Using non-negative matrix factorization for single-trial analysis of fMRI data

The analysis of single trials of an fMRI experiment is difficult because the BOLD response has a poor signal to noise ratio and is sometimes even inconsistent across trials. We propose to use non-negative matrix factorization (NMF) as a new technique for analyzing single trials. NMF yields a matrix decomposition that is useful in this context because it elicits the intrinsic structure of the single-trial data. The results of the NMF analysis are then processed further using clustering techniques. In addition to analyzing single trials in one brain region, the method is also suitable for investigating interdependencies between trials across brain regions. The method even allows to analyze the effect that a trial has on a subsequent trial in a different region at a significant temporal offset. This distinguishes the present method from other methods that require interdependencies between brain regions to occur nearly simultaneously. The method was applied to fMRI data and found to be a viable technique that may be superior to other matrix decomposition methods for this particular problem domain.     

The right temporoparietal junction in attention and social interaction: A transcranial magnetic stimulation study

The right temporoparietal junction (rTPJ) has been associated with the ability to reorient attention to unexpected stimuli and the capacity to understand others' mental states (theory of mind [ToM]/false belief). Using activation likelihood estimation meta‐analysis we previously unraveled that the anterior rTPJ is involved in both, reorienting of attention and ToM, possibly indicating a more general role in attention shifting. Here, we used neuronavigated transcranial magnetic stimulation to directly probe the role of the rTPJ across attentional reorienting and false belief. Task performance in a visual cueing paradigm and false belief cartoon task was investigated after application of continuous theta burst stimulation (cTBS) over anterior rTPJ (versus vertex, for control). We found that attentional reorienting was significantly impaired after rTPJ cTBS compared with control. For the false belief task, error rates in trials demanding a shift in mental state significantly increased. Of note, a significant positive correlation indicated a close relation between the stimulation effect on attentional reorienting and false belief trials. Our findings extend previous neuroimaging evidence by indicating an essential overarching role of the anterior rTPJ for both cognitive functions, reorienting of attention and ToM. Hum Brain Mapp 37:796–807, 2016. © 2015 Wiley Periodicals, Inc .     

Method development and validation of an in vitro model of the effects of methylphenidate on membrane-associated synaptic vesicles

In vivo methylphenidate (MPD) administration decreases vesicular monoamine transporter-2 (VMAT-2) immunoreactivity in membrane-associated vesicles isolated from the striata of treated rats while concurrently kinetically upregulating VMAT-2-mediated vesicular dopamine (DA) sequestration. The functional consequences of these MPD-induced effects include an increase in both vesicular DA content and exocytotic DA release. This report describes experiments designed to develop and validate an in vitro MPD model to further elucidate the molecular mechanism(s) underlying the effects of MPD on the VMAT-2 in membrane-associated vesicles. Method development experiments revealed that in vitro MPD incubation of striatal homogenates, but not striatal synaptosomes, increased DA transport velocities and decreased VMAT-2 immunoreactivity in membrane-associated vesicles. An incubation time of 30min with a MPD concentration of 10mM was optimal. Method validation experiments indicated that in vitro MPD incubation kinetically upregulated VMAT-2 in membrane-associated vesicles, increased vesicular DA content, and increased exocytotic DA release. These results reveal that the in vitro MPD incubation model successfully reproduced the salient features of in vivo MPD administration. This in vitro MPD incubation model may provide novel insights into the receptor-mediated mechanism(s) of action of in vivo MPD in the striatum as well as the physiological regulation of vesicular DA sequestration and synaptic transmission. Accordingly, this in vitro model may help to advance the treatment of disorders involving abnormal DA disposition including Parkinson's disease, attention-deficit hyperactivity disorder, and substance abuse.     

