Electroencephalogram (EEG) biosignals are widely used to measure human emotional reactions. The recent progress of deep learning-based classification models has improved the accuracy of emotion recognition in EEG signals. We apply a deep learning-based emotion recognition model from EEG biosignals to prove that illustrated surgical images reduce the negative emotional reactions that the photographic surgical images generate. The strong negative emotional reactions caused by surgical images, which show the internal structure of the human body  act as an obstacle in explaining the images to patients or communicating with the images with non-professional people. We claim that the negative emotional reactions generated by illustrated surgical images are less severe than those caused by raw surgical images. To demonstrate the difference in emotional reaction, we produce several illustrated surgical images from photographs and measure the emotional reactions they engender using EEG biosignals; a deep learning-based emotion recognition model is applied to extract emotional reactions. Through this experiment, we show that the negative emotional reactions associated with photographic surgical images are much higher than those caused by illustrated versions of identical images. We further execute a self-assessed user survey to prove that the emotions recognized from EEG signals effectively represent user-annotated emotions. From the early days of brain science, many researchers have studied negative human emotions that come from surgical images showing blood, injection, and injury (BII). Usually, the negative emotion caused by surgical images is classified as fear and disgust. Even though emotional responses can be different according to the subject’s experience, knowledge, and personality, the emotional responses are located in close distances when mapped on widely used Russell’s emotional coordinate .Ordinary people rarely have the chance to view surgical images. However, there are certain situations in which people should carefully inspect surgical images. For example, when we or our family members face surgical operation, surgeons explain the process of the operation by showing surgical images. Even though we feel very negative emotions in response to the images, we still have to study them very carefully to understand the procedure. In cases such as this, the negative emotional response to surgical images can prevent people from understanding necessary surgical procedures.Some studies have tried to reduce impact of the image by simplifying the color of the images through image abstraction schemes ,3. They Even though several image abstraction algorithms such as ,5 have dWe argue that objective and quantitative strategies including biosignal-based methods are needed to confirm the hypothesis that illustrated surgical images can reduce negative emotional reactions. The cost of developing an automatic algorithm that produces illustrative representations of surgical images with preserving sufficient details would be surprisingly expensive; before deciding whether to develop such an algorithm, we need concrete evidence that supports our hypothesis. Among the various kinds of biosignals, the electroencephalogram (EEG) is very widely used to measure emotional responses. Recently, many deep learning-based methods employing EEG have been presented ,16,17,18We employ an EEG-based emotion recognition framework in order to present a quantitative measure of the difference in emotional reactions to illustrated surgical images and photographic surgical images. To this end, we employ professional scientific illustrators to produce illustrations of surgical images, and execute a user study with a deep learning-based emotion recognition model with EEG biosignals. Our study seeks to provide a confidence that the negative emotional reactions caused by surgical images can be reduced through abstraction via illustration.We employ two groups of participants who view photographic surgical images and illustrated surgical images, respectively. Their emotional responses are measured through an EEG capturing device and processed with a deep learning-based emotion recognition model. To show the effectiveness of the model, we additionally execute a nine-metric user survey for the participants, then compare those results with those of the model. From the results of this experiment, we suggest that the illustrated surgical images successfully reduce the negative emotional responses caused by their photographic counterparts.Many researchers have studied human emotional reactions on BII  scenes including body mutilation , surgicaSurgical images incur various human reactions including anxiety, fear, disgust, and vicarious pain ,32. AmonFrom the great success of AlexNet  and VGGNTang et al.  proposedSchirrmeister et al.  presenteLi et al.  presenteSalama et al.  presenteMoon et al.  applied Chiarelli et al.  presenteLawhern et al.  presenteCroce et al.  applied Yang et al.  proposedThe spatio-temporal aspect of EEG biosignals invites the use of a recurrent neural network (RNN), which is known as an effective model for processing time-serial data, to analyze EEG signals.Khosrowabadi et al.  presenteAlhagry et al.  presenteSoleymani et al.  employedXing et al.  presenteOur assumption is that the negative emotions caused by photographic surgical images would hinder non-professional people in understanding necessary information conveyed by the images. Since these people are not trained with surgical images, the negative emotions such as fear and disgust arise at their first glance of the images. To reduce negative emotion and to increase the understanding of the information conveyed by surgical images, anatomy textbooks tend to use illustrations, rather than photographs. From this point, we build our assumption that illustrated surgical images evoke less negative emotion from ordinary people than photographic surgical images.To prove our assumption, we chose 10 photographic surgical images and produced their illustrated versions by hiring professional scientific illustrators. The photographic surgical images and their illustrated counterparts are presented in From the ten pairs of photographic and illustrated surgical images, we hired 40 participants to record their emotional reactions to both photographic surgical images and illustrated images. To record their emotional reactions, we employed two different processes. One was the usage of EEG biosignals; the EEG signals captured from participants were processed through a deep multi-channel emotion recognition model  and quanThe 40 participants were randomly partitioned into two groups. The first group underwent the above processes for photographic surgical images, while the second worked with illustrated images. The results of these two groups are analyzed and discussed; the outline of this study is illustrated in In this section, we describe our deep emotion recognition model, which was presented in our previous study . Our modFor the training of our model, we employ the DEAP dataset , one of The DEAP dataset is constructed using the EEG signals captured from 32 participants. We segment the dataset into three groups: training, validation and test. Out of the 32, EEG signals from 22 participants are used for training, validation and the remaining 5 for test. Each participant executed 40 experiments. Therefore, the numbers of the EEG signal data for training, validation, and test are 880, 200, and 200, respectively.We implemented our emotion recognition model with Pytorch library on a machine with an Intel Core i7 CPU, 64 GB main memory, and nVidia GTX 2080TI GPU. We employed LiveAmp32 with LiveCap , which sWhile preparing our dataset of surgical images, we surveyed various open emotional image datasets including IAPS , GAPED , NAPS 4, CAPD 4, SMID 4, ISEE 4 and COMPFor user annotation of emotional responses, we presented participants with a nine-point metric separated into valence and arousal. They were asked to mark the metric for the photographic and illustrated surgical images they saw. The leftmost point means very negative reaction, which matches to For the experiment, we hired 40 participants and separated them into two groups: We have two research questions regarding our experiment.RQ1 Are emotional responses from illustrated surgical images discernably less negative than those from photographic surgical images?RQ2 Is our emotional recognition model reliable? In other words, is there sufficient evidence that the emotions recognized by our model resemble self-assessed ones?We have set up our null hypothesis for RQ1 as follows:t-test is executed between p values of this t-test are presented in p values in To answer RQ1, a t-test regarding the emotions estimated by EEG and the emotions annotated by users, leads us to answer RQ2. RQ2’s null hypothesis is:Another p values for this second t-test are presented in The d values for the pairs of the emotions. The formula for Cohen’s d  is suggested as follows:X and Y, respectively, and X and Y.We estimate the effect size by calculating Cohen’s d to measure the difference between the emotional reactions of photographic and illustrated surgical images in the following four combinations in (i)the valence estimated by EEG between photographic and illustrated surgical images,(ii)the arousal estimated by EEG between photographic and illustrated surgical images,(iii)the valence estimated by user-annotation between photographic and illustrated surgical images,(iv)the arousal estimated by user-annotation between photographic and illustrated surgical images.We estimate Cohen’s d values for these four matches are greater than 0.8, which denotes that the effect size is very large.The Cohen’s d to measure the difference between the emotions estimated by EEG and the emotions estimated by user-annotation in the following four combinations in (i)the valence for photographic surgical images estimated by EEG biosignal and user annotation,(ii)the arousal for photographic surgical images estimated by EEG biosignal and user annotation,(iii)the valence for illustrated surgical images estimated by EEG biosignal and user annotation,(iv)the arousal for illustrated surgical images estimated by EEG biosignal and user annotation.We also estimate Cohen’s d values for cases (i)∼(iii) are less than 0.23, which denotes that the effect size is small, and the d value for case (iv) implies there is relatively larger effect size. The reason case (iv) has a medium effect size can be described as similar to the reason results from the case (iv) in the prior t-test are more weakly related.The Cohen’s In the relevant literatures, many models, including conventional machine learning techniques or deep learning techniques, have been employed to estimate valence and arousal from EEG signal. According to , models Our experiment reveals that the valence estimated from illustrated surgical images is significantly higher than the valence from photographic surgical images. We assume that the unpleasant feelings from photographic blood and flesh are decreased by substituting the color of photographic blood and flesh with a similar color that has higher saturation or intensity. Classic artistic media, such as pencil or watercolor brush, produce similar effects. It is also notable to invoke the conclusion of the work of Yang et al’s work  that theThe change in valence in our study, however, is greater than that in . We assuOur result shows a decrease in arousal for the illustrated surgical images compared to the photographic surgical images. Since photographic surgical images are distinguished from other images, their engendered arousal is very great. The reason for the photographic surgical images showing higher arousal is reasoned to be that seeing flesh and blood usually occurs only in very frightening or alerting situations. The decrease in arousal for the illustrated images can be explained by the fact that the realistic colors of flesh and blood are converted to less threatening colors frequently seen in animations or cartoons. The simple and friendly color of the illustrated flesh and blood reduces the sense of actual alert or frightening, which results in the decrease of arousal.