Peri-operative individually tailored psychological intervention in breast cancer patients improves psychological indices and molecular biomarkers of metastasis in excised tumors.

Perioperative stress and inflammatory signaling can invigorate pro-metastatic molecular processes in patients' tumors, potentially worsening long-term survival. Yet, it is unknown whether pre-operative psychotherapeutic interventions can attenuate such effects. Herein, three weeks before surgery, forty women diagnosed with stage I-III invasive ductal/lobular breast carcinoma were randomized to a 6-week one-on-one psychological intervention (6 meetings with a medical psychologist and bi-weekly phone calls) versus standard nursing-staff-attention. The intervention protocol was individually tailored based on evaluation of patients' emotional, cognitive, physiological, and behavioral stress response-patterns, and also included psychoeducation regarding medical treatments and recruitment of social support. Resected primary tumors were subjected to whole-genome RNA sequencing and bioinformatic analyses, assessing a priori hypothesized cancer-relevant molecular signatures. Self-report questionnaires (BSI-18, Hope-18, MSPSS, and a stress-scale) were collected three (T1) and one (T2) week before surgery, a day before (T3) and after (T4) surgery, and three weeks (T5) and 3-months (T6) following surgery. The intervention reduced distress (GSI), depression, and somatization scores (BSI-18: p < 0.01, p < 0.05, p < 0.05; T5 vs. T1). Additionally, tumors from treated patients (vs. controls) showed: (i) decreased activity of transcription control pathways involved in adrenergic and glucocorticoid signaling (CREB, GR) (p < 0.001), pro-inflammatory signaling (NFkB) (p < 0.01), and pro-malignant signaling (ETS1, STAT and GATA families) (p < 0.001, p < 0.01, p < 0.005); (ii) increased M1 macrophage polarization (p < 0.05), and CD4+ T cell activity (p < 0.01); and an unexpected increase in epithelial-to-mesenchymal-transition (EMT) signature (p < 0.005). This is the first randomized controlled trial to show beneficial effects of a psychological perioperative intervention on tumor pro-metastatic molecular biomarkers.

Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study.

BACKGROUND: Ketamine has been demonstrated to improve depressive symptoms.AimsEvaluation of efficacy, safety and feasibility of repeated oral ketamine for out-patients with treatment-resistant depression (TRD). METHOD: In a randomised, double-blind, placebo-controlled, proof-of-concept trial, 41 participants received either 1 mg/kg oral ketamine or placebo thrice weekly for 21 days (ClinicalTrials.gov Identifier: NCT02037503). Evaluation was performed at baseline, 40 and 240 min post administration and on days 3, 7, 14 and 21. The main outcome measure was change in Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Twenty-two participants were randomised to the ketamine group, and 19 to the control, with 82.5% (n = 33) completing the study. In the ketamine group, a decrease in depressive symptoms was evident at all time points, whereas in the control group a decrease was evident only 40 min post administration. The reduction in MADRS score on day 21 was 12.75 in the ketamine group versus 2.49 points with placebo (P < 0.001). Six participants in the ketamine group (27.3%) achieved remission compared with none of the controls (P < 0.05). The number needed to treat for remission was 3.7. Side-effects were mild and transient. CONCLUSIONS: Repeated oral ketamine produced rapid and persistent amelioration of depressive symptoms in out-patients with TRD, and was well tolerated. These results suggest that add-on oral ketamine may hold significant promise in the care of patients suffering from TRD in the community.Declaration of interestNone.

Automatic Measurement of Fetal Brain Development from Magnetic Resonance Imaging: New Reference Data.

