In vivo imaging enables high resolution preclinical trials on patients' leukemia cells growing in mice.

Xenograft mouse models represent helpful tools for preclinical studies on human tumors. For modeling the complexity of the human disease, primary tumor cells are by far superior to established cell lines. As qualified exemplary model, patients' acute lymphoblastic leukemia cells reliably engraft in mice inducing orthotopic disseminated leukemia closely resembling the disease in men. Unfortunately, disease monitoring of acute lymphoblastic leukemia in mice is hampered by lack of a suitable readout parameter

Modulation of Human Time Processing by Subthalamic Deep Brain Stimulation

Timing in the range of seconds referred to as interval timing is crucial for cognitive operations and conscious time processing. According to recent models of interval timing basal ganglia (BG) oscillatory loops are involved in time interval recognition. Parkinsońs disease (PD) is a typical disease of the basal ganglia that shows distortions in interval timing. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment of PD which modulates motor and cognitive functions depending on stimulation frequency by affecting subcortical-cortical oscillatory loops. Thus, for the understanding of BG-involvement in interval timing it is of interest whether STN-DBS can modulate timing in a frequency dependent manner by interference with oscillatory time recognition processes. We examined production and reproduction of 5 and 15 second intervals and millisecond timing in a double blind, randomised, within-subject repeated-measures design of 12 PD-patients applying no, 10-Hz- and ≥130-Hz-STN-DBS compared to healthy controls. We found under(re-)production of the 15-second interval and a significant enhancement of this under(re-)production by 10-Hz-stimulation compared to no stimulation, ≥130-Hz-STN-DBS and controls. Milliseconds timing was not affected. We provide first evidence for a frequency-specific modulatory effect of STN-DBS on interval timing. Our results corroborate the involvement of BG in general and of the STN in particular in the cognitive representation of time intervals in the range of multiple seconds

Clinical Outcome of Subthalamic Stimulation in Parkinson's Disease is Improved by Intraoperative Multiple Trajectories Microelectrode Recording

Background and Study Aims The use of multiple trajectories microelectrode recording (MER) during implantation of deep brain stimulation (DBS) electrodes into the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) is discussed controversially because of possible risks and unclear benefits. The aim of the study is to investigate whether MER combined with intraoperative evaluation of stimulation effects improve clinical outcome in PD patients undergoing STN DBS surgery.Material and Methods Prior to final DBS electrode implantation, we performed multiple trajectories MER and intraoperative test stimulations after magnetic resonance imaging (MRI)-guided planning in 32 PD patients. In further 10 patients no MER (only intraoperative test stimulation) was used.Results We found a significantly better clinical outcome (Unified Parkinson's Disease Rating Scale [UPDRS] III) in patients undergoing MER compared with non-MER patients. In MER patients, DBS electrode placement was performed using the central trajectory in 73%. Another than the central trajectory was taken in 27% of the patients. No difference in clinical outcome between DBS electrodes implanted on the central or a decentral trajectory was observed.Conclusions DBS surgery based on intraoperative multiple trajectories MER and test stimulation improves clinical outcome if compared with intraoperative test stimulation alone. The data suggest that DBS surgery solely based on MRI and intraoperative test stimulation without MER may lead to nonoptimal placement of DBS electrodes and consequently poorer clinical outcome

Mean results of time discrimination.

<p>Point of subjective equality (PSE) and just noticeable difference (JND) in ms (with SEM) for controls, PD-patients with stimulation OFF, > = 130 Hz and 10 Hz.</p

Patient characteristics with sex, age, disease duration, daily anti-parkinson medication, months since implantation in the subthalamic nucleus, disease type, predominant side, MDRS and BDI scores.

<p>Patient characteristics with sex, age, disease duration, daily anti-parkinson medication, months since implantation in the subthalamic nucleus, disease type, predominant side, MDRS and BDI scores.</p

Mean results of interval timing.

<p>A: Mean results of time reproduction; B: Mean results of time production. Mean relative deviation (with SEM) from the target interval of 5 and 15 s for controls, PD-patients with stimulation OFF, > = 130 Hz and 10 Hz. Significant differences: *p< = 0.05; **p< = 0.01, ***p< = 0.001. Comparisons: continuous line: stimulation effect within PD group, dashed line: disease effect.</p

Mean results of tapping.

<p>Mean intertap interval in ms (with SEM) of paced and unpaced tapping for controls, PD-patients with stimulation OFF, > = 130 Hz and 10 Hz. Significant difference between paced and unpaced: **p<0.01.</p

Paradigms.

<p>Illustration of the paradigms for time reproduction, time production, time discrimination and tapping. *10 cycles per interval, total of 20 trials; **10 steps of 80 ms, 5 cycles per interval, 10 cycles per each deviance (80, 160, 240, 320, 400 ms) from standard interval, total of 50 trials; ***total of 20 trials.</p

Stimulation parameters used for long term stimulation and active stimulation contact (monopolar, with impulse generator used as anode) for each hemisphere.

<p>Abbreviations: V  =  Volt; µs  =  Microseconds; Hz  =  Hertz.</p

Stimulated area.

<p>Mean location of active contacts highlighted and marked with a white arrow at axial slice 3.5 mm under MCP of the Schaltenbrand and Wahren Atlas. Mean coordinates ± standard deviation were: right hemisphere: x-coordinate  = 13.7±1.7, y-coordinate  = −0.5±2.1, z-coordinate  = −2.4±2.0; left hemisphere: x-coordinate  = 13.0±1.3, y-coordinate  = −0.3±2.3, z-coordinate  = −2.8±2.8 Figure is based on the Cerefy Clinical Brain Atlas <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024589#pone.0024589-Nowinski1" target="_blank">[53]</a>. Abbreviations: STN  =  Nucleus subthalamicus; Gpe  =  Globus pallidus pars externus; Gpi  =  Globus pallidus pars internus; RN  =  Nucleus ruber; SN  =  substantia nigra.</p