Longer Tau Research Articles

0018 Whole Genome Sequencing Study Identifies Novel Variants Associated with Intrinsic Circadian Period in Humans

Abstract Introduction Non-24 is a circadian rhythm disorder in which the master body clock runs either slightly earlier or, more commonly in the disorder, longer than 24 hours. Methods We conducted the first whole genome sequencing study of a non-24 population of 174 individuals that we identified as being totally blind with Non-24 Disorder. We have directly tested the association between SNPs and circadian period length (tau) (n=69). Linear regression corrected for PCs and covariates identified a strong signal in HCN1, Brain Cyclic Nucleotide-Gated Channel 1, HCN1. Results HCN1 channel is responsible for the feedback on the rods regulating the dynamic range of light reactivity under dim or intermediate light conditions. Minor allele rs72762058 associated with longer tau, a difference of 12 minutes, and mean tau of 24.71. In Drosophila there is only one HCN channel encoding gene, DmIh. Interestingly, DmIh mutant flies display alterations in the rest:activity pattern, and altered circadian rhythms, specifically, arrhythmic behavior or a shorter period in constant darkness. We report a variant that associated with longer tau. In addition, we identify others variants that strongly associate with tau, such as a missense variant (rs16989535), (minor allele associated with longer tau), within DEPDC5, GATOR Complex Protein). Subjects carrying the rare allele have a period > 25.2. DEPDC5 is part of GATOR1 complex, together with NPRL2 and NPRL3acts to inhibit the mTORC1 pathway. The GATOR1 seizure phenotype consists mostly of focal seizures, often sleep-related and drug-resistant and is associated with focal cortical dysplasia (20%). mTOR signaling is part of the photic entrainment pathway in the SCN, it regulates autonomous clock properties in a variety of circadian oscillators. Light-induced mTORC1 activation appears to be important for photic entrainment of the SCN clock, as rapamycin modulates light-induced phase shifts of wheel-running and body temperature rhythms in mice. Conclusion We identify variants in HCN1 and DEPDC5 implicated in significantly longer tau. Knowledge of the circadian clock and period length is not only essential for understanding of the basic clockwork mechanisms but also could provide insights into mechanistic links between circadian dysfunctions and human diseases such as epilepsy. Support Vanda Pharmaceuticals

0323 Associations Between Sleep and Activity Patterns in the Mother-Child Dyad

Abstract Introduction Animal studies show links between light-dark patterns in gestating dams and offsprings’ sleep and circadian rhythms. Activity patterns between mothers and infants show synchrony as early as 12 weeks postpartum. Our goal was to investigate maternal sleep/activity patterns at two points in the perinatal period and assess associations with activity in their young children. Methods Participants were 20 mother-child dyads recruited from previous studies. Mothers (age±SD = 31.7±5.5 years, range 21-40 years) wore wrist actigraphs during their 33rd week of pregnancy and 2nd week postpartum. Children (age±SD = 2.13±1.36 years, range 8 months-4.6 years) were assessed for 5 days and nights. Circadian patterns were analyzed using Maximum Entropy Spectral Analysis (MESA) to estimate best-fitting circadian period, tau. We used cosinor analysis to calculate rhythm amplitude, Midline Statistic of Rhythm (MESOR, representing mean activity), and acrophase (time of peak amplitude). We used circadian quotient (CQ; amplitude÷MESOR) to assess rhythm strength while normalizing for intersubject variation in activity levels. Autocorrelation, or degree to which data is consistent for a particular period, was calculated to analyze regularity of activity patterns. Results Mothers’ activity pattern autocorrelation was significantly correlated at the two time points (r=.530, p=.016), such that women with inconsistent activity patterns in pregnancy also demonstrated more irregularity at postpartum week 2. Child CQ correlated with age, with older children showing greater rhythm strength (r=.530, p=0.016). We observed a moderate correlation between mothers’ CQs during pregnancy and children’s CQs (r=.413,p=.07). In mother-child dyads, longer tau in mothers during pregnancy predicted lower autocorrelation of the child’s rhythm to a 24-hr period (r=-.520, p=.019). Finally, later maternal acrophase at postpartum week 2 was associated with longer tau in children (r=.504, p=.024). Conclusion These data show that associations between mother-child sleep/activity patterns may begin during pregnancy and support the notion that mothers’ perinatal sleep patterns could affect the health of both mothers and their children. Support Supported by R34MH104377, K23MH086689, the Seleni Institute, the Depression and Bipolar Disorder Alternative Treatment Foundation, and a Karen T. Romer Undergraduate Teaching and Research Award from Brown University.