(1)Color transform of the illustrated images is reasonable. Replacing vivid colors such as red and violet by less vivid colors can help reducing negative reactions from the people who do not have an experience in the surgical images(2)In the illustrated versions, the reflections on the surface of organs are illustrated as a narrow spot with higher brightness (the yellow circles in (3)The blood vessels, which play important role in many diagnosis cases, are not illustrated in a consistent way. In some figures, they are preserved in a very salient way (the blue circles in We have asked a surgeon to evaluate the illustrated surgical images. The surgeon marked some regions of the photographic and illustrated surgical images and suggested the following opinions:As a conclusion, the surgeon suggested a positive answer for using the illustrated images to reduce negative emotional reactions from ordinary people. However, he suggested several points to improve for educational or professional purposes.The limitation of this study is that we have not taken into account the opinions of experts, such as surgeons or pathologists in producing the illustrative surgical images. Surgeons may provide productive insights in the illustration of surgical images, for example, which fine details are important and must be kept. They may also be able to suggest proper colors to replace the original colors of flesh and blood.This limitation of this study can be addressed in two points. Similar studies ,3 hired In this paper, we produced illustrated surgical images to prove their ability to reduce the negative emotional responses engendered by photographic surgical images. We executed emotion recognition processes on 40 participants to compare their emotional responses to photographic and illustrated surgical images. The emotional responses were estimated in a bi-modal approach: a deep learning-based emotion recognition model from EEG biosignals was combined with a 9-point metric user annotation. From the results, we conclude that illustrated surgical images indeed capable of reducing the negative emotions of participants.In our future research, we will study relevant methods to create appropriate illustrated images. We will consult with experts including surgeons and pathologists to enrich the illustration schemes on surgical images. We will also examine the illustrated surgical images from experts to improve the quality of the illustrations. These approaches will help developing an automatic algorithm for generating illustrated surgical images that satisfy both ordinary people and experts.


Daphnia (Crustacea) and categorize the factors, especially secondary ones, affecting intraspecific variations in inducible defense. Primary factors, such as predator type and density, determine the degree to which inducible defense expresses and increases or decreases. Secondary factors, on the other hand, act together with primary factors to inducible defense or without primary factors on inducible defense. The secondary factors increase intraspecies variation in inducible defense, and thus, the level of adaptation of organisms varies within species. Future research will explore the potential for new secondary factors, as well as the relative importance between factors needs to be clarified.Phenotypic variation among individuals and species is a fundamental principle of natural selection. In this review, we focus on numerous experiments involving the model species  We identified seven secondary factors causing variations in inducible defense based on previous studies: abiotic factors, ecological and evolutionary traps, food, alarm substance, clone/genotypes, instars, and maternal effect. The ability of a single genome to produce a range of phenotypes in response to environmental conditions is called phenotypic plasticity Agrawal, . In geneThe change in traits observed in phenotypic plasticity may not be binary (high and low) or represented by an on/off reaction but rather a continuous process in individuals  is an excellent model system for studying predator‐induced plasticity  and/or other factors besides predators; the former is called primary factor and the latter secondary factor  variation can have significant ecological effect  and quantitative  traits. Moreover, Daphnia express a combination of several unique, species‐specific defensive traits in response to chemical cues  initiated by predators, such as fish and invertebrates  in phenotypic plasticity would be measured as a potential capacity for adaptation.Ecologist have long recognized intraspecific variation in inducible defense; here we explore the factors involved in intraspecific variation in the inducible defense of  Meester  used uniDaphnia might develop only a few inducible defense characteristics  in predator presence to physical stimuli and may be suppressed in the absence of relationships with cycles , such as pesticides  to speciation. We believe that these factors and variations will provide information regarding their effect on the early stages of speciation. Fortunately, Daphnia is useful for these kinds of experiments owing to its short generation time, ease of breeding, and the capability of using dormant eggs from previous generations. Future studies should focus on tracking both traits and genotypes through long‐term evolution experiments in order to reveal how various traits that appear disadvantageous are conserved.A major goal of evolutionary biology is to understand the mechanisms involved in creating biodiversity. Recent data concerning variations in phenotypic plasticity have promoted ecological speciation but with little empirical evidence ; Writing‐original draft (lead). Hideyuki Doi: Validation (lead).


The use of machine learning and other sophisticated models to aid in prediction and decision making has become widely popular across a breadth of disciplines. Within the greater diagnostic radiology, radiation oncology, and medical physics communities promising work is being performed in tissue classification and cancer staging, outcome prediction, automated segmentation, treatment planning, and quality assurance as well as other areas. In this article, machine learning approaches are explored, highlighting specific applications in machine and patient-specific quality assurance (QA). Machine learning can analyze multiple elements of a delivery system on its performance over time including the multileaf collimator (MLC), imaging system, mechanical and dosimetric parameters. Virtual Intensity-Modulated Radiation Therapy (IMRT) QA can predict passing rates using different measurement techniques, different treatment planning systems, and different treatment delivery machines across multiple institutions. Prediction of QA passing rates and other metrics can have profound implications on the current IMRT process. Here we cover general concepts of machine learning in dosimetry and various methods used in virtual IMRT QA, as well as their clinical applications. Machine learning (ML) has the potential to revolutionize the field of radiation oncology in many processes and workflows to improve the quality and efficiency of patient care , is already part of our everyday lives. The easiest way to explain the relationship of AI and ML is to visualize them as concentric circles with AI - the idea that came first, the largest; then ML - which blossomed later. In AI a general purpose algorithm that can reason about different problems is sought while in ML this idea is abandoned to search for a specific model that maps an input to an output using statistical learning techniques. Many classes of algorithms exist within ML that fit different functions, such as linear models like Lasso and Ridge regression .Unsupervised learning is a type of machine learning algorithm used to draw inferences from datasets consisting of input data without labeled responses. The most common unsupervised learning method is cluster analysis, which is used for exploratory data analysis to find hidden patterns or grouping in data. The clusters are modeled using a measure of similarity  model in three different algorithms  with a train/test split of 81 and 19% . Although the passing rates are site-dependent, different models were not built for each site because, conditional on the plan characteristics, this dependency disappears.In order to implement virtual IMRT QA in a clinic the following workflow should be followed: (1) collect or access IMRT QA data, (2) extract all the parameters of the IMRT fields from plan files, (3) extract the features for the calculation of all complexity metrics affecting the passing rates, (4) use a machine learning algorithm to build a virtual IMRT QA model. During this process, we identify the most impactful features that affect the passing rate.The process described in the previous section Early ML Models requires carefully designing features that describe the correlation between plan characteristics and passing rates. Using an algorithm capable of designing their own features, Dr. Valdes and his group compared a Deep Neural Network against their own Poisson regression model using the same patient QA data previously described  to train the models and predict gamma passing rates using a total of 1,497 IMRT beams delivered with portal dosiemtry  QA. Granville et al. built a ML model with 1620 VMAT plans (Elekta) to predict the results of VMAT QA measurements using not only treatment plan characteristics but also Linac performance metrics (Granville et al., Li et al. investigated the impact of delivery characteristics on the dose accuracy of VMAT (Li et al., Wall and Fontenot used 500 VMAT and MapCHECK2 data to build predictive models using four different machine learning algorithms and then compared their performance (Wall and Fontenot, Since the early ML models applied to machine and patient-specific QA were reported in early 2016, a significant improvements have been seen in more recent models as machine learning techniques in radiotherapy QA matured. The models grew from simple Poisson regressions to deep learning classification models, and then to complex hybrid models which improved prediction accuracy. Therefore, it is expected that future ML models built on the foundation of existing knowledge can continue to be refined. With deep learning models, there is a greater potential to make QA processes more efficient and effective in clinical settings. In the meantime, it is very important to fully understand the limitations of virtual QA. Kalet et al. has highlighted some of the unique challenges of ML applications in radiotherapy QA including data quality, model adaptability, and model limitations (Kalet et al., To date, many applications of ML to radiotherapy QA have focused on predicting machine performance and IMRT/VMAT QA results. Fully understanding and dissecting all factors that govern delivery accuracy is extremely important for clinical physicists to be able to implement a risk-based program as suggested in the AAPM TG-100 report. Further developments could lead to QA predictions being included in the treatment planning optimizer so that all QA could pass. We could also know ahead of time that we need to run a clinically-relevant QA on those plans with the lowest expected passing rates. It is clear that prediction of QA results could have profound implications on the current radiotherapy process. Before implementing in-house or commercial ML models to perform sanity check, second check, and automated or virtual QA in any clinical setting, we should carefully assess and address the limitations of both data and ML models.The materials were presented in a SAM Therapy Educational Course at the 61st AAPM Annual Meeting in San Antonio, TX, in July 2019.MC, AW, and GV have contributed to writing this review article. All authors contributed to the article and approved the submitted version.MC has no commercial or financial interests to declare. AW and GV report an ownership stake in Foretell Med LLC, which is developing machine learning models in medicine. However, this work was done before and outside of that company.