BACKGROUND: Accurate fetal brain volume estimation is of paramount importance in evaluating fetal development. The aim of this study was to develop an automatic method for fetal brain segmentation from magnetic resonance imaging (MRI) data, and to create for the first time a normal volumetric growth chart based on a large cohort. SUBJECTS AND METHODS: A semi-automatic segmentation method based on Seeded Region Growing algorithm was developed and applied to MRI data of 199 typically developed fetuses between 18 and 37 weeks' gestation. The accuracy of the algorithm was tested against a sub-cohort of ground truth manual segmentations. A quadratic regression analysis was used to create normal growth charts. The sensitivity of the method to identify developmental disorders was demonstrated on 9 fetuses with intrauterine growth restriction (IUGR). RESULTS: The developed method showed high correlation with manual segmentation (r2 = 0.9183, p < 0.001) as well as mean volume and volume overlap differences of 4.77 and 18.13%, respectively. New reference data on 199 normal fetuses were created, and all 9 IUGR fetuses were at or below the third percentile of the normal growth chart. DISCUSSION: The proposed method is fast, accurate, reproducible, user independent, applicable with retrospective data, and is suggested for use in routine clinical practice.

Schema benefit vs. proactive interference: Contradicting behavioral outcomes and coexisting neural patterns.

Prior knowledge can either assist or hinder the ability to learn new information. These contradicting behavioral outcomes, referred to as schema benefit and proactive interference respectively, have been studied separately. Here we examined whether the known neural correlates of each process coexist, and how they are influenced by attentional loading and aging. To this end we used an fMRI task that affected both processes simultaneously by presenting pairs of related short movies in succession. The first movie of each pair provided context for the second movie, which could evoke schema benefit and/or proactive interference. Inclusion of an easy or hard secondary task performed during encoding of the movies, as well as testing both younger (22-35y) and older (65-79y) adults, allowed examining the effect of attentional load and older age on the neural patterns associated with context. Analyses focused on three predefined regions and examined how their inter-subject correlation (inter-SC) and functional connectivity (FC) with the hippocampi changed between the first and second movie. The results in the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) matched and expanded previous findings: higher inter-SC and lower FC were observed during the second compared to the first movie; yet the differentiation between the first and second movies in these regions was attenuated under high attentional load, pointing to dependency on attentional resources. Instead, at high load there was a significant context effect in the FC of the left ventrolateral prefrontal cortex (vlPFC), and greater FC in the second movie was related to greater proactive interference. Further, older adults showed context effect in the PCC and vlPFC. Intriguingly, older adults with inter-SC mPFC patterns similar to younger adults exhibited schema benefit in our task, while those with inter-SC PCC patterns similar to younger adults showed proactive interference in an independent task. The brain-behavior relationships corroborate the functional significance of these regions and indicate that the mPFC mainly contributes to schema benefit, while the left vlPFC and PCC contribute to proactive interference. Importantly, our findings show that the functions of the regions are retained throughout the lifespan and may predict the predominant behavioral outcome.

Cortical Reorganization following Injury Early in Life.

The brain has a remarkable capacity for reorganization following injury, especially during the first years of life. Knowledge of structural reorganization and its consequences following perinatal injury is sparse. Here we studied changes in brain tissue volume, morphology, perfusion, and integrity in children with hemiplegia compared to typically developing children, using MRI. Children with hemiplegia demonstrated reduced total cerebral volume, with increased cerebrospinal fluid (CSF) and reduced total white matter volumes, with no differences in total gray matter volume, compared to typically developing children. An increase in cortical thickness at the hemisphere contralateral to the lesion (CLH) was detected in motor and language areas, which may reflect compensation for the gray matter loss in the lesion area or retention of ipsilateral pathways. In addition, reduced cortical thickness, perfusion, and surface area were detected in limbic areas. Increased CSF volume and precentral cortical thickness and reduced white matter volume were correlated with worse motor performance. Brain reorganization of the gray matter within the CLH, while not necessarily indicating better outcome, is suggested as a response to neuronal deficits following injury early in life.

The Impact of Childhood Hearing Loss on the Family: Mothers' and Fathers' Stress and Coping Resources.

