Substantia nigra activity level predicts trial-to-trial adjustments in cognitive control

Effective adaptation to the demands of a changing environment requires flexible cognitive control. The medial and the lateral frontal cortices are involved in such control processes, putatively in close interplay with the BG. In particular, dopaminergic projections from the midbrain (i.e., from the substantia nigra [SN] and the ventral tegmental area) have been proposed to play a pivotal role in modulating the activity in these areas for cognitive control purposes. In that dopaminergic involvement has been strongly implicated in reinforcement learning, these ideas suggest functional links between reinforcement learning, where the outcome of actions shapes behavior over time, and cognitive control in a more general context, where no direct reward is involved. Here, we provide evidence from functional MRI in humans that activity in the SN predicts systematic subsequent trial-to-trial RT prolongations that are thought to reflect cognitive control in a stop-signal paradigm. In particular, variations in the activity level of the SN in one trial predicted the degree of RT prolongation on the subsequent trial, consistent with a modulating output signal from the SN being involved in enhancing cognitive control. This link between SN activity and subsequent behavioral adjustments lends support to theoretical accounts that propose dopaminergic control signals that shape behavior both in the presence and in the absence of direct reward. This SN-based modulatory mechanism is presumably mediated via a wider network that determines response speed in this task, including frontal and parietal control regions, along with the BG and the associated subthalamic nucleus

Multifocal invasive ductal breast cancer with osteoclast-like giant cells: a case report

<p>Abstract</p> <p>Introduction</p> <p>To the best of our knowledge, this is the first case report of a multifocal (trifocal) invasive carcinoma of the breast containing osteoclast-like giant cells.</p> <p>Case presentation</p> <p>A 64-year-old Caucasian woman presented for routine mammography screening with three radiodense lesions in the lower inner quadrant of the right breast, a primary breast cancer. Microscopic examination showed three foci of invasive ductal carcinoma with multinucleated osteoclast-like giant cells. Osteoclast-like giant cells in breast cancer are a rare phenomenon. They are described in less than two percent of all breast cancers and occur in association with invasive ductal cancer and invasive lobular cancer. In addition, osteoclast-like giant cells have been described in several sarcomas and metaplastic carcinomas of the breast.</p> <p>Conclusion</p> <p>To the best of our knowledge, this is the first report of a multifocal infiltrating ductal carcinoma of the breast containing osteoclast-like giant cells. This could be an indication for a possible early event in carcinogenesis associated with a biological event or secretion that indicates the differentiation and/or migration of stromal cells or macrophages.</p

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A &lt; AV &gt; V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis

Efficient Visual Search from Synchronized Auditory Signals Requires Transient Audiovisual Events

BACKGROUND: A prevailing view is that audiovisual integration requires temporally coincident signals. However, a recent study failed to find any evidence for audiovisual integration in visual search even when using synchronized audiovisual events. An important question is what information is critical to observe audiovisual integration. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that temporal coincidence (i.e., synchrony) of auditory and visual components can trigger audiovisual interaction in cluttered displays and consequently produce very fast and efficient target identification. In visual search experiments, subjects found a modulating visual target vastly more efficiently when it was paired with a synchronous auditory signal. By manipulating the kind of temporal modulation (sine wave vs. square wave vs. difference wave; harmonic sine-wave synthesis; gradient of onset/offset ramps) we show that abrupt visual events are required for this search efficiency to occur, and that sinusoidal audiovisual modulations do not support efficient search. CONCLUSIONS/SIGNIFICANCE: Thus, audiovisual temporal alignment will only lead to benefits in visual search if the changes in the component signals are both synchronized and transient. We propose that transient signals are necessary in synchrony-driven binding to avoid spurious interactions with unrelated signals when these occur close together in time

Influence of patient and tumor characteristics on therapy persistence with letrozole in postmenopausal women with advanced breast cancer: results of the prospective observational EvAluate-TM study

Background: Treatment of postmenopausal, hormone receptor-positive metastatic breast cancer (MBC) patients varies despite clear therapy guidelines, favoring endocrine treatment (ET). Aim of this study was to analyze persistence of palliative aromatase inhibitor (AI) monotherapy in MBC patients. Methods: EvAluate-TM is a prospective, multicenter, noninterventional study to evaluate treatment with letrozole in postmenopausal women with hormone receptor–positive breast cancer. To assess therapy persistence, defined as the time from therapy start to the end of the therapy (TTEOT), two pre-specified study visits took place after 6 and 12 months. Competing risk survival analyses were performed to identify patient and tumor characteristics that predict TTEOT. Results: Out of 200 patients, 66 patients terminated treatment prematurely, 26 (13%) of them due to causes other than disease progression. Persistence rate for reasons other than progression at 12 months was 77.7%. Persistence was lower in patients who reported any adverse event (AE) in the first 30 days of ET (89.5% with no AE and 56% with AE). Furthermore, patients had a lower persistence if they reported compliance problems in the past before letrozole treatment. Conclusions: Despite suffering from a life-threatening disease, AEs of an AI will result in a relevant number of treatment terminations that are not related to progression. Some subgroups of patients have very low persistence rates. Especially with regard to novel endocrine combination therapies, these data imply that some groups of patients will need special attention to guide them through the therapy process. Trial registration Clinical Trials Number: CFEM345DDE1

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58–1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences