text:
Subtype-specific statistical causalities in parkinsonian tremor.
ABSTRACT Tremor is one of the cardinal symptoms of Parkinson's disease. Up to now, however, its pathophysiology remains poorly understood. Previously, oscillatory coupling at tremor frequency between the subthalamic nucleus und affected muscles was shown. In these studies, however, causality of coupling could not be demonstrated. Thus, we analyzed the statistical causality between intraoperatively recorded local field potentials in the subthalamic area and affected arm muscles during tremor episodes, using squared partial directed coherence, a recently developed causality measure. The analysis identified differential statistical causality patterns for Parkinson's disease patients of the akinetic-rigid subtype during tremor episodes (n=6) versus patients of the tremor-dominant subtype (n=8): for the akinetic-rigid Parkinson's disease patients significantly more cases of the subthalamic region were found to be statistically causal for electromyographic-tremor activity, a result in accordance with the standard basal ganglia model. In contrast, for the tremor-dominant patients, significantly more instances of electromyographic tremor activity turned out to be causal for activity of the subthalamic region. Furthermore, the clinical effective stimulation site coincided with the location of most input causalities from the periphery in seven out of eight tremor-dominant patients. The data suggest that, although tremor activity in tremor-dominant and akinetic-rigid Parkinson's disease patients was clinically similar, statistical causality between tremor electromyogram (EMG) and the subthalamic nucleus was fundamentally different. Therefore, we hypothesize different pathophysiological mechanisms to underlie the generation of tremor in the two subtypes of Parkinson's disease.
- Esther Florin, Haidar Salimi Dafsari, Christiane Reck, Michael T Barbe, K Amande M Pauls, Mohammad Maarouf, Volker Sturm, Gereon R Fink, Lars Timmermann[Show abstract] [Hide abstract]
ABSTRACT: Investigations of local field potentials of the subthalamic nucleus of patients with Parkinson's disease have provided evidence for pathologically exaggerated oscillatory beta-band activity (13-30 Hz) which is amenable to physiological modulation by, e.g., voluntary movement. Previous functional magnetic resonance imaging studies in healthy controls have provided evidence for an increase of subthalamic nucleus blood-oxygenation-level-dependant signal in incremental force generation tasks. However, the modulation of neuronal activity by force generation and its relationship to peripheral feedback remain to be elucidated. We hypothesised that beta-band activity in the subthalamic nucleus is modulated by incremental force generation. Subthalamic nucleus local field potentials were recorded intraoperatively in 13 patients with Parkinson's disease (37 recording sites) during rest and five incremental isometric force generation conditions of the arm with applied loads of 0g to 400g (in 100g increments). Repeated measures ANOVA revealed a modulation of LFP power in the upper beta-band (in 24-30 Hz; F(3.042)=4.693, p=0.036) and the gamma-band (in 70-76 Hz; F(4)=4.116, p=0.036). Granger-causality was computed with the squared partial directed coherence and showed no significant modulation during incremental isometric force generation. Our findings indicate that the upper beta- and gamma-band power of subthalamic nucleus local field potentials are modulated by the physiological task of force generation in patients with Parkinson's disease. This modulation seems to be not an effect of a modulation of peripheral feedback.Neuroscience 02/2013; · 3.33 Impact Factor - SourceAvailable from: Alfons SchnitzlerDavid J Pedrosa, Christiane Reck, Esther Florin, K Amande M Pauls, Mohammad Maarouf, Lars Wojtecki, Haidar Salimi Dafsari, Volker Sturm, Alfons Schnitzler, Gereon R Fink, Lars Timmermann[Show abstract] [Hide abstract]
ABSTRACT: Different tremor entities such as Essential Tremor (ET) or tremor in Parkinson's disease (PD) can be ameliorated by the implantation of electrodes in the ventral thalamus for Deep Brain Stimulation (DBS). The exact neural mechanisms underlying this treatment, as well as the specific pathophysiology of the tremor in both diseases to date remain elusive. Since tremor-related local field potentials (LFP) have been shown to cluster with a somatotopic representation in the subthalamic nucleus, we here investigated the neurophysiological correlates of tremor in the ventral thalamus in ET and PD using power and coherence analysis. Local field potentials (LFPs) at different recording depths and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm were recorded simultaneously in twelve ET and five PD patients. Data analysis revealed individual electrophysiological patterns of LFP-EMG coherence at single and double tremor frequency for each patient. Patterns observed varied in their spatial distribution within the Ventral lateral posterior nucleus of the thalamus (VLp), revealing a specific topography of 'tremor clusters' for PD and ET. The data strongly suggest that within VLp individual tremor-related electrophysiological signatures exist in ET and PD tremor.Experimental Neurology 07/2012; 237(2):435-43. · 4.62 Impact Factor
Page 1
E. FLORIN,a,b* M. HIMMEL,aC. RECK,aM. MAAROUF,c
A. SCHNITZLER,d,eV. STURM,cG. R. FINKa,bAND
L. TIMMERMANNa*
aDepartment of Neurology, University Hospital Cologne, Kerpener
Strasse 62, 50937 Köln, Germany
bInstitute of Neuroscience and Medicine (INM-3), Cognitive Neurology
Section, Research Center Jülich, Leo-Brandt-Strasse 5, 52425 Jülich,
cDepartment of Stereotactic Neurosurgery, University Hospital Co-
logne, Kerpener Strasse 62, 50937 Köln, Germany
dDepartment of Clinical Neuroscience, Medical Psychology, Heinrich-
Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
eDepartment of Neurology, Heinrich-Heine-University, Moorenstrasse
5, 40225 Düsseldorf, Germany
Abstract—Tremor is one of the cardinal symptoms of Parkin-
son's disease. Up to now, however, its pathophysiology re-
mains poorly understood. Previously, oscillatory coupling at
tremor frequency between the subthalamic nucleus und af-
fected muscles was shown. In these studies, however, cau-
sality of coupling could not be demonstrated. Thus, we ana-
lyzed the statistical causality between intraoperatively re-
corded local field potentials in the subthalamic area and
affected arm muscles during tremor episodes, using squared
partial directed coherence, a recently developed causality
measure. The analysisidentifieddifferentialstatisticalcausality
patterns for Parkinson's disease patients of the akinetic-rigid
subtype during tremor episodes (n?6) versus patients of the
tremor-dominant subtype (n?8): for the akinetic-rigid Parkin-
son's disease patients significantly more cases of the sub-
thalamic region were found to be statistically causal for elec-
tromyographic-tremor activity, a result in accordance with
the standard basal ganglia model. In contrast, for the tremor-
dominant patients, significantly more instances of electro-
myographic tremor activity turned out to be causal for activ-
ity of the subthalamic region. Furthermore, the clinical effec-
tive stimulation site coincided with the location of most input
causalities from the periphery in seven out of eight tremor-
dominant patients. The data suggest that, although tremor
activity in tremor-dominant and akinetic-rigid Parkinson's
disease patients was clinically similar, statistical causality
between tremor electromyogram (EMG) and the subthalamic
nucleus was fundamentally different. Therefore, we hypoth-
esize different pathophysiological mechanisms to underlie
the generation of tremor in the two subtypes of Parkinson's
disease. © 2012 IBRO. Published by Elsevier Ltd. All rights
Key words: deep brain stimulation, connectivity, directional-
ity, human, subthalamic nucleus.
In the 1980s, Albin and DeLong (Albin et al., 1989; De-
Long, 1990) put forward a well-recognized model (Alberts
et al., 2008; Mallet et al., 2008) of basal ganglia patho-
physiology in Parkinson's disease (PD). This model can
successfully explain rigidity in PD patients through inhibi-
tory mechanisms in the basal ganglia loops, but has been
unable to fully explain PD tremor. Even though several
advances have been made of this classical model, the
generation of tremor can still not be completely explained
by these models (Obeso et al., 2008). Evidence for a
putative differential pathophysiology has been given from a
histopathological study (Jellinger, 1999) in which different
regions of degenerated dopaminergic neurons were iden-
tified in the substantia nigra pars compacta (SNc) for the
two parkinsonian subtypes, that is, tremor-dominant and
Based on Jellinger's findings, we hypothesized differ-
ential (statistical) causality patterns between the two PD
subtypes. Moreover, as the Albin et al. (1989) and DeLong
(1990) model, which primarily explains the akinetic-rigid
disease progression, describes the subthalamic nucleus
(STN) as an efferent structure, we hypothesized for aki-
netic-rigid patients to detect more STN output to the pe-
riphery, that is, the muscle electromyogram (EMG), than
input from the latter to the STN. As previous studies have
only analyzed statistical causality during rigidity and the
*Correspondence to: Dr. E. Florin or Prof. Dr. L. Timmermann, De-
partment of Neurology, University Hospital Cologne, Kerpener Strasse
62, 50937 Köln, Germany. Tel: ?49-221-478-86416; fax: ?49-221-
478-89002 or Tel: ?49-221-478-7494; fax: ?49-221-87512.
E-mail address: email@example.com (E. Florin) or Lars.
firstname.lastname@example.com (L. Timmermann).