Parenting children who are deaf or hard of hearing (D/HH) presents unique long-term challenges that can place the parents at a greater risk for elevated levels of parenting stress. Adaptation of families to the various challenges presented by childhood hearing loss is influenced by their personal and social coping resources available for managing these stressors and challenges. The current study examined differences in parenting stress and personal (i.e., acceptance of the child who is D/HH and parents' sense of parenting self-efficacy) and social (i.e., formal and informal social support) coping resources between mothers and fathers of children who are D/HH in the Arab sector in Israel. Further, the study examined the relations between coping resources and parenting stress among these parents. Participants included 30 Israeli Arab mother-father couples (n = 60) having a child who is D/HH aged 3-8 years. Findings revealed no significant differences between mothers and fathers regarding parenting stress, child acceptance, or parental support systems. However, mothers reported significantly higher self-efficacy. In addition, correlation analysis indicated that higher coping resources decreased parenting stress levels. Theoretical and practical implications of parental gender in the context of cultural background are discussed regarding parent intervention programs.

On behalf of tradition: An analysis of medical student and physician beliefs on how anatomy should be taught.

Human anatomy, one of the basic medical sciences, is a time-honored discipline. As such, it is taught using traditional methods, cadaveric dissection chief among them. Medical imaging has recently gained popularity as a teaching method in anatomy courses. In light of a general tendency to reduce course hours, this has resulted in a decrease of dissection time and intense debates between traditional and modern approaches to anatomy teaching. In an attempt to explore trends in the attitudes of medical professionals toward the various methods of anatomy teaching, medical imaging in particular, the authors constructed a questionnaire and conducted a nationwide survey among medical students (in all stages at medical school), residents, and specialists in all fields of medicine. The survey results demonstrated indisputable appreciation of traditional methods of anatomy teaching, particularly cadaveric dissection, and showed that specialists believe significantly more strongly than clinical or preclinical students that anatomy and medical imaging should be taught separately. Strong correlations among the components of the traditional approach to anatomy instruction were also found. In light of the results, it was recommended that imaging should be incorporated into anatomy courses with caution, and, as far as possible, not at the expense of dissection time. It was advised that medical imaging has to be taught as a separate course, parallel to a traditional anatomy course. This will allow anatomical principles to be appreciated, which in turn will serve the students when they study radiology. "And we proceed in the following order: in front walks Nikolai with the slides or atlases, I come after him, and after me, his head humbly lowered, strides the cart horse; or else, if necessary, a cadaver is carried in first, after the cadaver walks Nikolai, and so on. At my appearance, the students rise, then sit down, and the murmur of the sea suddenly grows still. Calm ensues." -From "A Boring Story: From the Notebook of an Old Man" by Anton Chekhov.

Recurrent aphthous stomatitis: stress, trait anger and anxiety of patients.

In this case-control study, recent stress and trait anger/anxiety of otherwise healtlhy patients with active recurrent aphthous stomatitis were compared to those of dental patients with no history of RAS (controls). RAS group reported more angry/anxious feelings than controls (2.11 +/- 0.38/1.84 +/- 0.30, respectively; p < 0.001), and more recent stress (2.81 +/- 1.36/1.96 +/- 1.02; p < 0.01). Among subjects with high angriness/ anxiety, RAS subjects showed higher stress level (p < 0.005). The study revealed that anger/anxiety level mediates the relationship between stress level and RAS.

Comparing Indirect and Combined Effects of Mindfulness and Compassion Practice Among Schoolchildren on Inter- and Intra-personal Abilities.