People with Parkinson’s disease (PD) may live for multiple decades after diagnosis. Ensuring that effective healthcare provision is received across the range of symptoms experienced is vital to the individual’s wellbeing and quality of life. As well as the hallmark motor symptoms, PD patients may also suffer from non-motor symptoms including persistent pain. This type of pain (lasting more than 3 months) is inconsistently described and poorly understood, resulting in limited treatment options. Evidence-based pain remedies are coming to the fore but therapeutic strategies that offer an improved analgesic profile remain an unmet clinical need. Since the ability to establish a link between the neurodegenerative changes that underlie PD and those that underlie maladaptive pain processing leading to persistent pain could illuminate mechanisms or risk factors of disease initiation, progression and maintenance, we evaluated the latest research literature seeking to identify causal factors underlying persistent pain in PD through experimental quantification. The majority of previous studies aimed to identify neurobiological alterations that could provide a biomarker for pain/pain phenotype, in PD cohorts. However heterogeneity of patient cohorts, result outcomes and methodology between human psychophysics studies overwhelmingly leads to inconclusive and equivocal evidence. Here we discuss refinement of pain-PD paradigms in order that future studies may enhance confidence in the validity of observed effect sizes while also aiding comparability through standardisation. Encouragingly, as the field moves towards cross-study comparison of data in order to more reliably reveal mechanisms underlying dysfunctional pain processing, the potential for better-targeted treatment and management is high. While the aetiology of PD is not well understood a number of key studies have contributed to our understanding of the development of sporadic as well as familial PD7. The pathogenesis of PD involves the degeneration of dopaminergic neurons in the substantia nigra pars compacta, causing progressively diminished dopamine synthesis in the striatum. Diagnosis of PD follows physical examination of the motor symptoms of the disease, including tremor and postural instability, which appear once 50–70% of nigrostriatal neurons are depleted9. However, there is a significant loss of dopaminergic neurons during the prodromal phase, which is reported to last several years before motor symptoms manifest10. Although equally bothersome, the non-motor symptoms of PD are poorly recognised and underreported12 placing a significant burden on affected individuals’ quality of life15. Persistent pain is a particularly problematic non-motor symptom affecting up to 85% of individuals with PD17 and epidemiological studies highlight the need to systematically investigate pathophysiology based treatment strategies19.Parkinson’s disease (PD) is a progressive, chronic and complex neurodegenerative disease affecting 6.1 million people worldwide21. Therapeutic strategies that offer an improved analgesic profile remain an unmet clinical need. Clearly multi-disciplinary approaches for pain management that encompass new concepts in pathogenesis and treatment are required23.Pain is a multi-dimensional experience involving sensory discriminative and affective motivational descriptive axes. As such, pain perception is inherently subjective and influenced by multiple factors. While acute pain reflects an adaptive survival mechanism, persistent pain negatively impacts the quality of life of the affected individual and serves limited evolutionarily advantage. Unfortunately a large proportion of people with PD experience persistent pain and 50% of those individual’s receive no or inadequate treatment25. PD patients report more pain when ‘off’ Levodopa27 and painful sensations are ameliorated (though not eliminated) ‘on’ Levodopa28. Dopamine receptor agonism has shown promise. The RECOVER and DELORES studies, a pair of double blind, placebo-controlled trials, support the analgesic role of a rotigotine transdermal patch in PD30 while the multi-center, observational, open-label EUROINF study advocated the use of the apomorphine in improving the non-motor symptoms (NMS) scale, which includes a measure of pain31. Other therapies that have been explored include oxycodone-naloxone and duloxetine33. However despite progress in the field a recent Movement Disorders Society Task Force cited only two evidence-based pain treatment options34. Increasingly it is recognised that pathophysiologies may represent non-dopaminergic mediated effects35. Understanding why current treatment options are limited (and why those available are largely ineffective) is straightforward when considering that not only is pain multifactorial in origin, but also that the precise underlying mechanisms responsible for the initiation and maintenance of persistent pain in PD are not fully understood. Put broadly, the experience of pain is unique according to the individual and their pain type.The optimisation of dopaminergic therapies is generally accepted as a first step in the current clinical management of persistent pain in PD36 is advocated by the ‘International Parkinson’s and Movement Disorder Society Non-Motor PD Study Group’ for the evaluation of pain in PD. Encouragingly, an international multi-center validation study reported a strong correlation between the KPPS and quality of life scores, as well as excellent inter-rater and test-retest reliability36. Heralded as a novel approach for the assessment of pain in PD, the KPPS, while lengthy for routine clinical care, allows in-depth profiling in clinical trials based on the subjective reporting of an individual’s pain experience. Regarding pain classification, the Ford criteria26 classified PD-related pain into five groups: musculoskeletal, neuropathic/radicular, central/primary, dystonic and akathisia. The underlying mechanisms causing, for example, musculoskeletal versus central pain are very different in sensory terms and thus the analgesic regimen should be also. Understanding the complexities of pain processing pathways allows one to highlight and explain the heterogeneity of analgesic success with agents including Levodopa and dopamine receptor agonists.It is vital that the pain type experienced by the affected person with PD is explicitly and correctly assessed and classified in order that targeted therapies can be offered. Coupled with an elusive driving force , a lack of consensus regarding the appropriate assessment and classification of pain in PD patients has thwarted analgesic success. In pain assessment terms, the ‘King’s Parkinson’s Disease Pain Scale’ (KPPS)In order that novel and optimal pharmacotherapeutic targets may be identified, a deeper understanding of the pain circuitry in PD patients who experience persistent pain is required. Since we know that unique maladaptive changes occur in central modulatory pathways that govern pain and neurodegeneration, identifying pathophysiological hallmarks for persistent pain and Parkinson’s disease states, likely highly plastic and stage specific, is crucial.38. Temporal summation (TS), quantitative sensory testing (QST) and conditioned pain modulation (CPM) paradigms are three examples of tests that are psychophysical in nature as they assess the perception of pain via salience circuitry39, as opposed to the subconscious processing of stimuli, which may or may not reach conscious perception40. As such, psychological factors such as anxiety41, depression42 and cognitive factors including attention and anticipation43 can influence pain perception during psychophysical testing. A recent review beautifully summarises the peripheral and central changes induced in chronicity as well providing a coherent schematic representation of psychophysical paradigms used in experimental pain research settings44. Human psychophysics paradigms may control for the influence of these confounders by demanding test-retest paradigms in order that it be possible to unpick the fluctuating nature of each individual’s sensory profile when analysing data from multiple sessions. It is vital to acknowledge that, even when using human psychophysics testing, it is not possible to pinpoint where precisely in the pain neuraxis a dysfunction is . A focal measure of, for example, peripheral versus spinal malfunction, cannot be made.Psychophysical assessment is a clinical research technique that can improve our understanding of the mechanisms underlying the development of persistent pain. The ultimate goal of ‘personalised pain management’ requires a thorough understanding of the neuronal mechanisms that contribute to persistent pain in a given patient45. In addition to sensory detection thresholds the DFNS protocol involves pain thresholds to thermal (cold and heat) and mechanical (pressure and pinprick) stimuli. If QST responses are incongruous to normative reference values (i.e. refs. 46.) the dysfunction may be located anywhere along the neural axis, from peripheral nerve fibres48, to the spinal cord49 and cortical areas50. However the value of QST to distinguish central and peripheral mechanisms is limited. Nociceptive withdrawal reflex (NWR) thresholds offer a measure of central pain processing, specifically spinal nociceptive facilitation51.So-called static psychosocial paradigms refer to a range of quantitative sensory testing (QST) protocols, which were recently standardised and defined by the German research network on neuropathic pain (DFNS)52. For example CPM paradigms measure the functionality of the descending pain-inhibitory system. Interestingly, CPM is the human correlate of the diffuse noxious inhibitory control effect observed in animals where the ‘pain inhibits pain’ phenomenon is activated upon application of a testing stimulus concurrent to a conditioning stimulus54. Evidence from translational studies suggests that CPM reflects the functionality of pain-modulating brainstem regions in inhibiting the activity of spinal neurons56. In contrast, pain facilitation mechanisms can be assessed through TS paradigms where pain responses to single noxious stimuli are compared with frequency-dependent responses to serially presented  noxious stimuli57.Dynamic psychophysical paradigms are believed to better define central mechanisms of pain processing compared to static paradigms38. For example CPM deficiencies in patients with neuropathic pain can be targeted by manipulation of central noradrenergic and serotonergic transmission, where the pain-inhibiting impact of Tapentadol  potentiates impaired CPM in persistent pain patients in a manner that back translates to animal studies59. Psychophysical testing can also be used to predict analgesic treatment efficacy60.Since psychophysical testing offers the opportunity to explore the functionality of an individual’s pain