Using inspection time and ex-Gaussian parameters of reaction time to predict executive functions in children with ADHD

Slower and more variable performance in speeded reaction time tasks is a prominent cognitive signature among children with Attention Deficit Hyperactivity Disorder (ADHD), and is often also negatively associated with executive functioning ability. In the current study, we utilize a visual inspection time task and an ex-Gaussian decomposition of the reaction time data from the same task to better understand which of several cognitive subprocesses (i.e., perceptual encoding, decision-making, or fine-motor output) may be responsible for these important relationships. Consistent with previous research, children with ADHD (n = 190; 68 girls) had longer/slower SD and tau than non-ADHD peers (n = 76; 42 girls), but there were no group differences in inspection time, mu, or sigma. Smaller mu, greater sigma, longer tau, and slower inspection time together predicted worse performance on a latent executive function factor, but only tau partially mediated the relationship between ADHD symptomology and EF. These results suggest that the speed of information accumulation during the decision-making process may be an important mechanism that explains ADHD-related deficits in executive control.

Molecular Probe for a Fluorous Medium: Long-Lived Phosphorescence of α-Diketones in Perfluoromethylcyclohexane at Room Temperature

We found that alpha-diketones (2,3-butanedione (BD) and 1-phenyl-1,2-propanedione (PPD)) were very suitable luminescence probes for studying the properties of a perfluorinated solvent (i.e., fluorous solvent; perfluoromethylcyclohexane (PFMC)), since these compounds were soluble in PFMC and showed long-lived phosphorescence even at room temperature. The phosphorescence lifetime (tau(p)) of BD in PFMC (650 micros) was much longer than that in cyclohexane (CH, 270 micros). The longer tau(p) value of BD in PFMC was ascribed to the variation of the intersystem crossing rate constant (k(isc)) from the excited triplet state (T1) to the ground state (S0) with the solvent. Some possible reasons for the change in k(isc) were discussed in terms of solute-solvent interactions. Furthermore, by utilizing phosphorescence quenching of BD by pyrene, we, determined a rate constant of the diffusion-controlled reaction in PFMC. Characteristic behaviors of mixing/separation processes between PFMC and a common organic solvent observed by Schlieren photographs were also reported.

Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment.

Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (tau(SD)), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part reflects Na(+) conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer tau(SD). Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na(+) conductance, possibly associated with axonal regeneration or collateral sprouting.

Limitations in the use of RICH counters to detect tau-neutrino appearance

Abstract A comprehensive simulation study of the feasibility of an earlier proposed tau-neutrino appearance experiment based on a RICH with liquid radiator (C6F14) has been performed. Tau leptons, that are created in charged current interactions of incident tau neutrinos with the same momentum spectrum as that of the planned Gran Sasso beam (average 17 GeV /c ), have an average track length of about 0.5 mm . Cherenkov photons emitted in the liquid radiator from the short track of the tau lepton provide a characteristic pattern for tau-neutrino appearance. In the present report it is shown, on the basis of simulations performed with the GEANT4 code, that Cherenkov radiation from delta electrons, originating from the interaction of the long-lived tau decay products with the Cherenkov radiator, constitutes a severe background that renders the detection of the millimeter-short tau track unfeasible. Increasing the incident neutrino beam momentum results in longer tau tracks and therefore more signal photons, but this does not solve the background problem since the kink angle between the tau track and the secondary decay particle decreases with increasing neutrino momentum, leading to an increased overlap between the Cherenkov rings of these two particles.

Excitability of human muscle afferents studied using threshold tracking of the H reflex.

