Cortical representation of illusory body perception in healthy persons and amputees: implications for the understanding and treatment of phantom limb pain

A disturbed body perception is characteristic for various neurological and mental disorders and becomes particularly evident in phantom phenomena after limb amputation. Body illusions, such as mirror visual feedback (MVF) illusions, have been shown to be efficient in treating chronic pain and to be further related to a reversal of cortical reorganization. The present thesis aimed at identifying the neural circuitry of illusory body perception in healthy subjects and unilateral upper-limb amputees using functional magnetic resonance imaging. Study 1 investigated the perceived mirror illusion capacity and the neural correlates of a novel MVF-device (the mirror glasses) in comparison to the well-established mirror box in healthy persons. Study 2 investigated the neural circuitry of stimulus-evoked non-painful phantom phenomena in unilateral upper-limb amputees. During mirror illusions, movements of the affected limb are visually recreated by movements of the contralateral limb. The visual recreation of the affected limb seems to be linked to a recruitment of the primary sensorimotor representation of the affected limb. In contrast to the mirror box, the mirror glasses limit the user’s view to the visual reflection of the moving hand as opposed to seeing both hands moving in synchrony. It has been proposed that seeing the actually moving limb in addition to the mirror reflection might have a distracting effect. Study 1 evaluated the utility of mirror glasses based on a comparison to the mirror box and tested the hypothesis that increased interhemispheric communication between motor hand representations might drive the activation in the non-mirrored limb representation. Mirror illusion capacity and brain circuitry were measured in a within-subject design during both MVF-conditions with 20 healthy subjects in counterbalanced order. The self-reported mirror illusion capacity and brain activation patterns did not significantly differ between both mirror tasks. The representation of the non-mirrored hand was recruited in both mirror tasks. A significant increase in interhemispheric connectivity between the hand areas, however, was only found in the mirror glasses condition, suggesting divergent mechanisms for the recruitment of the non-mirrored hand representation between both mirror tasks. Most amputees still perceive their amputated limb (phantom limb awareness). Phantom phenomena comprise a variety of non-painful and painful sensations allocated to the amputated limb. Some amputees experience non-painful phantom phenomena when the residual limb or other parts of the body are stimulated (evoked phantom sensations). The neural correlates of non-painful phantom phenomena remain unknown. Study 2 aimed to identify the neural circuitry of evoked nonpainful phantom sensations. Twelve upper-limb amputees who reliably perceived non-painful phantom sensations upon stimulation of distal body parts and 12 yoked controls (matched for sex and age) were investigated. Amputees were stimulated at a body site eliciting phantom sensation with a stimulus related on- and offset and a control site without illusory perception. Controls were stimulated at matched body sites. A conjunction analysis showed specificity of the left ventral premotor and inferior frontal cortices (BA44/45) for the perception of referred sensations. Generalized psychophysiological interaction analyses revealed a widespread network showing significant positive intra-parietal and fronto-parietal connectivity. Our study indicates a high convergence between the neural correlates of nonpainful phantom sensations and (other) body illusions. Both studies of the present thesis offer new insights into the understanding the neuronal basis of illusory body perception. Such illusory body perceptions are frequent in chronic pain and targeting these distortions of body perception has been shown to be fruitful for relieving pain and disability

Digital Health Apps in the Context of Dementia: Questionnaire Study to Assess the Likelihood of Use Among Physicians

Background: Age-related diseases such as dementia are playing an increasingly important role in global population development. Thus, prevention, diagnostics, and interventions require more accessibility, which can be realized through digital health apps. With the app on prescription, Germany made history by being the first country worldwide to offer physicians the possibility to prescribe and reimburse digital health apps as of the end of the year 2020. Objective: Considering the lack of knowledge about correlations with the likelihood of use among physicians, this study aimed to address the question of what makes the use of a digital health app by physicians more likely. Methods: We developed and validated a novel measurement tool—the Digital Health Compliance Questionnaire (DHCQ)—in an interdisciplinary collaboration of experts to assess the role of proposed factors in the likelihood of using a health app. Therefore, a web-based survey was conducted to evaluate the likelihood of using a digital app called DemPredict to screen for Alzheimer dementia. Within this survey, 5 latent dimensions (acceptance, attitude toward technology, technology experience, payment for time of use, and effort of collection), the dependent variable likelihood of use, and answers to exploratory questions were recorded and tested within directed correlations. Following a non–probability-sampling strategy, the study was completed by 331 physicians from Germany in the German language, of whom 301 (90.9%) fulfilled the study criteria (eg, being in regular contact with patients with dementia). These data were analyzed using a range of statistical methods to validate the dimensions of the DHCQ. Results: The DHCQ revealed good test theoretical measures—it showed excellent fit indexes (Tucker-Lewis index=0.98; comparative fit index=0.982; standardized root mean square residual=0.073; root mean square error of approximation=0.037), good internal consistency (Cronbach α=.83), and signs of moderate to large correlations between the DHCQ dimensions and the dependent variable. The correlations between the variables acceptance, attitude toward technology, technology experience, and payment for the time of use and the dependent variable likelihood of use ranged from 0.29 to 0.79, and the correlation between effort of the collection and likelihood of use was −0.80. In addition, we found high levels of skepticism regarding data protection, and the age of the participants was found to be negatively related to their technical experience and attitude toward technology. Conclusions: In the context of the results, increased communication between the medical and technology sectors and significantly more awareness raising are recommended to make the use of digital health apps more attractive to physicians as they can be adjusted to their everyday needs. Further research could explore the connection between areas such as adherence on the patient side and its impact on the likelihood of use by physicians

Do Mirror Glasses Have the Same Effect on Brain Activity as a Mirror Box? Evidence from a Functional Magnetic Resonance Imaging Study with Healthy Subjects

Milde C, Rance M, Kirsch P, et al. Do Mirror Glasses Have the Same Effect on Brain Activity as a Mirror Box? Evidence from a Functional Magnetic Resonance Imaging Study with Healthy Subjects. PLOS ONE. 2015;10(5): e0127694

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.Peer reviewe

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)