system under controlled settings, a comprehensive assessment of various pain processing and modulatory pathways for use as a surrogate measure of the mechanisms driving the development of persistent pain in a given population/patient cohort is possible64. However, a frustratingly disparate range of psychophysical trials exists in the literature for the PD patient cohort, where significant differences in the type of pain considered and methodologies employed leads to incomplete conclusions, as discussed below.In people with PD, sensory profiling through psychophysical testing has been applied in order to provide insight of the underlying mechanisms of persistent pain. Thereafter, guidance for personalised pain medicine through mechanism-based treatments is a key goal for many chronic pain types73. Two recently published systematic reviews found the differences in PD patients’ sensitivity to pain to be significantly different from non-PD populations75. However, the data are inconsistent79 and considerable clinical heterogeneity and methodological inconsistencies throughout the literature limits comparison between studies and thus the clinical applicability of the findings. In total (1) failure to control for the clinical heterogeneity of people with PD including the correct characterisation of the pain type being assessed, and (2) methodological inconsistencies when performing the experimental quantification of pain impairs reliability between studies and contributes to the contradictory findings in the PD pain psychophysics literature. A lack of standardised pain definitions has led not only to result-impacting differences in inclusion and exclusion criteria, but also to result-impacting differences in the pain outcomes assessed. Additionally, on the whole, previous studies appear often underpowered, open label and missing relevant comparator groups. Future studies should include larger sample sizes and standardised pain classification (for example the KPPS) and methodological approaches in order to investigate the aetiology underlying different types of pain in PD, as each have unique mechanisms that need to be thoroughly understood in order to establish individualised therapeutic intervention.It is documented that PD patients have hyperalgesic responses upon psychophysical testing compared to healthy controls82. Worse still, patients with and without persistent pain may be grouped into one PD patient group81. In studies where people with PD with and without persistent pain are segregated, a lack of appropriate pain classification means that identification of whether pain status is the driver of potential altered psychophysical responses in comparison to healthy volunteers is complicated. As such, the substantial clinical heterogeneity within cohorts of PD patients influences psychophysical responses differentially leading to equivocal conclusions.One of the major issues with psychophysical testing in terms of pain studies in PD patient cohorts is that, despite a high prevalence of persistent pain, many participants tested do not actually suffer from persistent pain85, or not reported86. This is an issue when considering that it is well established that the presence of clinical pain, both persistent and acute, influences the way in which an individual reports their pain perception88. It is also a problem when considering that the pain type experienced by people with PD may influence the effect of dopaminergic medication, evidenced by Levodopa worsening dystonic pain89 but improving musculoskeletal pain90. The influence of Levodopa on psychophysical responses has been investigated in PD populations, but with conflicting results91. A meta-analysis by Thompson et al.75, revealed that pain threshold values in PD patients were significantly attenuated following Levodopa administration, suggesting that dopamine deficient states may contribute to hyperalgesia. However, interpretation of the literature is limited due to the variable nature of the methodologies utilised (see section below) and results reported, where the paramount concern regarding consistent pain assessment and classification was not considered between studies. The inconsistent reporting of pain type or even presence of persistent pain contributes to inconsistencies within the evidence, and standardised reporting and classification of pain is imperative if valuable conclusions are to be drawn. Several studies directly investigated the influence of clinical pain on psychophysical responses by comparing PD patients with pain against those without. Most reported that the presence of pain increased pain sensitivity94. However, several dispute these findings, reporting the presence of pain had no such influence96. These inconsistencies may be in part explained by the low statistical power of the trials as, of the studies that report clinical pain had no influence on psychophysical responses, only one included a cohort of more than 15 PD patients with pain74. Small sample sizes are confounded by considerable variability of pain characteristics across those studies cited, including primary central pain, musculoskeletal pain with dystonia, mixed non-dystonic, or undescribed pain. The inconsistent classification of pain is likely due to a previous lack of consensus regarding the appropriate assessment and classification of pain in PD97.The presence and categorisation of clinical pain, prescription of levodopa, disease severity, age, PD sub-types and symptomatic laterality , differed among the trials that were researched during our literature search. Regarding persistent pain characterisation, undefined clinical pain was often a criteria for exclusion77, and a high prevalence of persistent pain in late-stage PD98, suggests that, as with other chronicities100, impaired descending pain modulation may develop early in PD, and worsen with disease progression. However few clinical trials have investigated CPM functionality in PD patients and no significant difference in CPM response between PD patients and healthy controls has been reported in four studies96. However, the testing and conditioning stimuli varied between the studies and only one study used an individually calibrated conditioning stimulus69. This latter point is a vital consideration if only acknowledging the fact that pain perception is inherently subjective, so what is threshold noxious to one individual may be intolerable to another. A considerable methodological limitation, evidenced principally by the failure in all but one study61 in successfully eliciting a CPM response in healthy control subjects, means that no conclusions regarding the functionality of the endogenous descending pain-inhibitory pathways in people with PD can even be drawn; it should not be possible to state that CPM functionality is maladaptive in PD patients if functionality cannot be demonstrated in the healthy population with the paradigm applied.Identifying whether or not there is a difference in QST, TS and/or CPM responses in people with PD with persistent pain is hampered by the fact that, for many of the human psychophysical paradigms used, there is no consensus on the gold standard methodological approach. This is especially an issue when considering CPM paradigms where the variability between testing and conditioning stimuli is high. Previous evidence of a negative correlation between PD severity and CPM responses101. When reviewing case controlled QST studies to investigate pain in a PD population, only one used the standardised DFNS protocol76. Additionally, control for dopaminergic medication was inconsistent with one assessing QST in drug naïve patients76. Exclusion criterias were generally consistent throughout the literature with some notable variation. Depression was screened for a handful of studies with some using tools that have been previously validated for screening in a PD population102 while two studies did not exclude patients who suffered from chronic pain unrelated to PD72. While assessment of PD pain was completed with the Ford classification in six studies, an informal pain assessment was completed in two others103 and pain was not classified at all in one81. Pain status was used to compare outcomes in several studies92. No effect of pain status was found on pain thresholds, except for one electrical pain threshold outcome92.The major variable factor with QST studies is the method by which thresholds are determined, and therefore some are vulnerable to overestimation of pain thresholdsAs the field progresses psychophysical testing has the potential to advance our understanding of persistent pain in PD by elucidating the mechanisms which underlie pain in PD, and in doing so, identifying subgroups of patients with susceptibility to developing persistent pain while assisting in the development and monitoring of personalised pain management strategies for these patients.While we do not know the underlying mechanisms that drive PD singular, persistent pain singular, nor persistent pain in PD, bench and bedside research investigative efforts have partially defined some of the factors important in the initiation, propagation and maintenance of each. Continued forward and back translational preclinical and clinical research will provide comprehensive disease pathology insight and guide towards a mechanism based (as opposed to a disease based) therapeutic approach to facilitate analgesic target identification. Psychophysical testing in humans, with its promise to link animal and clinical pain studies, is essential to fully understand the mechanisms that contribute to the development of persistent pain.69 and without pain49 indicating that the central sensitisation and facilitation of nociceptive inputs may contribute to hyperalgesic psychophysical responses in PD75. In addition, several studies report significantly increased sensitivity to the TS of pain in PD patients compared with controls71. Cumulatively these data suggest that a functional enhancement of nociceptive transmission could mediate persistent pain in PD. Enhanced pain responses may be consequential to impairments within supraspinal pain-modulating pathways as dysfunction in striatal adreno-dopaminergic inhibitory projections to the dorsal horn have been shown to result in inefficient attenuation of neuronal responses104 and are impaired in several persistent pain conditions including PD107. Functional magnetic resonance imaging (fMRI) techniques also reveal higher activation of somatosensory brain regions in PD patients compared with healthy controls83. While discussion of fMRI studies in PD is beyond the scope of this review, cumulatively the data indicate abnormal central nociceptive processing and central sensitisation, which may contribute to hyperalgesic psychophysical responses and the development of persistent pain in PD.Hyperalgesic responses in PD may be attributed to excitability in