Objectives: During the last decade, mindfulness-based interventions have been implemented in the educational system. Such programs could follow several approaches, including an indirect approach, in which interventions are delivered only to teachers and a combination in which interventions are delivered to both teachers and students. Because of the importance of teacher's involvement in programs designed to help children, we compared students' impact of indirect, combined, and control groups over time. The indirect program delivered was the "Call to Care - Israel for Teachers," and the direct program was the "Call to Care Israel" for students. Both programs employ mindfulness, compassion, and training of social-emotional skills, with a unique emphasis on care. Methods: Two hundred 4th and 5th grade students were divided into indirect (2 classrooms), combined (3 classrooms), or control groups (3 classrooms). Each condition was implemented in a different school; schools were randomly divided into groups. The interventions were delivered by trained facilitators and included 20 weekly meetings. Outcomes for students were measured before the intervention, after it ended, and 6 months later. Results: Hierarchical linear models revealed that both the indirect and the combined approaches were effective in improving well-being, anxiety, attention, and teacher's availability and acceptance, while only the combined approach was effective in improving mindfulness, somatization, classroom atmosphere, and pro-social behavior. Conclusions: Our results suggest that the combined approach is more beneficial than the indirect approach. However, given the scalability and cost of the indirect approach, it should also be considered an effective alternative. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-01955-y.

Reducing Test Anxiety by Device-Guided Breathing: A Pilot Study.

Test anxiety remains a challenge for students and has considerable physiological and psychological impacts. The routine practice of slow, Device-Guided Breathing (DGB) is a major component of behavioral treatments for anxiety conditions. This paper addresses the effectiveness of using DGB as a self-treatment clinical tool for test anxiety reduction. This pilot study sample included 21 healthy men and women, all college students, between the ages of 20 and 30. Participants were randomly assigned to two groups: DGB practice (n = 10) and wait-list control (n = 11). At the beginning and the end of 3-weeks DGB training, participants underwent a stress test, followed by measures of blood pressure and reported anxiety. Anxiety reduction in the DGB group as compared to controls was not statistically significant, but showed a large effect size. Accordingly, the clinical outcomes suggested that daily practice of DGB may lead to reduced anxiety. We assume that such reduction may lead to improved test performance. Our results suggest an alternative treatment for test anxiety that may also be relevant for general anxiety, which is likely to increase due to the ongoing COVID-19 pandemic.

Abnormal white matter integrity in young children with autism.

This study investigated white matter integrity in young children with autism using diffusion tensor imaging (DTI). Twenty-two children with autism, mean age 3:2 years, and 32 controls, mean age 3:4 years, participated in the study. Tract-based spatial statistics (TBSS) revealed white matter abnormalities in several distinct clusters within the genu and body of the corpus callosum (CC), left superior longitudinal fasciculus (SLF) and right and left cingulum (Cg). TBSS-VOIs analysis was performed in the clusters where differences in fractional anisotropy (FA) were detected to investigate the relationship between changes in FA and diffusivity indices. In all VOIs, increase in FA was caused by a decrease in radial diffusivity (Dr), while no changes in axial diffusivity (Da) or mean diffusivity (MD) were observed. Tractography analysis was applied to further study the CC, SLF, and Cg. Witelson parcellation scheme was used for the CC. Significant increase in FA was seen in children with autism in the mid-body of the CC as well as in the left Cg. It is suggested that such abnormal white matter integrity in young children with autism may adversely affect connectivity between different brain regions and may be linked to some of the behavioral impairments apparent in autism.

A potential tool for the diagnosis of ALS based on diffusion tensor imaging.

Our objective was to quantify and better understand white matter (WM) impairment in patients with amyotrophic lateral sclerosis (ALS) and to propose a model based on diffusion tensor imaging (DTI) for diagnosing patients with suspected ALS with upper motor neuron (UMN) signs. Twenty-six ALS patients (24 with prominent UMN signs and two with an isolated lower-motor neuron (LMN) syndrome) and 22 healthy volunteers were examined using DTI. Data analysis included voxel-based WM tract-based spatial statistics (TBSS), volume-of-interest analysis of the TBSS results and stream-line tractography analysis. Converging evidence revealed WM impairment along the corticospinal tracts and in the mid-body of the corpus callosum. This was demonstrated by reduced fractional anisotropy values caused by increased radial diffusivity, without significant changes in axial diffusivity. There were no significant correlations between diffusivity indices and patients' disability or disease duration. A discriminant analysis model based on the tractography results was designed to distinguish between patients with UMN signs and controls, yielding 87.5% sensitivity and 85% specificity. In conclusion, DTI can detect WM impairment in patients with ALS in several brain regions, and might be a sensitive tool for the diagnosis of ALS in the early stages of the disease with UMN involvement.

