Portraying emotions at their unfolding: a multilayered approach for probing dynamics of neural networks

Dynamic functional integration of distinct neural systems plays a pivotal role in emotional experience. We introduce a novel approach for studying emotion-related changes in the interactions within and between networks using fMRI. It is based on continuous computation of a network cohesion index (NCI), which is sensitive to both strength and variability of signal correlations between pre-defined regions. The regions encompass three clusters (namely limbic, medial prefrontal cortex (mPFC) and cognitive), each previously was shown to be involved in emotional processing. Two sadness-inducing film excerpts were viewed passively, and comparisons between viewer's rated sadness, parasympathetic, and inter-NCI and intra-NCI were obtained. Limbic intra-NCI was associated with reported sadness in both movies. However, the correlation between the parasympathetic-index, the rated sadness and the limbic-NCI occurred in only one movie, possibly related to a "deactivated" pattern of sadness. In this film, rated sadness intensity also correlated with the mPFC intra-NCI, possibly reflecting temporal correspondence between sadness and sympathy. Further, only for this movie, we found an association between sadness rating and the mPFC-limbic inter-NCI time courses. To the contrary, in the other film in which sadness was reported to commingle with horror and anger, dramatic events coincided with disintegration of these networks. Together, this may point to a difference between the cinematic experiences with regard to inter-network dynamics related to emotional regulation. These findings demonstrate the advantage of a multi-layered dynamic analysis for elucidating the uniqueness of emotional experiences with regard to an unguided processing of continuous and complex stimulation.     

Interpretation for Discussions about End-of-Life Issues: Results from a National Survey of Health Care Interpreters

Abstract Background: Communication about end-of-life issues is difficult across language barriers. Little is known about the experience of health care interpreters in these discussions. Objectives: Objectives of this study were to: 1) assess the experiences of healthcare interpreters when interpreting discussions about end-of-life issues; 2) identify interpreter characteristics and experiences that may be associated with improved satisfaction and comfort with interpreting these discussions; and 3) describe interpreter training needs. Methods: The study utilized an electronically administered survey distributed nationally to health care interpreters in the United States. One hundred and forty-two health care interpreters participated. Measurements included general experiences, attitudes, and perceived training needs when interpreting discussions about end-of-life issues. Results: Most respondents had received a certificate in interpretation (71%, 101/142), completed more than 40 hours of training (89%, 127/142), and had more than 5 years of interpreting experience (65%, 93/142). Overall, 85% (121/142) of respondents had interpreted discussions about end-of-life issues and most interpreted multiple discussions per week. Of those interpreters who had experience with these discussions, the majority (85%, 103/121) reported feeling comfortable, but only half (48%, 58/121) reported that these discussions usually went well. Interpreters who felt clear about their role were more likely than interpreters who did not feel clear about their role to think that discussions went well (51% [57/112] versus 11% [1/9], p=0.02) and to feel comfortable interpreting (88% [98/112] versus 56% [5/9], p=0.01). Eighty percent (97/121) of respondents with experience in end-of-life discussions were personally interested in more specific training for these discussions. Attitudes and perceived training needs did not differ by interpreter demographics or qualifications. Conclusions: The majority of interpreters have experience with end-of-life discussions but, independent of interpreter training and experience, only half report that these discussions usually go well. Interpreters want and may benefit from targeted educational interventions that could improve the quality of care for vulnerable patients and families in these difficult situations. Health systems and interpreter certification programs should incorporate specific training on how to interpret discussion about end-of-life issues.     

Vamping: stereology-based automated quantification of fluorescent puncta size and density

The size of dendritic spines and postsynaptic densities (PSDs) is well known to be correlated with molecular and functional characteristics of the synapse. Thus, the development of microscopy methods that allow high throughput quantification and measurement of PSDs is a contemporary need in the field of neurobiology. While the gold standard for measurement of sub-micrometer structures remains electron microscopy (EM), this method is exceedingly laborious and therefore not always feasible. Immunohistochemistry (IHC) is a much faster technique for identifying biological structures such as PSDs, but the fluorescent images resulting from it have traditionally been harder to interpret and quantify. Here, we report on two new image analysis tools that result in accurate size and density measurements of fluorescent puncta. Anti-PSD-95 staining was used to target synapses. The new technique of vamping, using Volume Assisted Measurement of Puncta in 2 and 3 Dimensions (VAMP2D and VAMP3D) respectively, is based on stereological principles. The fully automated image analysis tool was tested on the same subjects for whom we had previously obtained EM measurements of PSD size and/or density. Based on highly consistent results between data obtained by each of these methods, vamping offers an expedient alternative to EM that can nonetheless deliver a high level of accuracy in measuring sub-cellular structures.     