dorsal horn neurons, evidenced by enhanced facilitatory responses to noxious stimuli in TS and nociceptive withdrawal (NWR) paradigms. Enhanced spinal nociception with reduced NWR thresholds to electrical stimuli was found in PD patients with pain108, and monoaminergic neurotransmission is affected by PD-specific neurodegenerative changes already at the prodromal stage of the disease109. It is possible that there is a link between an underlying mechanism of PD and the development of persistent pain, where an established link could be therapeutically targeted thus improving not only the level of pain experienced by the affected individual, but also PD progression. Performing the appropriately powered human psychophysics pain experimental quantification studies would have the potential to contribute to our understanding of how the nervous system acts endogenously to modulate pain perception in PD, reveal whether this is linked to the aetiology of PD, and therefore unveil targets for intervention in the management of chronic pain in a personalised manner.Do central processing abnormalities act as a catalyst for developing persistent pain in PD? And are they linked to those acting as a catalyst for the development of PD itself? We know that maladaptive central nervous system plasticity underlies the aetiology of PD, while multiple lines of evidence demonstrate that one important mechanism underpinning varied persistent pain states is maladaptive plasticity in central descending inhibitory pathways. Unique descending inhibitory pathways, including diffuse noxious inhibitory controls (DNIC), are sub-served by monoaminergic neurotransmission110, and by using UPDRS-III sub-type-based classifications111. It is recommended that future studies should classify sub-types according to the German AWMF guidelines .Future research should control for confounding factors by standardising variables across laboratories. For example, the presence of pain should be classified according to an internationally validated scale, e.g. the KPPS. PD sub-types should be standardised according to an internationally verified method. Although there is no gold standard for sub-type classification, distinctions have been made between tremor-dominant and non-tremor-dominant sub-typesNigrostriatal degeneration and Lewy body pathology in key structures involved with pain perception and modulation may predispose individuals with PD to the development of persistent pain early in the prodromal phase. This is evident clinically as persistent pain often precedes the cardinal motor signs of the disease. Pain sensitivity scales with PD severity with psychophysical pain thresholds and CPM responses negatively correlated with disease progression, likely contributing to the observed high prevalence of pain in late-stage PD. Overlapping pathophysiological mechanisms are common to the development of the two disease states (persistent pain and Parkinson’s) and this becomes more clinically and behaviourally relevant as the disease progresses. Psychophysical testing is a crucial clinical investigative technique that has the potential to advance our understanding of pain in PD and reach the goal of personalised pain management by (1) elucidating the mechanisms that underlie pain in PD, (2) identifying subgroups of patients susceptible to developing persistent pain and (3) assisting in the prescription and monitoring of mechanism-based neurotherapeutic treatment in these patients. A lack of standardisation amongst laboratories limits the comparability of studies and is a major drawback for understanding the relevance of these paradigms in relation to dysfunctional mechanisms that contribute to pain in PD. There is an urgent need for an internationally agreed definition of pain in PD and a universally agreed consensus on protocols to perform dynamic psychophysical testing. Clarity in this regard will expedite the process of improved analgesic outcomes for those affected individuals.


Worldwide over 40% of patients receiving renal replacement therapy (RRT) are aged 65 years or older, a number that is still increasing. Renal transplantation is the preferred RRT, providing substantial survival benefit over those remaining on dialysis, including the elderly. Only 3% of patients aged 65 years or older accepted on the waiting list actually received a kidney transplant offer within the Eurotransplant allocation region. To increase the chance for elderly to receive a timely kidney transplant, the Eurotransplant Senior Program was introduced. The ESP supports local allocation of older kidneys to older donors in order to decrease cold ischemia time, while disregarding former exchange principles based on matching for HLA antigens. As a consequence, more elderly received a kidney transplant and a relative higher incidence of acute rejection resulted in additional courses of high steroids and/or depleting antibody therapy. Since death with a functioning graft due to infections is the dominant reason of graft loss in elderly, more intense clinical immunosuppression to prevent or treat acute rejection is not a very attractive option. Therefore in elderly kidney transplant candidates, we advocate reintroduction of minimal histocompatibility criteria  followed by age-matching with mandatory local/regional allocation to also facilitate short cold ischemia. End stage renal disease (ESRD) is a rapidly becoming a critical problem worldwide. In The Netherlands, for instance, the prevalence of patients receiving renal replacement therapy (RRT) was 17531 or 1020 per million population (pmp) in the year 2017, an increase of almost 35% in the last decade  , 16. In Death due to infectious causes is the consequence of clinical overimmunosuppression, especially in elderly with an already immunosenescent immune system in the context of aging . In the It has become widely accepted that older transplant recipients may encounter less acute rejection episodes after transplantation as compared to younger recipients due to immunosenescence , 27. HowOverall the frequency of rejection declines within subsequent age categories, but a higher donor age is significantly associated with higher rejection rates –32. A stde novo donor specific antibodies against HLA antigens (dnDSAs) after transplantation gained more and more interest. Overall Lachmann et al.  working group and the Heidelberg algorithm, based on the CTS and data from the Heidelberg Transplant Center, all advise to test post-transplantation in pre-specified patient groups. All agree that patients most at risk are patients with a pre-activated immune system, measured by pre-existing antibodies or soluble CD30, in combination with periods of under-immunosuppression and should be monitored closely –53.HLA compatibility between donor and recipient is currently assessed by the number of HLA mismatches on serologic level although HLA antibodies recognize accessible polymorphic sequences of amino acids rather than whole HLA antigens. These polymorphic sequences, so called epitopes, can be shared between HLA antigens so the true mismatch is much more complicated than serologic level shows. Therefore, the question can be raised whether current matching principles are reliable enough to reduce or minimize the risk of dnDSA formation.de novo class-II DSAs in 286 kidney transplant recipients. Epitope mismatches were significantly more frequent in the patients who developed dnDSAs. In this study the optimal threshold for development of antibodies against HLA-DR was 10 mismatched epitopes and for HLA-DQ 17 mismatched epitopes  was implemented to shorten the waiting time for older transplant candidates and improve the perspective on patient survival with ESRD. In this program kidneys from donors > 65 years are allocated to recipients > 65 years with preferred local allocation in order to shorten cold ischemia times (CIT) and the likelihood of delayed graft function and/or rejection. To reach these goals, HLA matching was neglected, obviously resulting in a higher HLA mismatch rates in ‘old for old’ transplant programs. In 2008 the 5 years results were published and main goals were reached, waiting time decreased and CIT went down to 11.9 h compared to > 17 h in the regular ETKAS allocation program . HoweverAt the moment only a minority of selected elderly transplant candidates actually receive a kidney transplant and the mortality rate among this patient group is relatively high, especially the 1st year after transplantation or in case complications occur such as an acute rejection episode. In order to increase transplant rates, more older donors are accepted and preferably for older recipients, which in turn leads to more acute rejection episodes and rejection treatments.In younger transplant recipients, the increased risk of acute rejection with the use of older donors could possibly be overcome with induction therapy or more potent maintenance therapy. In elderly the complex interplay between immunosuppression on the one hand and immune defense on the other hand is even more challenging due to pre-existing comorbidities, changes in pharmacokinetics of immunosuppressive drugs, polypharmacy and the immunosenescence mentioned earlier. Probably more balanced immunosuppressive protocols and more advanced immunological monitoring strategies are needed to balance this critical equipoise. A second, more feasible and practical strategy could be to change the allocation protocol to decrease the risk of acute rejection and/or DSA formation without the need of more clinical immunosuppression.Calcineurin inhibitors (CNI) remain the most potent immunosuppressive drugs in preventing acute rejection and have been critical to improve short-term graft survival. Due to the nephrotoxic potential of CNIs on long-term graft failure, there has been an overall shift toward reduction or CNI-withdrawal preferably later after transplantation. Since elderly are more susceptible to infections and the other side effects of immunosuppressive drugs and older kidney grafts are more vulnerable to CNI induced vasoconstriction and/or nephrotoxicity, several studies have suggested that especially elderly could benefit from CNI withdrawal or avoidance . In addiVarious studies have indicated that CNI-withdrawal in the regular population of renal transplant recipients may not be successful –71. The In elderly, Arbogast et al.  used an 2. Benefits of the regimen with mTORi were a significantly reduced incidence of viral infections, which could be direct clinical benefit in the elderly. Although elderly were not excluded from this trial, mean age was 49.3 year  have been introduced and positioned. Several randomized trials have been performed of which the most recent one is the large TRANSFORM study. In this study 2037 renal recipients were randomized to standard dose CNI + MMF or reduced CNI + mTORi. The latter proved to be non-inferior regarding a