In human peripheral nerves, physiological evidence has been presented for a number of biophysical differences between cutaneous afferents and alpha motor axons. The differences in strength-duration properties for cutaneous afferents and motor axons in the median nerve have been attributed to greater expression of a persistent Na(+) conductance (I(Na,P)) on cutaneous afferents. However, it is unclear whether the biophysical properties of human group Ia afferents differ from those of cutaneous afferents. The present studies were undertaken to determine whether the properties of human group Ia afferents can be studied indirectly using 'threshold tracking' to measure the excitability changes in the H reflex, and to determine whether the excitability of group Ia afferents differs from that of cutaneous afferents. The strength-duration properties of the soleus H reflex and soleus motor axons were measured at rest and during sustained voluntary contractions. Similar experiments were performed on the median nerve at the wrist to study the strength-duration properties of cutaneous afferents, alpha motor axons and H reflex of the thenar muscles. In addition, the technique of 'latent addition' was used to determine whether there was a difference in a low-threshold conductance on soleus Ia afferent and motor axons. The present findings indicate that the strength-duration time constant (tau(SD)) for the H reflex is longer than that for alpha motor axons, but similar to that for cutaneous afferents. There were no differences in tau(SD) for the soleus H reflex at rest and during contractions, suggesting that tau(SD) for the H reflex is largely unaffected by changes in synaptic or motoneurone properties. Finally, the difference in latent addition suggests that the longer tau(SD) of the soleus H reflex may indeed be due to greater activity of a persistent Na(+) conductance on Ia afferents than on soleus alpha motor axons.

Oxygen uptake kinetics during exercise in chronic heart failure: influence of peripheral vascular reserve

Exercise performance in chronic heart failure is severely impaired, due in part to a peripherally mediated limitation. In addition to impaired maximal exercise capacity, the O(2) uptake (VO(2)) response during submaximal exercise may be affected, with a greater reliance on anaerobiosis leading to early fatigue. However, the response of VO(2) kinetics to submaximal exercise in chronic heart failure has not been studied extensively; in particular, the relationship between oxygen utilization and the peripheral response to exercise has not been studied. The present investigation examined the time-constant (tau, corresponding to 63% of the total response fitted from exercise onset) of the VO(2) kinetics on-response to submaximal exercise and its relationship to maximal peripheral blood flow in patients with chronic heart failure, and compared responses with those in healthy sedentary subjects. Subjects were 10 patients with chronic heart failure (NYHA class II/III). The mean age was 50+/-12 years, with a mean resting left ventricular ejection fraction of 25+/-9%. Controls were 10 age-matched healthy subjects. VO(2(max)) was first determined for all subjects. Repeated transitions from rest to exercise were performed on a cycle ergometer while measuring breath-by-breath responses of VO(2) at a fixed work rate of 50% of VO(2(max)) (heart failure patients and healthy controls) and at a work rate equivalent to the average in heart failure patients (65 W; healthy controls only). On a separate occasion, post-maximal ischaemic exercise calf blood flow was measured (strain-gauge plethysmography). Whereas heart failure subjects displayed a significantly prolonged VO(2) kinetics response at a similar absolute workload (i.e. 65 W), as indicated by a longer tau value (42 s, compared with 22 s in controls; P<0.01), there was no difference in tau at a similar relative work rate [50% of VO(2(max))]. In addition, heart failure subjects demonstrated a lower maximal calf blood flow (P<0.05) than control subjects. These results indicate that patients with heart failure have a prolonged VO(2) kinetics on-response compared with healthy subjects at a similar absolute work rate (i.e. 65 W), but not at a similar relative work rate [50% of VO(2(max))]. Thus, despite a reduced maximal calf blood flow response associated with heart failure, it does not appear that this contributes to an impairment of the submaximal exercise response beyond that explained by a reduced maximal exercise capacity [VO(2(max))].

Abnormal coronary flow dynamics at rest and during tachycardia associated with impaired left ventricular relaxation in humans: Implication for tachycardia-induced myocardial ischemia

Objectives. This study attempted to clarify the efect of ventricular relaxation abnormalities on coronary flow dynamics at rest and during tachycardia in humans.Background. Ventricular relaxation abnormality has been demonstrated in animals to have an adverse impact on early diastolic coronary flow dynamics. However, this relation has not been established in humans. Even if the advene effect were latent at rest, it might become evident during tachycardia because tachycardia reduces coronary flow reserve and facilitates the production of myocardial ischemia.Methods. Doppler phasic left coronary flow velocity pattern was obtained at rest and during tachycardia in 23 patients without coronary stenosis. The time constant of left ventricular isovolumic pressure (tau) was used to assess ventricular relaxation.Results. The time to peak flow velocity of the diastolic coronary flow wave was longer, and the fraction of the first third of diastolic coronary flow was smaller, in patients with a longer tau (r = 0.58, p < 0.01; r = −0.44, p < 0.05), indicating a close relation bstween early diastolic coronary flow dynamics and ventricular relaxation. Although rapid atrial pacing yielded an increase in the coronary flow velocity integral per minute in all patients, diastolic coronary flow velocity integral per minute increased in 9 patients with a normal (< 40 ms) tau at rest but decreased in 14 patients with a longer (> 40 ms) tau at rest.Conclusions. Impaired left ventricular relaxation was associated with decreased coronary flaw in early diastole at rest and decreased coronary flow throughout diastole during tachycardia in patients without coronary stenosis. These findings may provide more insight into the mechanism of tachycardia-induced subendocardial ischemia in patients with impaired ventricular relaxation but without concomitant coronary stenosis.