Competing interests. Esther Florin: no conflict of interests
Matthias Himmel: no conflict of interests
Christiane Reck: employee of Medtronic GmbH
Mohammad Maarouf: honoraria (Medtronic), grants (BMBF, DFG)
Volker Sturm: stock ownership in medically related fields (ANM GmbH,
Cologne, Germany), honoraria (Medtronic)
Alfons Schnitzler: grants from the DFG, BMBF, Helmholtz Society, and
Volkswagen Foundation. He served—unrelated to the current proj-
ect—on scientific advisory boards of Pitie Salpetriere, Novartis, UCB,
and Cephalon. He received—unrelated to the current project—hono-
raria for lectures from Boehringer Ingelheim, Novartis, UCB, and
Gereon R. Fink: honoraria (GlaxoSmithKline, Boehringer Ingelheim,
Pfizer Pharma), grants (DFG, BMBF)
Lars Timmermann: advisory boards (Medtronic Inc.; International Clin-
ical Advisory Board), honoraria (Medtronic, Desitin Pharma, Boehringer
Ingelheim, Orion Pharma, UCB-Schwarz Pharma, GlaxoSmithKline, GE
Medical, TEVA Pharma, Cephalon, Bracco International, GE Medical,
Lundbeck Pharma, Gianni PR), grants (Klüh Foundation, Hoffnungs-
baum e.V., German Ministry of Education and Research (BMBF),
"Manfred and Ursula Müller Foundation", Koeln Fortune, German Re-
search Foundation (DFG), NBIA disorders society, Medtronic Inc.).
Abbreviations: BIC, Bayesian information criterion; DBS, deep brain
stimulation; EMG, electromyogram; PD, Parkinson's disease; LFP,
local field potential; MVAR, multivariate autoregressive model; sPDC,
squared partial directed coherence; UPDRS, Unified Parkinson's Dis-
ease Rating Scale.
Neuroscience 210 (2012) 353–362
0306-4522/12 $36.00 © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.
Page 2
models mainly describe the akinetic-rigid patients, no hy-
pothesis exists on the statistical causality based on previ-
ous studies for the tremor-dominant PD patients. As pre-
vious studies using traditional methods to analyze oscilla-
tory activity, for example coherence, were only able to
identify coupling but no statistical causality between STN
and arm muscles during tremor (Timmermann et al., 2003;
Reck et al., 2009, 2010), we used the squared partial
directed coherence (sPDC) (Astolfi et al., 2006), a multi-
variate extension of Granger causality, to determine sta-
tistical causality. The term statistical causality is used in
the sense of Granger causality (Granger, 1969): if a signal
can be better predicted by incorporating past information
from another signal than by only using its own past infor-
mation, then the second signal is called causal for the first
one (Wiener, 1956). Consistent with this notion of Granger
causality as a temporal ordering, we use the term output
causality when the STN signal is statistically causal for the
EMG activity and input causality for the opposite.
To test our hypothesis of differential statistical causal-
ities of tremor generation in the two PD subtypes, we
analyzed local field potential (LFP) activity between the
subthalamalic region and affected arm muscles of 14 PD
patients with tremor in the upper extremity, six of which
classified as akinetic-rigid, and eight of which classified as
tremor-dominant. Our definition of the term "subthalamic
region" comprises the zona incerta as well as the STN. A
coherence analysis in this patient sample has been pub-
lished as Reck et al. (2010). While coherence measures
are interesting in their own right as a means to detect
frequency-specific connections, the question of the direc-
tionality of these couplings cannot be answered. The pres-
ent study adds to the insights gained by means of coher-
ence by computing the statistical causality between tremor
EMG and the STN region during resting tremor. The direc-
tionality information allows new insights on the tremor
pathways in PD tremor.
Finally, a recent study of the effectiveness of high-
frequency stimulation in parkinsonian rodents detected
that stimulating neither inhibitory nor excitatory neurons in
the STN alleviated the symptoms (Gradinaru et al., 2009).
In contrast, stimulation of afferent axons projecting to the
STN led to an improvement, suggesting that regions con-
taining many afferent connections may be particularly ef-
fective for treating PD with deep brain stimulation (DBS).
Based on these findings, we conjectured that the final
stimulation contact, which is the point with the best clinical
improvement, should coincide with the recording depths
where most input causalities to the STN are found. To test
this, we analyzed both the STN and the wider subthalamic
region, leaving open the possibility that regions surround-
ing the STN might exhibit the most input causalities.
Six akinetic-rigid PD patients and eight tremor-dominant PD pa-
tients were analyzed for this study. The PD classification was
made prospectively according to the patients' preoperative Unified
Parkinson's Disease Rating Scale (UPDRS) motor score (part III)
(Fahn et al., 1987). Patients were classified as akinetic-rigid,
mixed type, and tremor-dominant in accordance with Spiegel et al.
(Spiegel et al., 2007). We grouped the mixed type and the tremor-
dominant patients together, because all these patients had a
higher tremor than akinesia score. According to this classification
all patients were allocated to one of the mutually exclusive groups.
One akinetic-rigid patient had to be clinically classified after re-
cording as the UPDRS had not been documented preoperatively.
In this patient, an experienced movement disorder specialist not
affiliated with this study, classified this patient as akinetic-rigid,
which was also supported by his postoperative UPDRS. A sum-
mary of preoperative data are given in Table 1. The decision for
STN-DBS was made in accordance with the preoperative selec-
tion criteria reviewed in Lang et al. (Lang et al., 2006) and the
German guidelines for DBS in PD (Hilker et al., 2009). All patients
experienced ON/OFF fluctuations due to long-term side effects of
dopaminergic medication and/or had a disabling resting tremor. In
all patients DBS electrodes were implanted bilaterally in the STN.
All patients gave written informed consent to the implantation
of electrodes and the micro- and macroelectrode recordings. The
study was approved by the local ethics committee (study no. 2459
and 08-158) and conducted in accordance with the Declaration of
Implantation and intraoperative recordings
All patients were withdrawn from their anti-parkinsonian medica-
tion for at least 12 h so that influences due to medication were
minimized during operation. The target points in the dorsolateral
STN were assessed by stereotactic coordinates, as well as fused
stereotactic magnetic resonance imaging (MRI) and computed
tomography (Voges et al., 2002). The standard coordinates to
target the dorsolateral part of the STN used in our center are 1.8
mm posterior to the mid AC (commissura anterior)–PC (commis-
sura posterior) line (midcommissural point, MCP), 3.8 mm ventral
to MCP and 12 mm laterally to midline.
During implantation of the stimulation electrode, LFPs with up
to five combined micro- and macroelectrodes were recorded using
the INOMED ISIS MER-system (INOMED Corp., Teningen, Ger-
many). The electrodes were configured in concentric symmetry
with one central electrode and another four arranged in a circle at
a distance of 2 mm from the central electrode. All electrodes were
referenced to the stereotactic frame. Due to the individual anat-
omy and blood vessels in some patients less than five micro-
macroelectrodes could be used. The combined micro-macroelec-
trodes record single cell activity with a microtip 1 mm below the
ring of the macroelectrode. Local field potentials were recorded
with the macroelectrode ring. Simultaneously, surface EMGs were
recorded of the M. extensor digitorum communis (EDC) and M.
flexor digitorum superficialis (FDL). Both EMG and LFP signals
were sampled at 2500 Hz, high-pass filtered at 0.5 Hz, and
low-pass filtered at 1 kHz. The complete recording procedure has
been described in Florin et al. (Florin et al., 2008) in more detail.
The LFPs were recorded from at most 9 mm above the target point
in the STN in steps of 1 mm downward until up to 1 mm below the
target point. In those patients where recording started as high as
9 mm above the target point, no thalamic activity was present.
Note that the reported recording depths take into account that the
macroelectrode ring is 1 mm above the microelectrode. Localiza-
tion of the electrodes in the STN was confirmed from microelec-
trode recordings of typical cell activity for each structure. When
entering the STN, background activity increases and neurons
spike with a high amplitude and mean frequency of about 37 Hz
(Hutchison et al., 1998). This makes analysis of single cell activity
currently the best way for accurately localizing the STN in vivo
(Hutchison et al., 1998), even though a definitive confirmation of
the correct localization can only be obtained from postmortem
E. Florin et al. / Neuroscience 210 (2012) 353–362354
Page 3
studies (Gross et al., 2004). Furthermore, we cannot exclude that
the macroelectrode recordings also included far-field potentials.
However, these effects should be minor, without having a great
influence on the overall results. Furthermore, if the signals were
only driven by far-field potentials, the local field potentials re-
corded from electrodes recorded only 2 mm apart should be very
similar. However, as we have demonstrated in previous studies,
recordings from neighboring electrodes differ in their frequency
and coupling characteristics (Reck et al., 2009, 2010). To analyze
resting tremor, patients were asked to rest without moving their
arm for at least 30 s at each recording depth. Thus, the analysis
does not include postural tremor.