binary endpoint of BPAR or glomerular filtration rate (GFR) < 50ml/min/1.73m9.3 year . RecentlAs expected, the ESP program achieved the goal to minimize cold ischemia time and also the anticipated reduction in the rate of delayed graft function. The higher incidence of acute rejection was not expected and this could suggest a greater role of immunogenicity in the context of less histocompatibility. One could overcome this increased rejection risk by increasing clinical immunosuppression. The elderly, however, already have a compromised immune system and are more vulnerable for infectious complications. In addition, marginal donors are more vulnerable for the nephrotoxic side effects of immunosuppressive drugs. Therefore, at least in theory, this may be a suitable strategy in a proportion of younger patients receiving older and more immunogenic kidneys but may not be the best options for the older transplant recipients.A different strategy is to require a minimal degree of histocompatibility between donor and recipient while maintaining the shorter CIT and therefore the benefit of less delayed graft function. Due to a high degree of linkage between HLA-DR and HLA-DQ antigens, matching for HLA DR frequently results in matching on HLA-DQ . As prevGiven the inherent limited life expectancy of older patients, their best option when encountering ESRD would be the option of a kidney transplant as soon as possible. In order to reach this goal age matching is a suitable strategy and most patients will receive a kidney from an older deceased donor.Even with a timely kidney transplant offer from an age-matched donor, there are other issues to consider in elderly recipients. Recipients of older kidneys are more susceptible to acute rejection with HLA class-II mismatch being a potentially preventable key risk factor also for the subsequent formation of DSAs. The mere fact that the older recipient has an older immune system as compared to adolescents, does not overcome the dominant effect of donor age over recipient age.We therefore underlined the importance of prospective HLA matching in the allocation algorithm of older kidneys to older kidney transplant candidates. Since most DSAs are directed against HLA class II antigens, HLA-DR matching is likely to reduce the need for more intense clinical immunosuppression and/or additional acute rejection treatments, ensuing reduction of excess infectious cause morbidity and mortality while delivering the prospect of prolonged life expectancy.To reintroduce prospective matching for HLA class-II antigens, the Eurotransplant Senior DR-compatible Program (ESDP) study was designed and the results will be important to guide future clinical practice.GD wrote the first draft of the manuscript. JF wrote sections of the manuscript and revised the manuscript. Both authors contributed to the final manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cognitive neuroscience research has traditionally focused on understanding the brain mechanisms that enable cognition by means of experimental laboratory tasks. With a budding literature, there is growing interest in the application of the related methods and findings to real-world settings. In this opinion paper we explore the potential and promise of employing current cognitive neuroscience methodologies in the field of design. We review recent evidence from preliminary studies that have employed such methods toward identifying the neural bases of design thinking and discuss their impact and limitations. Further, we highlight the importance of pairing neuroscience methods with well-established behavioral paradigms during ecologically-valid, real-world design tasks. Experimental investigations that meet these requirements can generate powerful datasets of neurocognitive measures that can offer new insights into the complex cognitive and brain systems enabling design thinking. We argue that this new knowledge can lead to the development and implementation of new techniques toward cultivating and improving design thinking in design education and professional practice. Some of these techniques have also occasionally provided evidence for causal brain-behavior relationships that have supported interventions to alter, treat, or augment brain function in healthy and diseased populations Cognitive neuroscience is the subfield of neuroscience that focuses on the neural mechanisms enabling mental processes—from perception and memory, to higher-order thinking and problem solving. For a little over three decades, cognitive neuroscience methodologies—including structural and functional brain imaging, electroencephalography, and noninvasive brain stimulation—have allowed researchers to capture 2.Design thinking pertains to the neurocognitive processes supporting the development of design concepts  from their inception to their final description design neurocognition has introduced new possibilities for understanding design thinking through the integration of traditional design research techniques such as protocol analysis, with methods from cognitive neuroscience, neurophysiology, and artificial intelligence Designing is the cognitive act of intentionally generating new ways to change the world instead of simply repeating existing ways. It is ubiquitous—carried out by both professional designers and by anyone who executes the same cognitive acts Design research involving cognitive neuroscience methods has typically employed techniques that allow for the recording of neural activity while designers think and as they generate design products. Such techniques typically entail methods that emphasize spatial resolution—namely, where in the brain a particular process may take place, whereas others emphasize temporal resolution—namely, when a particular neural process occurs relative to the task performed, with some techniques combining both approaches or emphasizing the organization of brain regions in large-scale networks 3.Among the first studies to investigate the neural bases of design cognition was an examination of the potential differences in brain engagement between designing and problem solving These early functional neuroimaging approaches are additionally challenged by the technique's limited temporal resolution, as they fail to capture one of the most critical aspects of designing, namely, its inherently multifaceted and rapidly evolving temporal nature. The focus on the temporal variability of neural processing during design has been the target of investigations within design neurocognition that have employed EEG or ERP recordings. For example, recent experimental work has shown that higher alpha-band activity over temporal and occipital regions can distinguish between open-ended problem descriptions, relative to close-ended and decision-focused problem descriptions during design problem-solving in expert designers To address the high-costs and potential limitations of functional brain imaging and EEG for design studies in ecologically valid, real-world settings, recent research in design neurocognition has also used fNIRS as a method of capturing functional brain changes during design in real-time. A benefit of fNIRS paradigms is that the participant can freely move, speak, interact with others, and use devices during tasks, thus, allowing for data collection in naturalistic educational and professional settings. Thus far, only a handful of pilot studies have used this approach to examine design thinking, though the preliminary results suggest that fNIRS measurements can detect cortical shifts as a result of design constraints Though not exhaustive, the above review of the evidence from the emerging field of design neurocognition has generated interesting preliminary findings regarding the neural bases of design thinking that promise to differentiate among competing theoretical propositions on the elements of the design process, thus impacting design theory, education, and practice  are examined in isolation by means of paradigms loosely based on experimental cognitive psychology and neuroscience methods in vivo examinations of the neurocognitive processes taking place while designers work on real-world design problems. Toward this goal, one potential avenue for future research entails the combination of verbal protocol analysis and multi-modal neuroimaging-based methods, such as fMRI, with concurrent EEG or other psychophysiological measures . Recent technological advances have made it possible for participants to complete real-world design tasks using MRI-compatible tablets for sketching and design problem-solving tasks We invite the field to address these shortcomings through meaningful collaborations between cognitive neuroscience and design neurocognition researchers. We propose that advancing our understanding of design thinking can only be achieved through Moreover, a clear and methodologically-rigorous account of the neural systems involved in design cognition creates new opportunities for determining whether we can actively augment and improve design thinking through altering brain function. For example, task-synchronous manipulations of designers' brain activity can be achieved through behavioral, neurofeedback, or non-invasive brain stimulation interventions, such as transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS). By combining the complementary fields of cognitive neuroscience and design, while leveraging recent technological and methodological advances, research on the cognitive neuroscience of design can generate—using real-world design problems—an unprecedented dataset of neurocognitive measures that can provide a unique understanding of the complex cognitive and brain systems enabling design thinking. The significance of this new knowledge can, then, be manifested in the opportunity to develop and implement new techniques toward cultivating and improving design thinking.5.Designing is a real-world, dynamic system of interacting, temporally-distributed activities and is among the most complex aspects of higher-order human cognition. In this opinion paper we propose that cognitive neuroscience studies of design need to embrace this complexity and examine the attendant neurocognitive processes taking place while designers work on real-world design problems. Such work can establish a neurocognitive framework toward understanding design thinking that focuses on how the dynamic process of designing takes place within the human cognitive architecture. This emerging knowledge can support the development of new techniques to augment real-world design thinking by causally altering the neural networks involved in design. The productive pairing of cognitive neuroscience and design neurocognition approaches will pave the way toward developing new techniques for improving design thinking, which can be applied to individual designers or can be extended to design teams in future work.