Critical Dynamics in Spontaneous Resting-State Oscillations Are Associated With the Attention-Related P300 ERP in a Go/Nogo Task.

Sustained attention is the ability to continually concentrate on task-relevant information, even in the presence of distraction. Understanding the neural mechanisms underlying this ability is critical for comprehending attentional processes as well as neuropsychiatric disorders characterized by attentional deficits, such as attention deficit hyperactivity disorder (ADHD). In this study, we aimed to investigate how trait-like critical oscillations during rest relate to the P300 evoked potential-a biomarker commonly used to assess attentional deficits. We measured long-range temporal correlations (LRTC) in resting-state EEG oscillations as index for criticality of the signal. In addition, the attentional performance of the subjects was assessed as reaction time variability (RTV) in a continuous performance task following an oddball paradigm. P300 amplitude and latencies were obtained from EEG recordings during this task. We found that, after controlling for individual variability in task performance, LRTC were positively associated with P300 amplitudes but not latencies. In line with previous findings, good performance in the sustained attention task was related to higher P300 amplitudes and earlier peak latencies. Unexpectedly, we observed a positive relationship between LRTC in ongoing oscillations during rest and RTV, indicating that greater criticality in brain oscillations during rest relates to worse task performance. In summary, our results show that resting-state neuronal activity, which operates near a critical state, relates to the generation of higher P300 amplitudes. Brain dynamics close to criticality potentially foster a computationally advantageous state which promotes the ability to generate higher event-related potential (ERP) amplitudes.

The functional significance of the P600: Some linguistic P600's do localize to language areas.

A recent paper in the journal Neuroreport suggested that, upon source localization, the semantic P600 localizes to executive function areas, that is, outside language. But is this true for all types of linguistic P600? We report a cross-sectional source localization study of a classical (agreement) syntactic paradigm.The results show a clear localization to the temporal lobe, in classical language areas.The P600 is probably not a unitary phenomenon in term of source localization, and the question whether it localizes within or outside the language system depends on the type of P600.

Macro- and microstructural gray matter alterations in sexually assaulted women.

BACKGROUND: Studies with trauma survivors documented structural alterations in brain regions involved in posttraumatic stress disorder (PTSD) neurocircuitry. Nonetheless, whether such alterations exist in women who were sexually assaulted in adulthood is not clear. We investigated the macro- and microstructure of key regions implicated in PTSD pathophysiology, namely the amygdala, hippocampus, anterior cingulate cortex (ACC), and insula, in this population. METHODS: Thirty-eight sexually assaulted women (PTSD, n = 25; non-PTSD, n = 13) and 24 non-exposed controls (NEC) were studied with T1- and diffusion-weighted MRI. Gray matter volume, mean diffusivity (MD), and fractional anisotropy (FA) were calculated for each region. Between-group comparisons and correlations with PTSD symptom severity were performed. RESULTS: Volumetric analyses revealed lower amygdala and insula volumes in the PTSD compared with the non-PTSD group. In contrast, altered microstructure was observed in both traumatized groups compared with NEC, including higher MD and lower FA in the right amygdala, and higher FA in the ACC bilaterally. Finally, the non-PTSD group had higher FA in the right insula compared with the PTSD group. PTSD symptom severity was correlated with amygdala and insula volumes, as well as with hippocampal FA and MD. LIMITATIONS: Sample size may have led to reduced statistical power. CONCLUSIONS: Sexual assault and the development of PTSD in women are linked with structural alterations in key regions implicated in PTSD following other trauma types (e.g., combat), though hippocampal and ACC volumes were preserved. Further studies are needed to disentangle the unique contribution of trauma type and of sex/gender to these observations.

The influence of mindfulness meditation on inattention and physiological markers of stress on students with learning disabilities and/or attention deficit hyperactivity disorder.