Statistical causality analysis with squared partial
directed coherence
After the implantation, macroelectrode and EMG recordings from
each patient were carefully visually inspected off-line for move-
ment artifacts. If artifacts were detected, the respective sequences
were excluded from further analysis. Furthermore, only se-
quences with a clearly identifiable resting tremor were included in
the analysis. Note that in some patients no rest tremor was
present during the assessment of the UPDRS. However, the
assessment of the UPDRS is always only a momentary picture,
and in patients where the tremor is relatively mild, it might not have
been present. Therefore, we confirmed the presence of tremor
during the recording from the EMG activity. For the statistical
causality analysis only consecutive sequences were used. Fig. 1
presents a typical raw LFP and EMG recording during tremor once
for a tremor-dominant patient and once for an akinetic-rigid pa-
tient. Additionally, a 2-Hz high-pass filter was used for the EMGs
to remove drifts due to movements and a 50-Hz notch filter was
used to remove potential electric artifacts. These filter settings
were chosen in accordance with a previous simulation study that
showed their compatibility with statistical causality analysis (Florin
et al., 2010). At first sight, the band edge of the 2-Hz high-pass
filter might seem too low to completely remove all movement
artifacts. This conservative high-pass setting was chosen for two
reasons. First, there is reason to believe that excessive filtering
may interfere with statistical causality measures (Sargent, 1987;
Roebroeck et al., 2005; Florin et al., 2010). Hence, we wanted to
leave the frequency band of parkinsonian tremor (4–7 Hz) unal-
tered. Due to the finite slope of practical filter functions, a 2-Hz
high-pass filter may still affect frequency ranges up to 3 Hz.
Second, movement during the operation with a frequency of more
than 2 Hz seems rather fast given that patients were lying on the
operation desk and their heads were fixated in a stereotactic
frame. Smirnov et al., in the context of a directional coupling
analysis, also used a 2-Hz high-pass filter. They also tried higher
band edges and demonstrated that the results were not changed
by a higher band edge (Smirnov et al., 2008). This suggests the
sufficiency of this filter. We did not rectify the EMG for the same
reasoning given in Florin et al. (2011). Furthermore, in a recent
paper, it was shown that rectifying changes the power and coher-
ence spectra (Neto and Christou, 2010). Matlab (version 7.5.0
R2007b, the MathWorks, Inc., Natick, MA, USA) and the BioSig-
toolbox (http://biosig.sourceforge.net) were used for the analysis
of statistical causality.
To determine statistical causality between the local field po-
tentials and the EMG, we used the squared partial directed co-
herence (Astolfi et al., 2006). Simulations indicated that this is the
most robust measure compared with other truly multivariate cau-
sality measures like directed transfer function (DTF) and partial
directed coherence (Florin et al., 2011). The sPDC identifies caus-
ing signals based on the idea of Granger causality (Granger,
1969) using a spectral extension:
Table 1. Fourteen PD patients aged between 50 and 76 y at implantation and with disease duration between 4 and 18 y were implanted bilaterally in the STN. The number of trajectories indicates
the number of recording electrodes for the respective implantation side
No. of
No. of
Resting tremor
hand item 20
Postural tremor
upper extremity
item 21 right/left
Rigidity upper
extremity item22 right/left
item 23?24?25
STN le/
STN le/STN ri
STN ri
STN le
STN le/STN ri
STN le
STN le/STN ri
STN ri
STN ri
STN le
STN le
STN le
STN ri
STN ri
Abbreviations: M, male; F, female; le, left; ri, right; UPDRS, motor score of the Unified Parkinson's disease rating scale; ON, with medication; OFF, without medication; AR, akinetic-rigid subtype;
TD, tremor-dominant subtype; MT, mixed subtype.
E. Florin et al. / Neuroscience 210 (2012) 353–362355
Page 4
A(f) are the autoregressive coefficients of the multivariate
autoregressive model (MVAR) in the frequency domain. sPDCij
describes the proportion of information transfer from the jth signal
to the ith signal with respect to the total information flow to channel
j. The values of sPDCij
??f? range from 0 to 1, where 1 indicates that
all of signal i is caused by signal j. As the statistical causality
measures like the sPDC consider only past time points, a
conventional coherence between two signals, which considers
the instantaneous correlation, does not imply that also causality
exists between the two signals. The model order of the MVAR
was determined using the Bayesian information criterion (BIC).
The BIC was chosen as it is consistent, that is, the probability of
it asymptotically choosing the correct model order is 1 (Luetke-
pohl, 2005).
The significance threshold for the individual statistical causal-
ities was computed by the leave one out method (LOOM) (Efron,
1981; Schlögl and Supp, 2006), which traces out the distribution of
the respective statistical causality measure under the null hypoth-
esis of no causality. For the LOOM the causality structure in the
data is destroyed by simply deleting and leaving out a set of
observations xifrom a sample X. For the resulting shorter sample
X(-i), the statistical causality measures are then calculated. This
procedure was repeated n times with
data length
segment length?
In this study, we chose n to be 200. The resulting segment
length was in accordance with the suggestions made by Schlögl
and Supp that are not repeated here for brevity (Schlögl and Supp,
2006). Let T(-i)denote the respective multivariate causality mea-
sures applied to the shorter sample. The standard error of the
statistic can then be estimated as (Efron, 1992):
where T???
akinetic-rigid Parkinson patient
tremor-dominant Parkinson patient
30 2520 10
frequency [Hz]
frequency [Hz]
Fig. 1. A local field potential (LFP) and an electromyogram (EMG), once from a tremor-dominant patient and once from an akinetic-rigid patient, with
the resulting coherence spectra between EMG and LFP.
E. Florin et al. / Neuroscience 210 (2012) 353–362356
Page 5
For the analyzed statistical causality measures, a 95% confidence
interval was computed from the estimated standard error by using
the t-distribution with n degrees of freedom. If the actually com-
puted significance measure exceeds this threshold, the statistical
causality is significant.
Statistical analysis
In a first step, we analyzed the statistical significance of the
causality measures at the single subject level. After computing the
sPDC and the confidence intervals, we counted all cases in which
the statistical causality measure in the frequency range from 3 to
45 Hz exceeded the patient-specific significance threshold. This
frequency range was chosen as it (i) is the frequency range in
which most pathological activity in Parkinson patients has been
determined and (ii) should be unaltered by the preprocessing with
a 2-Hz high-pass and a 50-Hz notch filter. Unfortunately, the
sPDC as well as similar statistical causality measures like the DTF
practically do not allow for a detailed frequency resolution (Schlögl
and Supp, 2006). Although the sPDC as a frequency-dependent
measure based on multivariate autoregressive modeling is at least
in principle capable of distinguishing frequency ranges, the dis-
crimination relies on model order, which in our case was deter-
mined by the BIC. With this criterion, we determined the model
order for our data in the range from 9 to 56. To obtain a better
frequency resolution, a higher model order than the optimal one
indicated by the BIC would be required, thereby decreasing the
efficiency of the MVAR-estimation and increasing the likelihood of
false and missed statistical causalities. Thus, distinguishing be-
tween connections at tremor and double tremor frequency, as was
done in previous studies using measures of coherence, is impos-
sible (Timmermann et al., 2003; Reck et al., 2009). In a previous
study, we calculated the coherence spectra for the patients (Reck
et al., 2010). Coherence ranges between 0 and 1, with 1 repre-
senting a perfect linear relationship between the two examined
signals and 0 no linear relationship of both signals. The 95%
significance level was estimated according to Halliday et al. (Hal-
liday et al., 1995). Fig. 1 presents the examples of one akinetic
patient and one tremor-dominant patient. The coherence spectra
in these two patients are dominated by coherence in the tremor
frequency. In the whole group, coherence was found in double as
well as single tremor frequency. Therefore, we can exclude the
possibility that the results are driven by the alpha band for
tremor-dominant patients and the beta band for akinetic-rigid
patients because the main frequency component in all signals
is in the tremor frequency range. Still, overall the tremor fre-
quency of the akinetic-rigid patients was about 1 Hz higher than
for the tremor-dominant patients. The statistical causality anal-
ysis performed in the present study improves on the previous
findings by identifying the directionality of the connections be-
tween STN and muscle EMG.
As mentioned previously, due to the individual anatomy and
blood vessels in some patients only fewer than five macroelec-
trodes could be used for recording. To make the occurrence of
input and output causalities comparable between patients, the
number of input and output causalities was divided by the number
of possible connections for each recording depth of each patient.
Further, statistical (intrapatient and intergroup) analysis was con-
ducted with this quotient. As the Shapiro–Wilk test rejected nor-
mality of our data (P?0.05), intrapatient testing was performed
with the nonparametric Wilcoxon test (Wilcoxon, 1945). We com-
pared the occurrence of output causalities (i.e. the LFP of the
subthalamic region is causal for EMG) and input causalities (i.e.
the EMG is causal for the LFP of the subthalamic region) for all
recording depths of all patients and for the two subgroups: tremor-
dominant and akinetic-rigid PD patients. Intergroup comparison
was made with the Mann–Whitney U-test (Mann and Whitney,
1947). To correct for the inflated type 1 error due to the multiple
pair-wise testing, a step-down procedure suggested by Benjamini
and Hochberg was used (Benjamini and Hochberg, 1995). This
procedure has more statistical power than the classically used
Bonferroni correction (Bonferroni, 1936; Miller, 1991).