This study aimed to examine how stressors and positive events are related to sleep duration in daily life and whether these associations differed by age. The second wave of National Study of Daily Experiences of Midlife in the United States study was used . Reports of daily events was coded as two categorical variables indicating experiences of concurrent and previous-day daily events: experiencing both stressors and positive events, only stressors, only positive events, and neither (reference). Results from multilevel analysis showed that experiencing an event, either a stressor or a positive event, was associated with shorter amount of sleep the same day compared to a non-event day. In particular, sleep duration was shorter when individuals experienced stressors compared to when they only reported positive events the same day. There were no age differences in these associations. Findings suggest that stressors exert a stronger influence on daily sleep than positive events.


These results indicate autonomous motivation is associated with improved mental health outcomes and higher levels of PA in children. Thus, PA interventions that promote autonomous motivation may enhance children’s mental health compared to interventions that promote mainly controlled forms of motivation. While motivation for physical activity (PA) and PA participation have been linked, research on the relationship between motivation for PA and mental health outcomes is scant, with studies involving children largely underrepresented. Grounded in self-determination theory, this cross-sectional study aimed to determine whether autonomous motivation versus external motivation (a form of controlled motivation) for PA is associated with fewer emotional and behavioural difficulties and higher levels of PA in children. A sample of 87 children (aged 8–12 years) were recruited from five primary schools in Victoria, Australia. An adapted version of the Behavioural Regulation in Exercise Questionnaire (BREQ) was used to measure motivation for PA and structured parent-report questions were used to assess moderate-to-vigorous PA (MVPA) levels. Parents also completed the Strengths and Difficulties Questionnaire (SDQ) to measure children’s emotional and behavioural difficulties. Children’s autonomous motivation was associated with fewer emotional and behavioural difficulties ( It is estimated that 14% of Australian children and adolescents have experienced a mental health disorder such as Attention-Deficit/Hyperactivity Disorder  or deprEffective public health promotion of PA is therefore paramount, not only for physical health but also mental health. As such, research into factors that explain PA behaviours and associated mental health outcomes has increased in recent years. Studies exploring motivation for PA, based on self-determination theory , conceptBoth motivation types direct behaviour, but according to self-determination theory, autonomous motivation results in stronger and longer lasting behaviour change than controlled motivation ,17. As sControlled motivation has been found as a weaker predictor of PA relative to autonomous motivation and may also contribute to an increased risk of mental health problems via the thwarting of the basic needs ,26. Ng en = 134), reported no overall changes in intrinsic (autonomous) motivation  = 3.34, p = 0.014, adjR2 = 0.10). The individual effects of age, gender and external regulation were nonsignificant, whereas autonomous motivation shared a significant positive relationship with MVPA .A second regression analysis was conducted to assess the association between autonomous motivation and external regulation with MVPA levels, adjusting for age and gender see . The oveThe primary aim of this study was to examine the relationship between motivation for PA and children’s emotional and behavioural difficulties. The results supported the hypothesis that autonomous motivation is associated with fewer emotional and behavioural difficulties in a sample of Australian children. The secondary aim of this study was to examine the relationship between motivation for PA and children’s PA levels. Once again, the results supported the hypothesis that autonomous motivation is associated with higher levels of MVPA in a sample of Australian children.Mage = 8.7 years) found no direct relationship between motivation and mental health [In response to our primary aim, this study provides support for the self-determination theory notion that autonomous motivation will underpin improved mental health outcomes. However, not all studies have found significant results between autonomous motivation and mental health in children . A nonral health . The samExternal regulation was not associated with emotional and behavioural difficulties in the current study. When considered with the significant results of autonomous motivation, this confirms the hypothesis that autonomous motivation would be associated with fewer emotional and behavioural difficulties, whereas controlled motivation would not. This finding is congruent with the results reported by other studies . HoweveStudies investigating motivation for PA in children remain underrepresented. Thus, the secondary aim of this study was to explore the relationship between motivation for PA and levels of MVPA within the Australian context. A positive relationship between autonomous motivation and MVPA was found in the regression model, whereas the model did not support a relationship between external regulation and MVPA. These results indicate that children who either enjoy or value PA are more likely to be active than children who are motivated by rewards or competition. Interestingly, external regulation was found to negatively relate to MVPA levels in the bivariate correlation analysis. This finding may indicate the presence of a confounding variable . Lower perceptions of competence may contribute to lower PA levels and higher external regulation in children , thus exGiven the multidimensional nature of both mental health  and PA pAlthough research into self-determined motivation and mental health is becoming more popular, studies predominantly utilise adolescent or adult samples . The preThe findings should be interpreted in light of some limitations in the study. One limitation is related to the subjective measurement of MVPA. Subjective measurements of MVPA, while cost and time effective, are more vulnerable to error via biases such as social desirability and recall compared to objective measures such as accelerometers ,59. AddiThe findings of this study support an association between autonomous motivation and mental health. However, due to the relatively small sample, further research is needed to replicate the findings in larger samples. Additionally, while the results suggest that autonomous motivation for PA is associated with reduced mental health problems, the size of the effect was relatively small. Further, the cross-sectional nature of this study precludes causal inferences. Thus, research testing motivation for PA alongside other well-established determinants of mental health in experimental and/or longitudinal designs is necessary.The present study offers a preliminary investigation into the relationship between motivation for PA and mental health in children aged 8–12 years. The results indicate that children who are autonomously motivated to participate in PA may be less likely to experience emotional and behavioural difficulties. This finding is important, as it suggests that interventions that focus on fostering children’s genuine interest in PA over competition or rewards may improve both PA and mental health outcomes. Further research of child-specific interventions is needed to better understand the interactions between motivation, PA and mental health to ascertain whether motivation can be leveraged to improve children’s health outcomes in the future.