BACKGROUND: Over recent decades, the number of students diagnosed with learning disabilities and/or attention deficit hyperactivity disorders has substantially increased. These students face various challenges and experience stress when receiving higher education. AIMS: The purpose of this study was to compare two non-pharmacological interventions: mindfulness and device-guided slow breathing, with a control group. METHODS: Seventy-three students (age = 25.76, std. dev = 3.10) with attention problems and/or learning disabilities were randomly assigned to three groups: mindfulness meditation, device guided breathing practice and waiting-list control. Before and after the intervention physiological and psychological measures were collected. RESULTS: Our results show that only mindfulness practice improved awareness of the present moment and decreased hyperactivity and inattention. Furthermore, both mindfulness and practice with device-guided breathing were associated with stress reduction, as shown by an increase in the galvanic skin response only in the control group. CONCLUSIONS: Implementation of the study results may lead to an advance in treating attention deficit disorders and learning disabilities, especially among higher education students.

Placental vascular tree characterization based on ex-vivo MRI with a potential application for placental insufficiency assessment.

INTRODUCTION: Understanding regarding the whole placental vascular network structure is limited. Our aim was to quantitatively characterize the human placental vascular tree ex-vivo using high-resolution MRI. METHODS: 34 normal placentas were rinsed and injected with a solution of gelatin and contrast agent through the umbilical vessels. A sample of six placentas taken from pregnancies with intrauterine-growth-restriction (IUGR) was used to demonstrate the potential application to cases with placental insufficiency. Structural ex-vivo MR scans of the placenta were performed using high resolution T1 weighted images. A semi-automatic method was developed to segment and characterize the placental vascular architecture: placental volume and cord insertion location; number of bifurcations, generations and vessels diameters. RESULTS: Different vascular patterns were found in placentas with central versus marginal cord-insertion. Based on the placental volume and number of bifurcations we were able to predict birth weight. Furthermore, preliminary results on IUGR sample demonstrated the potential of this method to differentiate between small newborns with suspected IUGR from small normal newborns who reached their full growth potential. Results obtained using the automatic method were validated against manual values demonstrating no significant differences or bias. Histopathology supported the imaging findings. DISCUSSION: This is the first study to quantitatively characterize the human placental vascular architecture using high resolution ex-vivo MRI. Different patterns of vascular architecture may be related to different functioning of the placenta and affect fetal development. This method is simple, relatively fast, provides detailed information of the placental vascular architecture, and may have important clinical applications.

Placental vascular tree characterization based on ex-vivo MRI with a potential application for placental insufficiency assessment.

INTRODUCTION: Understanding regarding the whole placental vascular network structure is limited. Our aim was to quantitatively characterize the human placental vascular tree ex-vivo using high-resolution MRI. METHODS: 34 normal placentas were rinsed and injected with a solution of gelatin and contrast agent through the umbilical vessels. A sample of six placentas taken from pregnancies with intrauterine-growth-restriction (IUGR) was used to demonstrate the potential application to cases with placental insufficiency. Structural ex-vivo MR scans of the placenta were performed using high resolution T1 weighted images. A semi-automatic method was developed to segment and characterize the placental vascular architecture: placental volume and cord insertion location, number of bifurcations, generations and vessels diameters. RESULTS: Different vascular patterns were found in placentas with central versus marginal cord-insertion. Based on the placental volume and number of bifurcations we were able to predict birth weight. Furthermore, preliminary results on IUGR sample demonstrated the potential of this method to differentiate between small newborns with suspected IUGR from small normal newborns who reached their full growth potential. Results obtained using the automatic method were validated against manual values demonstrating no significant differences or bias. Histopathology supported the imaging findings. DISCUSSION: This is the first study to quantitatively characterize the human placental vascular architecture using high resolution ex-vivo MRI. Different patterns of vascular architecture may be related to different functioning of the placenta and affect fetal development. This method is simple, relatively fast, provides detailed information of the placental vascular architecture, and may have important clinical applications.