The active stimulation contact was determined for each
patient by a neurologist as the contact with the best clinical
outcome. To determine the Schaltenbrand-Wahren coor-
dinates of the active stimulation contact, the localization of
the DBS electrode was confirmed by stereotactic X-ray
and was projected on the preoperative MRI. For all pa-
tients, the average active stimulation contact was in the
dorsolateral part of the STN, known to be the most effec-
tive location for DBS in PD (Benabid et al., 1994) (STN
right x?11.7?1.1 mm; y??1.4?1.2 mm; z??3.8 ?2.1
mm; STN left: x??12.8?1.6 mm; y??2.2?1.7 mm;
z??2.6?1.8 mm, coordinates are given in relation to the
individual midcommissural point). No significant difference
was found in the stimulation location between the akinetic-
rigid and tremor-dominant patients (STN right: x: P?0.857,
y: P?0.857, z: P?0.629; STN left: x: P?1.000; y:
P?0.286, z: P?0.413). In patient 14, possibly in connec-
tion with a head accident, a postoperative displacement of
the electrode occurred. To be on the safe side, we ex-
cluded the coordinates of this patient from the analysis
of the average placement of the effective stimulation loca-
tion. The electrode was replaced 3 months later and put back
to the original target location. However, according to the
microelectrode recordings, the intraoperative placement was
correct so that the LFP recordings were obtained from the
subthalamic area and could, hence, be used for the analysis.
For the statistical causality analysis only signals with
sufficiently long tremor periods during rest (i.e. at least
10 s), but without artifacts, were included. For the akinetic-
rigid patients this led to more rejections, as their tremor is
usually not as continuous. Overall, 107 recording depths
could be included (tremor-dominant patients: 65 depths;
akinetic-rigid patients: 42 depths).
As shown in the previous study (Reck et al., 2010), the
tremor amplitude of the akinetic-rigid patients was three
times smaller than the one of the tremor-dominant pa-
tients. To exclude that all following statistical causality
results are biased by this difference in the signal to noise
ratio, we performed a short simulation study. For this
study, a bivariate autoregressive system was generated
with three different scenarios: (1) no influence between the
two signals; (2) the signal with the three times higher/the
same amplitude causes the other signal; (3) the signal with
the three times higher/same amplitude is caused by the
other signal. For each of these models, the sPDC was
estimated with a 5% significance threshold from the
LOOM. This procedure was repeated 100 times and in all
cases at most five false positive connections were de-
tected, indicating that the test size is correct and sPDC is
not crucially affected by these differences in the signal to
noise ratio. This is consistent with the results reported in
Florin et al. (2011).
Fig. 2a shows the statistical causality analysis for one
patient and one recording depth. Each subplot represents
E. Florin et al. / Neuroscience 210 (2012) 353–362357
Page 6
102030 40
10 203040
1020 30 40
from EDC to
from FDL to
centralanterior medial lateral
to EDC from
to FDL from
frequency [Hz] frequency [Hz] frequency [Hz] frequency [Hz]
Fig. 2. Statistical causalities for one typical tremor-dominant patient. (A) Statistical causality spectra for the recording at the target point. Each subplot
represents one potential causality obtained with the sPDC. x-axis: frequency; y-axis: sPDC; red line: individual significance threshold determined by
the LOOM. (B) Summary of the occurred statistical causalities over all recording depths: Note that more input causalities occur, that is, connections
from the arm to the brain. The recording depth of each disk is given in mm in relation to the surgical target point. The gray disks are those located
in the STN, and the red-marked part of the electrode indicates the finally chosen active stimulation contact. Black arrows indicate an input causality;
red arrows indicate output causality and green ones bidirectional causality. Abbreviations: C-central electrode; A-anterior electrode; L-lateral electrode;
M-medial electrode; P-posterior electrode; EDC-M. extensor digitorum communis; FDL-M. flexor digitorum superficialis.
E. Florin et al. / Neuroscience 210 (2012) 353–362358
Page 7
one potential statistical causality. The x-axis plots the fre-
quency range under consideration from 3 to 45 Hz. The
y-axis shows the value of the sPDC, which ranges be-
tween 0 and 1. The red line indicates the individual signif-
icance threshold determined by the LOOM. Fig. 2b, in
which the statistical causalities are denoted by arrows,
visualizes the detected statistical causalities over all re-
cording depths for one patient. It shows that for this rep-
resentative tremor-dominant patient, more input causali-
ties (black arrows) than output causalities (red arrows)
were found.
To test our first hypothesis that tremor pathology may
be different in the two PD subtypes, we compared the
occurrence of output and input causalities for all recording
depths between the two subtypes. For the tremor-domi-
nant patients significantly more input than output causali-
ties were found (P?0.003). In contrast, for the akinetic-
rigid patients significantly more output causalities were
detected (P?0.040). When directly comparing both patient
groups, significantly more output causalities (P?0.001)
and input causalities (P?0.001) were found in the tremor-
dominant than in the akinetic-rigid patients (Fig. 3).
Our second hypothesis was that the most effective
stimulation contact should coincide with the depth of most
input causalities. For this analysis, we had to exclude one
patient of each patient group because we did not have
recordings with sufficient tremor periods to determine the
input causalities during tremor on the depths of stimulation.
With typical clinical stimulation parameters, stimulation ef-
fects may, however, not be confined to exactly one depth
but rather affect a small area surrounding the stimulation
depth. If, therefore, the depth 1 mm above and below the
stimulation contact is included into this analysis, the active
stimulation contact coincides with the depths of most input
causalities in seven of eight analyzed hemispheres of the
tremor dominant patients. Using a binomial distribution, the
null hypothesis of this occurring due to pure chance
(P0?0.5) can be rejected (P?0.05). For the akinetic-rigid
patients in three of seven hemispheres the active stimula-
tion contact coincided with the depths of most input
From these results, it seems likely that the height with
the most input causalities also determines the optimal
electrode placement. To check if there are differences in
the optimal stimulation location between subtypes, we nor-
malized the recording heights relative to the entry point of
the STN, that is, where characteristic STN activity was
detected for the first time. This height was set to zero. All
other coordinates were determined relative to this point.
Due to this normalization not all possible relative heights
were recorded in all patients. Hence, we only considered
those heights where at least half of the patients actually
had recordings. We then calculated the mean over all
patients for each recording height. For both patient groups,
most input causalities were detected 1 mm above the STN,
whereas most output causalities were detected 2 mm
above the STN for the tremor-dominant patients and 2 mm
in the STN for the akinetic-rigid patients. This difference in
output causalities also underpins our first hypothesis of a
different pathophysiology underlying tremor generation in
the two subtypes.
In the present study, we analyzed the statistical causality
between oscillatory activity in the subthalamic region and
muscle tremor activity of the upper extremity of Parkinson
patients during tremor episodes. The aim was to identify
whether a differential statistical causality pattern between
local field potentials and EMG underlies tremor in the two
subtypes of PD, that is, akinetic-rigid versus tremor-dom-
inant and to identify whether the most effective stimulation
contact coincides with the region of most input causalities.
Tremor-dominant patients versus akinetic-rigid
Consistent with our first hypothesis of a differential statis-
tical causality pattern between the two parkinsonian sub-
types the neural activity in the wider subthalamic area
reflected more output than input causalities for the akinetic-
rigid patients, and more input than output causalities for the
tremor-dominant patients. This indicates a different neuro-
nal processing due to the different PD subtypes. Even
though the sPDC can distinguish between direct and indi-
rect causalities, it cannot determine, if a pathway runs via
stations that are not included in the model. Thus, we are
not suggesting a direct pathway from the STN to the arm
muscle or backwards. Rather, there are two possible path-
ways for input causalities from the muscle to the subtha-
lamic area as detected by tremor EMGs, one pathway
could be via spinocerebellar tracts to the cerebellum.
These input signals can then be projected to the cortex via
the dentato-thalamic tracts. The dentato-thalamic tract
passes through the zona incerta (Coenen et al., 2011). The
second pathway could be through the posterior column-
medial lemniscus system, which projects via the thalamus
to the cortex. From the motor cortex direct connections
exist to the nucleus subthalamicus. As we are not able to
% detected causalities
Fig. 3. Comparison of output and input causalities for the two parkin-
sonian subtypes akinetic-rigid and tremor-dominant in the subthalamic
area: * P?0.05 after correcting for type I error; x-axis: conditions;
y-axis: percentage of causalities; the error bars indicate the standard
error of mean.
E. Florin et al. / Neuroscience 210 (2012) 353–362359
Page 8
record from the possible interim stations of these path-
ways, one can only speculate which pathway is the more
likely one.
