional effects in humans.

This is the first controlled study demonstrating the beneficial effects of transcranial laser stimulation on cognitive and emotional functions in humans. Photobiomodulation with red to near-infrared light is a novel intervention shown to regulate neuronal function in cell cultures, animal models, and clinical conditions. Light that intersects with the absorption spectrum of cytochrome oxidase was applied to the forehead of healthy volunteers using the laser diode CG-5000, which maximizes tissue penetration and has been used in humans for other indications. We tested whether low-level laser stimulation produces beneficial effects on frontal cortex measures of attention, memory and mood. Reaction time in a sustained-attention psychomotor vigilance task (PVT) was significantly improved in the treated (n=20) vs. placebo control (n=20) groups, especially in high novelty-seeking subjects. Performance in a delayed match-to-sample (DMS) memory task showed also a significant improvement in treated vs. control groups as measured by memory retrieval latency and number of correct trials. The Positive and Negative Affect Schedule (PANAS-X), which tracks self-reported positive and negative affective (emotional) states over time, was administered immediately before treatment and 2 weeks after treatment. The PANAS showed that while participants generally reported more positive affective states than negative, overall affect improved significantly in the treated group due to more sustained positive emotional states as compared to the placebo control group. These data imply that transcranial laser stimulation could be used as a non-invasive and efficacious approach to increase brain functions such as those related to cognitive and emotional dimensions. Transcranial infrared laser stimulation has also been proven to be safe and successful at improving neurological outcome in humans in controlled clinical trials of stroke. This innovative approach could lead to the development of non-invasive, performance-enhancing interventions in healthy humans and in those in need of neuropsychological rehabilitation.