This symposium begins by fist comparing features of the Japanese elder abuse prevention law to 3 other abuse prevention laws - child abuse, domestic abuse and abuse against people with disabilities. It highlights amendments that have been made to the child abuse and domestic abuse prevention laws since their enactment based on implementation experience, drawing contrast to the lack of amendments made to the elder abuse prevention law despite its three-year requirement for amendment review. Overall strengths and weaknesses of the elder abuse law are discussed including needed areas of revision. Second, a case study of nearly two decades of elder abuse prevention activities in Matsudo-city are presented and the subsequent enactment in April 2020 of a new regulation of the city is discussed. In addition, interim outcomes of a related research study in Matsudo-city on elder abuse involving non-caregivers for elderly people that will expand understanding of abuse prevention efforts are presented. Third, how can we abolish elder abuse in institutional settings will be discussed by analyzing elder abuse case studies. Finally, the most updated research outcomes conducted in in-home care service settings in 2020 will be presented. Its preliminary analyses revealed out of 1,417 responses, 2.9% were found to be ”body restraints.” Such abusive actions are less likely to be detected by others. The symposium concludes by assessing challenges for preventing elder abuse in policy and practice.


Multidimensional molecular analysis of tumor tissue intensively over space and time can provide insight into how cancers evolve and escape treatment. Attitudes of participants in such trials have not been assessed. We explored patient views regarding an intensive study incorporating multiple biopsies, multidimensional molecular testing, and drug response predictions that are reported to the oncologist and patient.A structured, self-administered survey was conducted among the first 15 patients enrolled in ITOMIC-001 . Patients with metastatic triple-negative breast cancer were accrued at two sites in Washington state. Surveys containing 17 items were administered at enrollment and after the return of results. Surveys explored perceptions regarding risks, personal benefits, benefits to others, uncertainties associated with interpreting complex molecular results, concerns regarding multiple biopsies, and potential loss of confidentiality. At follow-up, three additional unique items explored patient coping.All participants expressed a strong desire for their experiences to benefit others, and all perceived a higher likelihood of deriving benefit than described during detailed consent discussions. Loss of confidentiality ranked lowest among patient concerns. Despite acknowledging uncertainties and risks inherent in complex molecular testing for clinical reporting, participants wanted access to findings in evaluating treatment choices, even if the best available evidence was weak. Follow-up surveys demonstrated relatively little change in attitudes, although concern about study biopsies generally declined. Study participation helped several patients cope better with their disease.In advanced breast cancer, these findings demonstrate the feasibility of engaging motivated patients in trials that navigate the uncertainties associated with intensive spatial and longitudinal multidimensional molecular testing for the purpose of advancing precision medicine. However, we and others have found significant discordance between the results of next-generation sequencing testing of tumor tissue versus circulating cell-free DNA.62Longitudinal monitoring can provide insight into how cancers evolve and escape treatment.ClinicalTrials.gov identifier: NCT01957514). ITOMIC-001 enrolls patients with metastatic triple-negative breast cancer and involves repeated biopsies of multiple metastatic sites over time, an extensive multidimensional molecular analysis, a distributed network of investigators to analyze results and predict drug susceptibilities,63 and return of results to the patient and her oncologist. At their discretion, the patient can then be treated with the predicted drugs, allowing hypothesized drug susceptibilities to be tested in each patient.To address these obstacles, we initiated ITOMIC-001  in a single setting ; performing whole-genome sequencing (or whole-exome sequencing), RNA sequencing, and deep sequencing of a panel of cancer-associated genes on multiple samples; employing a distributed network of experts to analyze findings and suggest treatments; reporting results to clinicians and participants for shared decision making; and repeating biopsies before switching to other drug treatments. Outside of the trial, we offer an intensive drug- and clinical trial–matching process to help patients who wish to be treated in accordance with our predictions access the recommended drugs. Patients were contacted 1 day and 1 week after biopsies to assess for adverse events .ITOMIC-001 was launched in October 2013 and has been described previously.The study has been approved by the Fred Hutchinson Cancer Research Center Institutional Review Board. The consent process was intended to clearly emphasize that patients are not expected to benefit directly from their participation, in addition to describing potential risks associated with extensive genomic testing .Participants were asked to complete structured, self-administered surveys that gauged their understanding and attitudes regarding key features of ITOMIC-001. Individual survey items and major thematic domains are listed in 64 Participants chose from among five responses for each survey item: agree strongly, agree a little, neither agree nor disagree, disagree a little, or disagree strongly. For purposes of analysis, these responses were transformed into five ordinal numeric values ranging from 2 (agree strongly) to −2 (disagree strongly). Descriptive statistical analyses of the numeric baseline and follow-up survey results are based on the mean and standard deviation (SD) calculated for each item across all respondents. Two of the three items unique to the follow-up survey varied response options because of the nature of the items (M19 and M20). These options were a great deal, a good deal, somewhat, a little, or not at all  or whole-genome sequencing (patients 13 to 15) of both germline  and tumor DNA, and items M10 to M13 gauged perceptions regarding information from germline sequencing  of accessing the drugs that were predicted to be effective than patients enrolled in molecular drug-matching trials.67Linking comprehensive molecular profiling of distinct metastatic sites to treatments and responses holds promise for improving our understanding of how cancers evolve and escape therapy72 Patients seemed to be similarly motivated by a desire that their experiences benefit others, consistent with recent studies suggesting that altruism can be an important motivator for participation in clinical trials.75The most consistent responses pertained to the motivations for participation. All participants expressed an exaggerated expectation of benefit, which contrasts information that had been provided during our detailed consent process. This previously described overestimation of personal benefit has been hypothesized to reflect expressions of hope and optimism rather than a misunderstanding of facts presented at the time of consent.Ranking lowest among patient concerns were the potential for loss of confidentiality and the possibility that incidental findings from germline testing might uncover genetic risk factors for diseases other than cancer. Somewhat greater levels of concern were attached to the prospect of undergoing multiple biopsies and the possibility that information from genetic testing may be used to reduce or deny insurance coverage now or in the future. Encouragingly, concerns regarding multiple biopsies fell substantially in follow-up surveys. Nevertheless, one patient found the biopsies to be somewhat more difficult than expected at follow-up, and one of the two patients who dropped out cited concerns regarding multiple biopsies as the reason. ITOMIC-001 differs from commonly known mandatory research biopsy drug trials in that the final decision about drug matching is made by the treating oncologist outside the ITOMIC-001 protocol.Most participants seemed to understand the uncertainties inherent in using complex molecular testing for making treatment recommendations. Responses regarding the manner in which results of complex molecular testing should be applied in reaching treatment decisions varied according to how the question was asked. Collectively, however, responses suggest that most patients understood the difficulties inherent in interpreting results from complex molecular testing but nevertheless wanted the opportunity to have these findings thoughtfully applied in their care.78 particularly in individuals with a low tolerance for ambiguity55 or in hypothetical scenarios.79 However, patients with advanced cancer making real-world decisions tend to perceive this information as either useful information for family80 or seemingly insignificant in the context of their cancer.80All patients underwent germline testing, and all wanted access to results to assess their risk for genetic diseases other than cancer and to assess family members’ risk for cancer or other genetic diseases. However, 14 of 15 participants agreed with the statement that “the use of genetic testing to guide the treatment of my cancer is much more important to me than learning about my risk for other diseases in the future.” Incidental genomic findings can be perceived as burdensome,81 both patients who felt that participation had made coping with their cancer a little more difficult had received treatments on the basis of molecular results. Notably, these same two individuals also indicated that genetic test results had made it easier to cope with their cancer, and it will be important to understand the basis for these responses to further improve satisfaction levels among all study participants.Our study is limited by its small size and incomplete follow-up. Many of our patients were particularly motivated and may not be representative of the general cancer population. It is encouraging that eight of 10 patients viewed participation in ITOMIC-001 as having helped them cope with their cancer. Although this relatively high degree of satisfaction may be related to a high rate of accessing drugs that were predicted to be effective,Although preliminary, our findings establish the feasibility of partnering with motivated patients in intensive clinical trials that seek to better understand how cancers evolve and escape therapy. In exchange, patients expect best efforts in interpreting results (however difficult) and in accessing the drugs from which they hope to benefit.