Following the histological findings of Jellinger (1999),
one could argue that different SNc-STN pathways may be
predominantly affected in both subtypes, thereby explain-
ing the differential statistical causality pattern observed in
our data. Tremor in the two subtypes might originate from
different pathways from the SNc to the subthalamic region,
thereby creating specific pathological loops in each PD
type. However, our results are also compatible with differ-
ent explanations for this observed pattern. In particular, we
were only able to measure brain activity in the subthalamic
region. Furthermore, we are not able to test this putative
pathway as opposed to any other and can only offer this
tentative explanation based on the previous literature as a
starting point for future research. The results for the wider
subthalamic area also support our second hypothesis that
there should be more output than input causalities for the
akinetic-rigid patients.
Further support for our hypothesis of a differential cau-
sality pattern associated with the two subtypes of PD
stems from the observation of a significantly higher cou-
pling between STN and EMGs in tremor-dominant patients
compared with akinetic-rigid patients. While we found only
few functional connections in akinetic-rigid patients (2.5%
of all possible connections in the subthalamic area), sig-
nificantly more were detected for the tremor-dominant pa-
tients (25.3% of all possible connections in the subthalamic
area). This result is due to both less output and input
causalities in the akinetic-rigid patient group compared
with the tremor-dominant patients. Due to this low number
of overall detected causalities for the akinetic-rigid pa-
tients, the statistical comparisons for this patient group
should be interpreted with caution. However, note that this
lower number of statistical causalities for akinetic-rigid pa-
tients does not necessarily imply differing signal-to-noise
ratios between both types, but only that the signal compo-
nents of the STN and EMGs are better able to predict each
other, as opposed to other not identified signals. The am-
plitude of the tremor in our patients has been analyzed in
our previous paper (Reck et al., 2010), and it differed
between the two patient groups in the most extreme case
by a factor of 3. Here, we performed simulations with
differing amplitudes in signals. The results of the short
simulation study indicate that the sPDC with LOOM is
relatively robust against this kind of amplitude differences
as well as differences in the signal to noise ratio, see also
Florin et al. (2011).
This surprising pattern of fewer statistical causalities
may be the result of either a stronger pathological tremor
network in the tremor-dominant patients or of a reduced
signal processing in the wider subthalamic area due to
akinesia and rigidity. The hypothesis of a pathological
tremor network which has already further progressed in
tremor-dominant patients than in akinetic-rigid ones is sup-
ported by previous data showing the existence of clusters
of "tremor cells" in tremor-dominant PD patients (Bergman
et al., 1994; Reck et al., 2009). Furthermore, a single cell
study detected tremor cells almost exclusively in tremor-
dominant patients. However, even in these former tremor-
dominant patients, only 10% of the recorded STN cells
were tremor cells (Levy et al., 2000). Therefore, our finding
of fewer statistical causalities in the akinetic-rigid patients
than in the tremor-dominant patients might be due to
tremor cells being more sparse in the akinetic-rigid patients
as tremor is only a "secondary" symptom. This may render
the detection of tremor-related statistical causality more
difficult in the akinetic-rigid patient group.
Comparison to previous studies
Previously, Wang et al. analyzed statistical causality be-
tween LFPs of the STN and EMG activity of the contralat-
eral arm in four PD patients by means of bivariate Granger
causality (Wang et al., 2007). They found bidirectional
connectivity during discontinuous tremor and output cau-
salities during continuous tremor. For three PD patients,
Smirnov et al. (2008) also found a bidirectional coupling for
a zero phase shift and output causality for a phase shift of
1–2 tremor periods by means of phase dynamical model-
ing. In accordance with the results of prior studies we
found significantly more output than input causalities for
the akinetic-rigid patients with tremor during rest in the
subthalamic region as a whole, which was not the case for
the tremor-dominant subtype. However, Wang et al. (2007)
did not give an exact classification of the four patients and
Smirnov et al. (2008) used a different analysis approach,
which limits a direct comparison of the results.
Deep brain stimulation
A recent study detected that high-frequency stimulation of
the afferent axons projecting to the STN led to an improve-
ment of parkinsonian symptoms in rodents (Gradinaru et
al., 2009). We therefore tested, if regions containing many
input causalities are the most effective ones for treating
Parkinson's disease in humans. Importantly, one has to
note that the present study cannot distinguish, whether
DBS is effective through the stimulation of the STN or
whether DBS has an influence on the motor cortex projec-
tions and is thereby effective. Interestingly enough, we
found such a relation for the tremor-dominant patients, if
depths 1 mm above and below the active stimulation con-
tact were also considered, whereas this relationship was
less clear for the akinetic-rigid patients. Including the depth
of 1 mm above and below the active stimulation contact is
reasonable because the electric stimulation is likely to also
have an influence on those regions (McIntyre et al., 2004).
A limitation of our experimental setup is that we could only
match the depth with the active stimulation contact across
patients. Thereby, we are only able to consider the accor-
dance along the dorsal-ventral axis and not along the other
two axes. While the spatial standard deviation along these
axes is relatively small, future studies should nevertheless
try to trace out whether the results are robust with regard to
the other two axes as well.
The location with most input causalities over all tremor-
dominant patients was found to be 1 mm above the entry
point in the STN. This supports the idea that stimulation
E. Florin et al. / Neuroscience 210 (2012) 353–362 360
Page 9
above the STN is most effective. A possible explanation
why the relation between recording depth and active stim-
ulation contact was not observed for the akinetic-rigid pa-
tients is that we only looked at continuous tremor periods
and not at periods during akinesia and rigidity and that for
the akinetic-rigid patients fewer statistical causalities were
detected. In addition, the final stimulation contact was
chosen in such a way that it also reduced akinesia and
rigidity. For both patient groups, the active stimulation
contact was chosen not only to have the best clinical
outcome, but to reduce side effects. This potential differ-
ence in objectives suggests that future studies should also
consider input causalities during akinesia and rigidity for
akinetic-rigid patients.
Summarizing our results, we have identified a differen-
tial pattern of statistical causality between tremor-dominant
and akinetic-rigid patients during episodes of tremor. Al-
though more output causalities from the STN were found in
akinetic-rigid patients, more input causalities were found in
the same region for tremor-dominant patients. Moreover,
for tremor EMGs, we detected both more output and input
causalities for the tremor-dominant than for the akinetic-
rigid patients. Even though the present study cannot di-
rectly identify the pathological mechanisms underlying
tremor generation, the results hint at different pathological
mechanisms for tremor generation of the two PD types.
Future work should aim at directly testing this hypothesis.
In any case, our results are consistent with different path-
ological mechanisms for tremor generation of the two PD
Acknowledgments—Lars Timmermann is supported by the
Deutsche Forschungsgemeinschaft (KFO 219; TI 319/2-1), the
German Ministry of Research and Education (BMBF), the medical
faculty of the University of Cologne "Fortune-Program", the "Man-
fred and Ursula Müller Foundation" (Ti 159/2006), the "Klüh-
Foundation", and "Hoffnungsbaum e.V." Gereon R. Fink gratefully
acknowledges additional support from the Deutsche Forschungs-
gemeinschaft (KFO 219; SCHU, 1439/3-1). Esther Florin thanks
Johannes Pfeifer for his critical review of the manuscript and his
support with the statistical analysis. Alfons Schnitzler acknowl-
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(Accepted 23 February 2012)
(Available online 3 March 2012)
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Blackburn defender Bradley Orr loaned to Ipswich Town
Ipswich have secured the loan signing of defender Bradley Orr from Blackburn until the New Year.
The 30-year-old has struggled to cement a starting place since the arrival of boss Henning Berg.
After 11 appearances in the Championship this season, Orr was an unused substitute in the 1-1 draw at home to Birmingham, having to make way for 18-year-old Adam Henley.
Orr's deal with Mick McCarthy's side is due to end on 26 January.
The veteran defender moved to Ewood Park in January this year after a spell of nearly three years with QPR.
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Senior Member
Bump. This spell is OP
I think it is slightly OP, but I think it would be a mistake to overnerf it. If anything, it shines in the current metagame of mainly physical dps combined with stun spells. If you have a power nuker on your team you can often remove her shield in a single nuke, making it much less powerful. So anyway, nerf it, but don't overnerf it, because if nukers ever really come in vogue it will be totally useless. And let's not forget that she honestly isn't that powerful in lategame teamfights anyway, so her shield on Yi is her biggest contribution.
Sean Connery
This needs a nerf badly. It devours ultimates, and she can have it up way too often.


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This is the third product line from Bruell and Heinen's. In addition to the olive oil, Heinen's also carries Zack's Brews—a custom line of coffees representing each Zack Bruell restaurant. To learn more about Zack's Brews and Zack Bruell Olive Oil, 100% Extra Virgin, click here.
Herb Vinaigrette
1 cup Zack Bruell Extra Virgin Olive Oil 1/3 cup Zack Bruell Balsamic Vinegar ¼ tsp. chopped fresh tarragon ¼ tsp. chopped fresh thyme ¼ tsp. chopped fresh basil Salt and cracked black pepper to taste
Whisk above together in mixing bowl and pour lightly over mixed greens. Balsamic Dipping Sauce
½ cup Zack Bruell Balsamic Vinegar ½ cup Zack Bruell Extra Virgin Olive Oil ¼ tsp. pepperoncini ¼ tsp. crack black pepper ¼ tsp. sea salt 1/8 cup grated parmesan cheese
Mix together in bowl and use as a dipping sauce for fresh bread. White Balsamic Gastrique
1 cup Zack Bruell White Balsamic Vinegar 1 tbs. salt 1 tbs. sugar ½ cup water 2 cloves garlic 2 tbs. fresh rosemary
Bring to boil and let cool with all solid ingredients together. Let sit for several hours. Strain through fine sieve. Spray over roasted or grilled chicken, salmon or pork.