Physiological properties of primate lumbar motoneurons

1. Intracellular recordings were obtained from 149 motoneurons innervating triceps surae (n = 109) and more distal muscles (n = 40) in 14 pentobarbital-anesthetized monkeys (Macaca nemestrina). The variables evaluated were resting membrane potential, action potential amplitude, conduction velocity (CV), input resistance (RN), membrane time constant (tau m), electrotonic length (L), whole-cell capacitance (Ctot), long current pulse threshold (rheobase), short current pulse threshold (Ishort), afterhyperpolarization (AHP) maximum amplitude (AHPmax), AHP duration (AHPdur), time to half maximum AHP amplitude (AHP t1/2), depolarization from resting potential to elicit action potential (Vdep), and threshold voltage for action potential discharge (Vthr). 2. Mean values +/- SD for the entire sample of motoneurons are as follows: resting membrane potential -67 +/- 6 mV; action potential amplitude 75 +/- 7 mV; CV 71 +/- 6 m/s; RN 1.0 +/- 0.5 M omega; tau m 4.4 +/- 1.5 ms; L 1.4 +/- 0.2 lambda; Ctot 7.1 +/- 1.8 nF; rheobase 13 +/- 7 nA; Ishort 29 +/- 14 nA; AHPmax 3.5 +/- 1.3 mV; AHPdur 77 +/- 26 ms; AHP t 1/2 21 +/- 7 ms; Vdep 11 +/- 4 mV; and Vthr -56 +/- 5 mV. CV is lower in soleus than in either medial or lateral gastrocnemius motoneurons, and RN is lower and tau m is longer in soleus than in lateral gastrocnemius motoneurons. 3. RN is higher in motoneurons with longer tau m and slower CV. A linear relationship exists between log(CV) and log(1/RN) with a slope of 1.8-2.2 (depending on the action potential amplitude acceptance criteria used), suggesting that membrane resistivity (Rm) does not vary systematically with cell size. 4. Rheobase is higher in motoneurons with lower RN, longer tau m, shorter AHP time course, and higher CV. Ishort and normalized rheobase (i.e., rheobase/Ctot) vary similarly with these motoneuron properties, except that Ishort is independent of tau m and normalized rheobase is independent of CV. 5. Vthr tends to be more depolarized in motoneurons with large Ctot, but the relationship is sufficiently weak so that any systematic variation in Vthr according to cell size probably contributes only minimally to recruitment order. Vthr does not vary systematically with CV, AHP time course, RN, or tau m. 6. Quantitative differences between macaque and cat triceps surae motoneurons are apparent in CV, which is slower in macaque than in cat, and to a lesser extent in tau m and RN, which are lower in macaque than in cat.(ABSTRACT TRUNCATED AT 400 WORDS)

Noninvasive Measurement of Cardiac Function during Exercise, Using Resaturation Curves

The resaturation curve, a noninvasive indicator-dilution test using an ear oximeter to detect rates of change in arterial oxygen saturation during breathing of various concentrations of oxygen, was used to assess cardiac performance in normal subjects and in 108 patients with cardiac valvular disease. Measurements made during exercise included the time constant of resaturation (tau) and beat-to-beat changes in arterial oxygen saturation (the left heart clearance fraction). At maximum rates of voluntary work, patients had a significantly reduced clearance fraction and longer tau than normal subjects. Clearance fraction and tau improved in patients after aortic valve replacement; deterioration occurred in tau and clearance fraction over time in patients treated medically, as compared to normal subjects who showed little change during a ten-year period. Clearance fraction and tau correlated with hemodynamic data obtained during cardiac catheterization. The resaturation curve provides an objective measure of cardiac impairment that can be readily repeated during follow-up of patients with heart disease.