Sex differences in panic-relevant responding to a 10% carbon dioxide-enriched air biological challenge

The current study examined sex differences in psychological (i.e., self-reported anxiety, panic symptoms, and avoidance) and physiological (i.e., heart rate and skin conductance level) response to, and recovery from, a laboratory biological challenge. Participants were a community-recruited sample of 128 adults (63.3% women; M(age)=23.2 years, SD=8.9) who underwent a 4-min 10% CO(2)-enriched air biological challenge. As predicted, women reported more severe physical panic symptoms and avoidance (i.e., less willingness to participate in another challenge) and demonstrated increased heart rate as compared to men above and beyond the variance accounted for by other theoretically relevant variables (recent panic attack history, neuroticism, and anxiety sensitivity). Additionally, women demonstrated a faster rate of recovery with respect to heart rate compared to men. These results are in line with literature documenting sex-specific differences in panic psychopathology, and results are discussed in the context of possible mechanisms underlying sex differences in panic vulnerability.     

Detection of asymptomatic nigrostriatal dopaminergic lesion in rats by exhaled air analysis using carbon nanotube sensors

The ante-mortem diagnosis of Parkinson's disease (PD) still relies on clinical symptoms. Biomarkers could in principle be used for the early detection of PD-related neuronal damage, but no validated, inexpensive, and simple biomarkers are available yet. Here we report on the breath-print of presymptomatic PD in rats, using a model with 50% lesion of dopaminergic neurons in substantia nigra. Exhaled breath was collected from 19 rats (10 lesioned and 9 sham operated) and analyzed using organically functionalized carbon nanotube sensors. Discriminant factor analysis detected statistically significant differences between the study groups and a classification accuracy of 90% was achieved using leave-one-out cross-validation. The sensors' breath-print was supported by determining statistically significant differences of several volatile organic compounds in the breath of the lesioned rats and the sham operated rats, using gas chromatography combined with mass spectrometry. The observed breath-print shows potential for cost-effective, fast, and reliable early PD detection.     

Magnetic resonance-guided focused ultrasound surgery (MRgFUS). Four ablation treatments of a single canine hepatocellular adenoma

Background. Canine hepatocellular adenomas are benign, well-differentiated, primary hepatic tumors. Surgical resection is technically demanding and is considered a major procedure with relatively high morbidity rates. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) uses focused ultrasonic energy to non-invasively create a heat-coagulated lesion deep within the body. This effect can be achieved in a controlled, accurate manner. The aim of this study was to evaluate the safety, accuracy and efficacy of non-invasive focal ablation of tissue volumes of a canine benign liver tumour by consecutive MRgFUS sonications. Materials and methods. Four MRgFUS procedures were performed in a 10-year-old, male, mixed large breed dog (45 kg) under general anaesthesia. The exact location and volume of the ablated areas were planned on the MR images. Real-time MR imaging and temperature mapping enabled the immediate evaluation of the effect of each sonication. Different areas were chosen within the tumour. These volumes of tumoral tissue were ablated by multiple sonications. To allow accurate targeting and quality imaging, sonications were performed during 20–30 s of apnoea. Between the sonications the dog was normally ventilated. The dog was operated 21 days after the fourth ablative procedure. The tumour was resected and histopathologically examined. Results. The MRgFUS created necrosis with contiguous areas of complete tissue destruction within the liver tumour, in full accordance with the planning. A focal thermal injury to the cartilage of the right lower ribs was noted after the fourth treatment. This lesion became infected and was treated surgically. Ten months after the last treatment the dog is well and healthy. Conclusions. Focused ultrasound ablation of liver tumoral tissue with MR guidance under general anaesthesia and controlled apnoea is a safe and accurate treatment modality. Its main advantage is that it is a completely non-invasive image-guided treatment. The ablation of significant volumes of a highly vascular liver tumoral tissue was achieved. Such tissue can be ablated in a very accurate manner, exactly according to the pretreatment planning on the MR images. The MR imaging characteristics, including real-time temperature mapping, enable real-time control of every step of the ablation process. Mechanical ventilation with intermittent apnoea periods overcomes the problem of the respiratory movements of the liver. Care must be taken to avoid the passage of the ultrasound beam through energy-absorbing calcified tissue.     