Information courtesy of Zack Bruell
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Related Searches: 1000 gallon propane tank, propane tank gallon, 500 gallon propane tank, propane tank 500 gallon
20 Results for 1000 Gallon Propane Tank in Jackson Mi - Business for Sale Classifieds
1000 gallons sealcoat tank in good condition $1200.00 o.b.o 248-249-8133 please call debbie no agitator
1 month ago on ebay.comBundle includes two pumps, two tanks and self serve console. Everything is in working condition and great shape!
1 month ago on ebay.comCURTIS PROPANE POWERED COMPRESSOR HEAD MOUNTED ON TOP OF 240 GALLON TANK NEW NEVER USED MDL#: E-57 SERIAL#: AS0090077 SELLING AS IS WHERE IS BUYER IS RESPONSIBLE FOR ALL SHIPPING AND RIGGING COSTS
1 month ago on ebay.comBiodiesel Settle column tank liquid storage tank 1000 Gallons EachTanks are 17' in height and 62" in diameter. Tanks are made of carbon steel, and have 1" outlet on bottom and 1" lower side discharge. and 1" outlet on
1 month ago on ebay.comUL Fuel tank – never used, 3 years old, never used. • 1000-gallon • UL 142 • Dual wall • Dimensions: 138-inch L x 48-inch DIA. • Good condition, original paint. • Purchased new for $2,560. Make offer.
1 month ago on ebay.comBiodiesel Settle column tank liquid storage tank 1000 Gallons EachTanks are 17' in height and 62" in diameter. Tanks are made of carbon steel, and have 1" outlet on bottom and 1" lower side discharge. and 1" outlet on
1 month ago on ebay.com*** CLICK ON THUMBNAILS TO VIEW FULL SIZE PICTURES *** For sale is a Mueller 1,000 gallon stainless laboratory process tank. It was used by an international corporation making contact lenses. Pristine condition tank
1 month ago on ebay.comHave Questions? Frequently Asked Questions | Contact Us | Store Policy Rockford 1 Gallon Air Compressor OUR SKU# IXS1000 | MPN: CAT944-4 Condition Brand New Shipping Free Shipping! Ships In 2 days. With a transit time
1 month ago on ebay.comdrain board Separate hand sink Titan hot water heater (2.5 gallon) 30 gallon gray water tank in truck fitted under truck for 3 compartment sink mounted under truck 10 gallon gray water tank for hand sink mounted under truck
1 month ago on ebay.compropane tank less water heater will heat the water to 150 degrees· 25 gallon fresh water tank FDA compliant· 33 gallon waste water tank FDA compliant (33% LARGER THAN FRESH WATER)· D.O.T. Highway approved heavy duty trailer
1 month ago on ebay.complumbing as you will see is new. Provisions for the propane tanks are in place in front of trailers over hitch. Tanks are not included. The front room of the trailer is set up for the use of propane. There are two access doors
1 month ago on ebay.com-duty frame with low center of gravity Increased stability and tractionCapacity of 16-cubic feet (453 liters)Powered by a Honda GX390 engine with recoil startLarge 5.5-gallon (20.8 liters) fuel tank for extended uninterrupted
1 month ago on ebay.comchamber door on top, load the block, close the door and hit the button and it drops the block in. No chance of getting splashed with hot glue. Tank capacity is 14.79 gallons each. There are six separate tanks. Melting rate is
1 month ago on ebay.com0.58 gallon tank. It operates on 115 to 120 volt power. Technical SpecificationsItemCompact Hip Dry VacuumAmps6Air Flow59 cfmVoltage115-120Filter TypeHEPASeriesIndustrialStatic Pressure76"Height14-19/32"Length7-7/8"Width
1 month ago on ebay.com.Machine ratings:Racks per hour: 53, 1,325 dishes per hour, 2,385 glasses per hour.Table to table-inside tank at table connection: 25 1/4".Wash tank capacity: 16 gallons. Wash pump capacity: 160 gallons per minute.Burner capacity
1 month ago on ebay.com


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Ice Choir Clears Up A Sunny Day in Glasgow for 'Bye Bye Big Ocean' Remix
Track hails from limited-edition 'No Death' EP, available in the U.K.
A Sunny Day in Glasgow's Sea When Absent is their most reined-in album yet — an impressive feat considering it was written largely over email by six people who kept living their disparate lives in various time zones. For a band as unbound as ASDIG, a "clarified" sound means slightly more discernible vocals and a faint sense of logic running through the shoegaze clamor.
On the No Death EP, a five-song bonus release accompanying ASDIG's new album, Ice Choir (a.k.a. Kurt Feldman, ex-drummer of the Pains of Being Pure at Heart) remixes opening track "Bye Bye Big Ocean (The End)." The original cut blasts off with amorphous guitar noise and then drops off of a cliff into a pretty falsetto-harmony sequence, skipping between moods as it pleases. Feldman's reworking pulls a single thread out of the ASDIG plasma and gives it a crisp, retro-synth gloss. The lyrics get a 'gaze-free spotlight, and are suddenly sing-along-worthy: "Had this dream about you / An endless dream about you."
Stream Ice Choir's remix of "Bye Bye Big Ocean (The End)" below.


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ADFA class of 2014 celebrate milestone achievement
11 December 2014 : Following three years of military and academic studies, 220 officer cadets and midshipmen graduated from the Australian Defence Force Academy (ADFA). They are now ready to become junior leaders in the Australian Defence Force (ADF).
Opening of Joint Logistics Unit (North) at Robertson Barracks, Holtze, NT
11 December 2014 : A modern, purpose built wholesale storage facility, Joint Logistics Unit – North was officially opened at Robertson Barracks in Holtze, Northern Territory. Minister for Defence's representative, Senator Linda Reynolds said the logistics unit was one of seven being constructed under the Defence Logistics Transformation Program.
Australian Command and Staff Course (Joint) Graduation
08 December 2014 : The ACSC(J) class of 2014, along with families and friends, gathered at the Llewellyn Hall at the Australian National University (ANU) for their graduation ceremony. The ceremony ends a demanding year of full-time study at the Australian Defence College in Weston Creek, ACT, which culminates in the award of the Passed Staff Course (Joint) qualification and a Master of Military and Defence Studies from the ANU for the majority of the 168 graduates.
Defence and Strategic Studies Course Graduation
02 December 2014 : The 2014 Defence and Strategic Studies Course (DSSC) graduation was held. The DSSC is an 11 month course postgraduate level professional development program that provides students with the skills and knowledge to operate at the highest levels of leaderships, command, policy formulation and management. In recognition of her outstanding achievements on the DSSC, Commodore Michele Miller was awarded the CDF/SEC Award.
New partnership to explore virtual simulation opportunities
28 November 2014 : Defence has entered a partnership with the University of Newcastle (UoN) to explore how virtual simulation can be used to further enhance education and training. The Australian Defence College (ADC) signed a Memorandum of Understanding (MOU) with the University of Newcastle at the Directorate of Simulation at RAAF Base Williamtown. Through the MOU, UoN honours and postgraduate students will undertake virtual simulation research and development projects that are directly relevant to the ADC.
Vice Chief launches Parliamentarians Against Family Violence
20 October 2014 : White Ribbon Ambassador Vice Admiral Ray Griggs launched Parliamentarians Against Family Violence at Parliament House. He discusses his role as Ambassador, why he encouraged the Navy to become a White Ribbon accredited workplace, and more broadly what Defence is doing to raise awareness of violence against women.
Defence personnel go bridge to bridge in support of White Ribbon Day 2014
17 October 2014: Around 700 Defence personnel walked and ran around Canberra's Lake Burley Griffin to demonstrate their commitment to White Ribbon Day. Vice Chief of the Defence Force and White Ribbon Ambassador, Vice Admiral Ray Griggs launched the event, one of a number of activities being undertaken by Defence in the lead up to White Ribbon Day 2014 on Tuesday, 25 November 2014.
Australian Defence Force Mental Health Day
10 October 2014: Held each year, World Mental Health Day is a day dedicated to mental health education, awareness and advocacy. It is also the Australian Defence Force (ADF) Mental Health Day, a day to recognise the ADF's commitment to taking care of its key capability – its people.
This year the Vice Chief of the Defence Force Vice Admiral Griggs spoke to Defence personnel at Australia's Defence Force Headquarters.
Admiral addresses mental health at Grace Groom Oration
9 October 2014: On the eve of World Mental Health Day 2014, Vice Chief of the Australian Defence Force, Vice Admiral Ray Griggs gave the keynote address at Mental Health Australia's annual Grace Groom Memorial Lecture.