Age‐dependent differences in dopamine transporter and vesicular monoamine transporter‐2 function and their implications for methamphetamine neurotoxicity

The abuse of methamphetamine (METH) is a serious public health problem because METH can cause persistent dopaminergic deficits in the brains of both animal models and humans. Surprisingly, adolescent postnatal day (PND)40 rats are resistant to these METH‐induced deficits, whereas young adult PND90 rats are not. Studies described in this report used rotating disk electrode voltammetry and western blotting techniques to investigate whether there are age‐dependent differences in monoamine transporter function in PND38–42 and PND88–92 rats that could contribute to this phenomenon. The initial velocities of dopamine (DA) transport into, METH‐induced DA efflux from, and DA transporter (DAT) immunoreactivity in striatal suspensions are greater in PND38–42 rats than in PND88–92 rats. DA transport velocities into vesicles that cofractionate with synaptosomal membranes after osmotic lysis are also greater in PND38–42 rats. However, there is no difference in vesicular monoamine transporter‐2 (VMAT‐2) immunoreactivity between the two age groups in this fraction. This suggests that younger rats have a greater capacity to sequester cytoplasmic DA into membrane‐associated vesicles due to kinetically upregulated VMAT‐2 and also have increased levels of functionally active DAT. In the presence of METH, these may provide additional routes of cellular efflux for DA that is released from vesicles into the cytoplasm and thereby prevent cytoplasmic DA concentrations in younger rats from rising to neurotoxic levels after drug administration. These findings provide novel insight into the age‐dependent physiological regulation of neuronal DA sequestration and may advance the treatment of disorders involving abnormal DA disposition including substance abuse and Parkinson's disease. Synapse 63:147–151, 2009. © 2008 Wiley‐Liss, Inc.     

Evidence-based practice and the road to Magnet status

Conducting research and using evidence-based practice play a major role in achieving Magnet status, the sought-after recognition awarded by the American Nurses Credentialing Center to healthcare institutions that exhibit nursing excellence. The authors present a synopsis of a conference sponsored by a Sigma Theta Tau International consortium in which a panel of nurse leaders distinguishes between research and evidence-based practice and discusses strategies to achieve both in the journey to Magnet status.     

Altered drug disposition of the platelet activating factor antagonist apafant in mdr1a knockout mice.

The aim of the present study was to determine a potential impact of P-glycoprotein (P-gp) on the tissue distribution and disposition of apafant (WEB 2086, CAS 105219-56-5), a selective platelet-activating factor antagonist, and on digoxin in mdr1a(-/-) and wildtype mice. Transport experiments in Caco-2 monolayers at low concentrations (<10 microM) showed that the secretory flux of [(14)C]apafant and [(3)H]digoxin exceeded the absorptive flux nine times. This efflux was concentration dependent and subject to inhibition by the P-gp substrates verapamil and cyclosporin A. This indicates that active drug transporter P-gp was involved in apafant and digoxin absorption. Mdr1a(-/-) mice showed a more than 70-fold higher concentration of digoxin-related radioactivity (P<0.001) in the brain than wildtype mice after intravenous doses of 0.05 mg/kg [(3)H]digoxin. Differences were less pronounced in other tissues. Both liquid scintillation counting and whole body autoradiography yielded comparable results and they also matched recently published data. Apafant-related radioactivity was about ten-fold higher in the brain of mdr1a(-/-) mice compared to wildtype mice following intravenous doses of 2 mg/kg radiolabelled apafant. Only slight or negligible differences were observed in other tissues. In wildtype mice, intestinal excretion of [(14)C]apafant (54.9%) exceeded biliary excretion (26.5%). However, in mdr1a(-/-) mice biliary excretion (50.7%) exceeded intestinal excretion (6.8%). These differences were mirrored in the urinary and faecal excretion. Pharmacokinetic parameters of apafant and radioactivity did not differ between wildtype and mdr1a(-/-) mice. The conclusions were: (1) apafant and digoxin are P-gp substrates, and (2) absence of mdr1a encoded P-gp significantly alters tissue distribution (especially in brain) and excretion routes (biliary and intestinal) of apafant.