Germline mutations in RAD51C in Jewish high cancer risk families

Germline mutations in BRCA1 and BRCA2 account for ~30 % of inherited breast cancer. RAD51C was reported as an additional breast/ovarian cancer susceptibility gene in some populations. There is a paucity of data on the putative contribution of this gene to inherited breast/ovarian cancer in Jewish high risk families. High risk Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1 or BRCA2, were screened for RAD51C germline mutations by direct sequencing of exons and flanking intronic sequences. Overall, 206 high risk women, 79 (38.3 %) of Ashkenazi origin, were genotyped for RAD51C mutations: 190 (92.3 %) with uni- or bilateral breast cancer (mean age at diagnosis 51.3 ± 11.1 years), 14 with ovarian cancer (mean age at diagnosis 55.6 ± 8.7 years), and two with both breast and ovarian cancer. No truncating mutations were noted, and two previously described missense mutations were detected: p.Ile144Thr and p.Thr287Ala in Iraqi and mixed ethnicity Balkan-North African participants, respectively. These missense mutations were evolutionarily conserved, possibly pathogenic, based on some prediction algorithms, and were not detected in any of healthy Iraqi (n = 60) and mixed ethnicity (n = 140), cancer free controls, respectively. Germline mutations in RAD51C contribute marginally to breast and ovarian cancer susceptibility in ethnically diverse, Jewish high risk families. The p.Thr287Ala missense mutation may be a recurring, pathogenic RAD51C mutation in ethnically diverse populations.     

Phenocopy breast cancer rates in Israeli <Emphasis Type="Italic">BRCA1</Emphasis><Emphasis Type="Italic">BRCA2</Emphasis> mutation carrier families: is the risk increased in non-carriers?

BRCA1 and BRCA2 mutation carriers have an increased risk for developing breast (and ovarian) cancer. Non-carriers from within such families (=true negatives) are counseled that their risk for developing breast cancer is similar to that of the average-risk population. Breast cancer diagnosed in a non-carrier from a family with a known mutation is coined phenocopy. The rate of breast cancer phenocopy and the risk for breast cancer in true negatives are unsettled. The rate of phenocopy breast cancer was assessed in non-carriers from Jewish families with a BRCA1 or BRCA2 mutation, identified at the Sheba medical center. Analysis was performed by t test for comparison of mean age at counseling or breast cancer diagnosis, and by calculating a standardized incidence ratio (SIR). Overall, 1318 females from 884 mutation carrying families (620 with BRCA1 264 with BRCA2 mutations) were genotyped, of whom 307 women from 245 families were assigned a true negative status (mean age at counseling 43.01 ± 13.03 years (range 19.7–92.8 years). Of these true negatives, 20 women (6.51–2.26% of families) developed breast cancer at a mean age of 54.1 ± 12.9 years (range 48.1 –60.1 years). The SIR for breast cancer in true negatives was not significantly different than the expected in the average-risk Israeli population [observed 20-expected 23.8 cases SIR = 0.84, 95% CI (0.51, 1.30)]. The rate of phenocopy breast cancer in non-carriers from Israeli BRCA1 BRCA2 mutation carrier families is 2.26% with no increased breast cancer risk over the average-risk population.     

Appendectomy and cancer risk in Jewish BRCA1 and BRCA2 mutation carriers

Previous studies suggested that appendectomy may affect cancer risk in the general population. No data on the effect of appendectomy on cancer risk in BRCA1 and BRCA2 carriers is available. Data on appendectomy, cancer type, and age at diagnosis were collected from BRCA1 (n = 677) and BRCA2 (n = 270) female Jewish Israeli mutation carriers counseled in a single medical center. Data were also collected on 225 consecutive ovarian cancer cases treated at the same medical center. Overall, 367/947 (38.7%) of mutation carriers had breast cancer (age at diagnosis 44.1 ± 10.4 years), 142 (15.0%) ovarian cancer (53.6 ± 10.1 years), and 438 (46.25%) were asymptomatic carriers (age at counseling 41.4 ± 11.2 years). Mean age at diagnosis of consecutive ovarian cancer cases was 53.6 ± 10.1 years. Of mutation carriers, 28/367 breast cancer cases (7.6%), 15/142 ovarian cancer cases (10.6%), and 11/438 asymptomatic carriers (2.5%) underwent prior appendectomy (P = 0.001 for breast/ovarian cancer when compared with asymptomatic carriers). In all but two cases, appendectomy was performed more than 10 years before cancer diagnosis or age at counseling. Of ovarian cancer patients, 12/225 (5.3%) underwent appendectomy, and in 10 appendectomy was performed 10 years or more before ovarian cancer diagnosis (P = 0.068 when compared with inherited ovarian cancer cases). This study suggests that prior appendectomy is more frequently noted in BRCA1 and BRCA2 carriers with breast and ovarian cancer than in unaffected mutation carriers. The mechanism for this association is elusive, and future analyses of ethnically diverse mutation carriers are needed to validate these results.