Held at the National Press Club, VCDF outlined many of the issues facing a modern defence force that is looking to respond to the issue of mental health and wellbeing amongst service men and women.
South Australian employers of Reserves recognised
11 September 2014: Five employers were recognised for their support of the Australian Defence Force (ADF) Reserves at the Employer Support Awards held at Adelaide Oval last night.
The event, organised by the South Australian Defence Reserves Support Council, recognised employers who have been particularly supportive of their Reservist employees.


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Magister Negi Magi has had up to 25 volumes, but the series is not over yet. Akamatsu stated back when the series was starting that this could be a 30+ volume manga series, so the end may not be here for a year or two.
Spice and Wolf is not a manga, but rather a light novel series. The series isn't done yet, but currently there are 8 published novels out in Japan.


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What does WAYN mean in Chat?
This page is about the meanings of the acronym/abbreviation/shorthand WAYN in the Internet field in general and in the Chat terminology in particular.
Find a translation for WAYN in other languages:
Select another language:
Discuss this WAYN abbreviation with the community:
Use the citation below to add this abbreviation to your bibliography:
"WAYN." Abbreviations.com. STANDS4 LLC, 2015. Web. 1 Mar. 2015. <http://www.abbreviations.com/term/1383018>.
WAYN also stands for:
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Alternative search:
- Search Where Are You Now? on Amazon
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text:
Jade Vasquez '12 was recently featured in an article in Norwood News, a Bronx-area newspaper, for her work as a Youth Development Volunteer with the Peace Corps, in rural El Salvador. Vasquez, who was one of four members of the Classes of 2012 to have been accepted to serve in the Peace Corps, has helped establish a scholarship program to help students in El Salvador go to high school or college.... More >>
Award-winning Cuban writer Mirta Yáñez will read from her work on Wednesday, Oct. 8. For more than four decades, Yáñez has been a distinguished participant in Cuban literary cultural and academic scenes. She has won numerous awards for literature and, on four occasions, received the prestigious Critics' Prize in Cuba. The reading will begin at 4:30 p.m. in the Sanford Room of the Warren Hunting S... More >>
Hand in Hand, a company founded by Bill Glaab '06 and Courtney Apple '08, was recently featured in Vanity Fair. The article notes the company is "leading the charge to change the world, one bar of soap at a time." For every bar of soap purchased from Hand in Hand, a bar of soap and a month's worth of clean water is donated to a child in a developing nation. "As of today, they have provided more t... More >>


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Book this hotel and collect nights after your stay
Conveniently near the airport in Denver, Country Inn & Suites By Carlson, Denver International Arpt is close to Aurora Sports Park and Anschutz Medical Campus. Additional area attractions include The Children's Hospital and University of Colorado Hospital.
Hotel Features.
Country Inn & Suites By Carlson, Denver International Arpt has an indoor pool, a spa tub, and a fitness center. Complimentary wireless and wired high-speed Internet access is available in public areas. The hotel features business amenities including a 24-hour business center and meeting rooms. Guests are served a complimentary breakfast each morning. Additional amenities include a library, multilingual staff, and laundry facilities. Guests have complimentary access to a roundtrip airport shuttle (available 24 hours). The property has designated areas for smoking.
The 193 air-conditioned guestrooms at Country Inn & Suites By Carlson, Denver International Arpt include coffee/tea makers and complimentary weekday newspapers. Beds have pillowtop mattresses, down comforters, and premium bedding. Guests can use the in-room complimentary wireless and wired high-speed Internet access. 32-inch LCD TVs are equipped with premium cable channels and pay movies. All accommodations provide desks along with free local calls (restrictions may apply). Bathrooms offer shower/tub combinations, hair dryers, and complimentary toiletries. In-room microwaves and refrigerators are provided. Additional amenities include irons/ironing boards and blackout drapes/curtains. In addition, housekeeping is offered daily and amenities available on request include hypo-allergenic bedding.
For transfers, guests must contact the property before arrival at the number on the booking confirmation.
Food and drink |
Things to do |
Working away |
Services |
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Sleep well |
Freshen up |
Be entertained |
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Food and drink |
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For transfers, guests must contact the property before arrival at the number on the booking confirmation.
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.


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We offer discount to nonprofits, government agencies, and federal contractors
The AILA Career Center offers more than access to the best possible industry candidates.
AILA Doc No. 09051468 | Dated May 6, 2009 | File Size: 3409 K
Download the DocumentA 5/6/09 memo from Donald Neufeld, Lori Scialabba and Pearl Chang consolidating USCIS guidance on unlawful presence from AFM Chapter 30.1 into Chapter 40.9, which provides comprehensive guidance concerning the accrual of unlawful presence and the resulting inadmissibility.
Cite as AILA Doc. No. 09051468.
Open the DocumentAmerican Immigration Lawyers Association
1331 G Street NW, Suite 300
Washington, DC 20005
Copyright © 1993-2015
American Immigration Lawyers Association.


text:
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To comprehensively identify proteins interacting with 14-3-3 sigma in vivo, tandem affinity purification and the multidimensional protein identification technology were combined to characterize 117 proteins associated with 14-3-3 sigma in human cells. The majority of identified proteins contained one or several phosphorylatable 14-3-3-binding sites indicating a potential direct interaction with 14-3-3 sigma. 25 proteins were not previously assigned to any function and were named SIP2-26 (for 14-3-3 sigma-interacting protein). Among the 92 interactors with known function were a number of proteins previously implicated in oncogenic signaling (APC, A-RAF, B-RAF, and c-RAF) and cell cycle regulation (AJUBA, c-TAK, PTOV-1, and WEE1). The largest functional classes comprised proteins involved in the regulation of cytoskeletal dynamics, polarity, adhesion, mitogenic signaling, and motility. Accordingly ectopic 14-3-3 sigma expression prevented cellular migration in a wounding assay and enhanced mitogen-activated protein kinase signaling. The functional diversity of the identified proteins indicates that induction of 14-3-3 sigma could allow p53 to affect numerous processes in addition to the previously characterized inhibitory effect on G2/M progression. The data suggest that the cancer-specific loss of 14-3-3 sigma expression by epigenetic silencing or p53 mutations contributes to cancer formation by multiple routes.
Welcome to NIF. Explore available research resources: data, tools and materials, from across the web
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404 File Not Found
Host by NetBox Version 2.8 Build 4128
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Grocery Products & Nutritional Supplements: These products are made primarily of natural ingredients with minimal processing. Natural ingredients are extracted directly from plants or animal products as opposed to being produced synthetically. These products do not contain any substances on our Banned Ingredients List.
Personal Care, Beauty, Cleaning & Baby Care Products: These products are made primarily of plant-based, naturally-derived and non-petroleum ingredients, pure essential oils and gentle preservatives. They do not contain any substances on our Banned Ingredients List.
Evanger's Grain Free Rabbit
Evanger's Grain Free Rabbit diet is formulated for dogs with specific food allergies. This canned food is a great source of protein and is ideal for protein rotation diets. The formula is totally grain- and gluten-free. This diet can be used as top garnishing and can be mixed with a normal diet as dogs love the delicious flavor. The diet provides all the vital nutrients that are required to make dogs more energetic, alert and healthy. This meat diet is easy to digest.
Evanger's Grain Free Rabbit:
A Closer Look: Evanger's Grain Free Rabbit is made with rabbit meat and other natural ingredients. The diet is totally grain free and is suitable for dogs that have food allergies. This diet is full of proteins, vitamins and minerals that can help maintain overall health.
Made Specially for: Dogs of all ages
Free of: Grain and gluten
It's the most convenient way to get your everyday essentials (baby, pet, health, beauty, household, grocery) automatically delivered right when you need them. Here's to never running out again!
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Buttoned grandad-style neckline with pretty topstitched braiding. Short sleeves. Length approx. 65 cm. Loose-fit blouse in 100% cotton.
La Redoute
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text: New member here so please forgive me if I've posted this in the wrong section. I'm needing to downsize from my GMC 2500HD and looking at a double cab longbed. My boys and I ride dirtbikes and currently in the stable is a CRF50, CRF100 and CR250. I'm trying to figure out if all three bikes will fit in a 2005-06 Tacoma longbed without any problem? Thank you in advance for any assistance or pics you can share!


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Edge Products sells its Juice with Attitude performance module with either a color screen (CS) or a color touch screen (CTS) for the in-cab unit. The CTS is available for Dodge/Ram Truck, Chevrolet/GMC, and Ford trucks, diesel and gas versions. MSRP for the Juice with Attitude CS starts at about $500. The CTS is more expensive, depending on year, make, and model.
During a recent visit to Edge's facilities in Ogden, Utah, we installed the Juice with Attitude CTS on a 2007 Dodge Ram HD 2500 with the 5.9-liter Cummins. Our test vehicle was mostly stock, except for an aFe intake and air filter, and a MBRP dual exhaust. Using factory-style connections, it took less than 30 minutes for the complete installation.
1. This module is said to add as much as 100 horsepower and 250 pound-feet of torque in six power levels, and can keep track of your truck's vitals, such as boost and coolant, oil, exhaust gas, and transmission temperatures. It can also store performance data, and has programmable protection for boost, transmission slip, and more.
2. This is the heart of the module. The Juice communicates along the engine's CAN-BUS data stream, from which it receives vital engine, transmission, and fuel-system information.
3. To begin the installation, plug in the injector and map connectors. On the 2007 Ram, these are located just below the valve cover on the driver side behind the intake manifold. Use a small screwdriver to unlatch the plastic clips.
4. The Edge Y connector is installed and the factory OEM connector plugs into the Y's pigtail. Install the map connector, located down lower on the block. Make sure the wires are routed away from hot engine components and tied out of harm's way. Also find a ground source; on this truck, it was just above the battery.


text:
What does COAH mean in Unclassified?
This page is about the meanings of the acronym/abbreviation/shorthand COAH in the Miscellaneous field in general and in the Unclassified terminology in particular.
City on a Hill
Find a translation for COAH in other languages:
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"COAH." Abbreviations.com. STANDS4 LLC, 2015. Web. 5 Mar. 2015. <http://www.abbreviations.com/term/1516784>.
COAH also stands for:
- Campus on a Hill
- Coahuila
- College of Arts and Humanities
- Come Over and Help
- Council On Affordable Housing
... see them all »
Nearby & related abbreviations:
Alternative search:
- Search City on a Hill on Amazon
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Ok, so this has got me confused. JHP are banned for use in the military becuase it has been thought that if a person is shot by the JHP then other soldiers would have to come to aid. In other words you take out 2-3 soldiers for every one that is actually shot. The logic is to use FMJ so that the bullet "will kill better". How does it makes sense that the JHP which causes more damage would be less likely to kill/ more likely to injure? Where is the logic that FMJ will kill an enemy quicker/ easier?
Another thought to consider: Bullets coming from high powered rifles fragment upon impact thus turning into many damaging objects. What would be the difference between JHP and FMJ if they both fragment upon impact? (shooting from rifle velocities)
I am just confused where the logic is coming from...ignorant polititions or what?


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I would recommend - very trending - bought for master bedroom to tie in red and black art - very nice!
This is a very affordable and well constructed comforter set. I absolutely love this set and highly recommend it. The colors are accurately displayed in the picture.
When we got a new bed we looked all over for a comforter set. When i saw this i fell in love with it and ordered it right away. when it came i loved it, it was a great color and came with a lot of pillows. after having it a couple months the comforter started coming apart, and the insilation got in clumps and spread holes all over in the inside, kind of like the fake spider webs for halloween. so after spending $*** on a comforter that i only had a couple months, now i have to spend more money on a new one. it would be good if you only used it for decoration
The colors are beautiful but this set is cheaply made. It feels cheap and and out of the box there are loose strings hanging everywhere where I am going to have to have it sewed. I got this for my daughter who is 4 hrs from me or I would return it. I have purchased other sets on this site and they have been of good quality...Dissapointed the one I got as a gift was made so poorly.
I was a bit disappointed that the red isn't actually red as it is stated.... it is more of a burgundy. Regardless, this is a beautiful set with lots and lots of pillows! Very exotic yet inviting feel to it! Shipped promptly and arrived safely and in good condition.
Im doing my apartment in a safari theme and i really love this comforter set! absolutely beautiful! cant wait to get it!
Fabulous product, fabulous price, fabulous service and shipping. Just love it and will definitely deal with Overstock.com again. I have already been telling my family and friends about it! What quality!!!!! Love it!
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H&R Block CIO discusses benefits of open source adoption
H&R Block consumes a great deal of open source software: Alfresco, MuleSource, Zimbra, JBoss, MySQL, Red Hat, Jive, and others. In this OSBC keynote, CIO Marc West talks about why H&R Block has turned to open source to drive product and service innovatio
Marc West, CIO of H&R Block, keynoted this year's Open Source Business Conference, and gave excellent insight into why a multi-billion dollar financial services company has turned to open source to deliver innovation and better service to its customers.
InfoWorld just uploaded all the videos from the event today, which you can access here. Marc's keynote is available below.


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According to a Pew Charitable Trusts survey, the United States has reclaimed the top spot in clean energy investment, toppling China from its number one global ranking. Meanwhile, investment in renewables around the world continues to surge, reaching $237.2 billion in 2011, up almost 8 percent from the previous year. Despite austerity measures, expiring tax [...]
read more
China invested $54.4 billion on clean energy in 2010, $20 billion more than the U.S., according to the latest report from Pew Charitable Trusts and... Read Post
Movement within the clean energy sector during 2012 has been put under the microscope by The Pew Charitable Trusts in their fourth-annual Who's Winning the Clean Energy Race? report. Released on Wednesday, the report states that a t... Read Post
Today the Pew Charitable Trust released its annual ranking of how countries are faring against one another in the clean energy race, and China has for the fourth time in the past five years overtaken the United States as the global ... Read Post


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Posted: Friday, October 5, 2012, 9:07 am
In brief
Inspiring stories about women making a difference worldwide!
Vital Voices started as a government initiative under the Clinton Administration with the goal of bringing women's issues to the forefront. Now, as a nonprofit, they work with women all over the world to develop leaders and support women's health, safety, education and empowerment. Women make up half the world (or as a Chinese proverb puts it, hold up half the sky) and Vital Voices believes the more we invest in women, the better our world can be.
The book is separated into five chapters, each a pillar of the Vital Voices organization: sense of mission, roots in the community, connecting across lines that divide, bold ideas and bold action and paying it forward. Each chapter expounds on the history of the organization and its goals, and gives the reader short, compelling stories about women leaders and activists.
I was equal parts saddened by the hardships women face around the world and inspired by the women who are making a difference. What an inspiring read.


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Seems like the least he could do.
Reader comments are listed below. Comments are currently closed and new comments are no longer being accepted.
Seems like the least he could do.
I almost said something about that, Doug. But I didn't want Mr. York (he's only Mr. Blue on live-blogging days as far as I'm concerned) to feel bad about letting me down and destroying my life. Perhaps he will adopt a British accent to mitigate his grave insult?
Hagel, Bitterfig. Hegel is disqualified at least due to German birth and probably also due to having died.I hope someone is there to comfort La Chevre when he discovers that Mr. Blue is American.
Cherney -
"It has but 15 EC votes. Georgia is no Florida, Pennsylvania, Ohio, or Michigan."
It is nevertheless the joint-9th largest state, with changing demographics, and a wide range of polling numbers. If, for example, the 2 or 4% that Insider Advantage have recorded there are accurate, differential turnout due to apathetic Republicans, could bring this into the Democratic column. Which, it must be remembered, Bill Clinton managed in 1992.
cherny, your obsession with supposed "sexism" is becoming tiresome. Hillary Clinton will not be Vice President and has lost the Democratic nomination to a more talented politician who doesn't share her hawkish tendencies, thank god. Get over it.
And why the obsession over Georgia? McCain is leading in the state by ten points. It has but 15 EC votes. Georgia is no Florida, Pennsylvania, Ohio, or Michigan. Is it because a state in the Deep South is where a female running-mate, specifically Hillary Clinton, wouldn't help? Maybe our blogger is so sexist that he can't bring himself to say anything in favor of picking Hillary? With Webb out of the picture, the chance of her getting the nomination has certainly increased.
i think you are all misunderstanding the blog post. i figure that hilary and sebelius are not mentioned because there probably wasn't an intrade bump for them. if intrade went up on them, i presume the "ethical blogger" would have reported on it.
likewise, hegel is mentioned because he is such a wacky choice, "gee, sam nunn is doing worse than this guy, who is totally hopeless." in some ways, mentioning hilary in that sense would be the affront.
I guess Hillary Soprano made webb an offer he could not refuse.VJ Machiavellihttp://www.vjmachiavelli.blogspot.comps Obama is the Neville Chamberlain of the Democ"rat"ic Party, and that is "CHANGE" for the worst.
Chuck Hagel is "anti-Israel"? Or is he just not a pawn of Israel and AIPAC like most of the Republican Party.
And Chuck Hagel, a pro-life, anti-Israel REPUBLICAN is a good choice?If only Hillary was omitted, we can attribute it to anti-Clintonism, but Sebelius also wasn't mentioned. It's sexism.
I would be interested to hear a little more about some of these other VP candidates that Intrade seems to be favouring. I had no idea that Dick Gephardt was in the running.
Might someone close to McCain's age be a bonus? Especially if they were willing to pledge to only serve for one term... it brings the 'safety' factor that cheney did in 2000, without overshadowing the candidate's future. It also puts McCain on the spot: did he pledge before to serve one term? if so, why, and if not, will he?
I'm not even sure that the downside of Nunn is worth it, even if he did flip Georgia to Obama.
Cherny-How so? I can think of a number of reason which make Clinton a poor choice which have nothing to do with gender.Nice trolling though.
A reminder to Clinton supporters: The failure to mention her among possible VP candidates is yet another sexist affront.
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