Neural response to working memory demand predicts neurocognitive deficits in HIV.

Human immunodeficiency virus (HIV) continues to have adverse effects on cognition and the brain in many infected people, despite a reduced incidence of HIV-associated dementia with combined antiretroviral therapy (cART). Working memory is often affected, along with attention, executive control, and cognitive processing speed. Verbal working memory (VWM) requires the interaction of each of the cognitive component processes along with a phonological loop for verbal repetition and rehearsal. HIV-related functional brain response abnormalities during VWM are evident in functional MRI (fMRI), though the neural substrate underlying these neurocognitive deficits is not well understood. The current study addressed this by comparing 24 HIV+ to 27 demographically matched HIV-seronegative (HIV-) adults with respect to fMRI activation on a VWM paradigm (n-back) relative to performance on two standardized tests of executive control, attention and processing speed (Stroop and Trail Making A-B). As expected, the HIV+ group had deficits on these neurocognitive tests compared to HIV- controls, and also differed in neural response on fMRI relative to neuropsychological performance. Reduced activation in VWM task-related brain regions on the 2-back was associated with Stroop interference deficits in HIV+ but not with either Trail Making A or B performance. Activation of the posterior cingulate cortex (PCC) of the default mode network during rest was associated with Hopkins Verbal Learning Test-2 (HVLT-2) learning in HIV+. These effects were not observed in the HIV- controls. Reduced dynamic range of neural response was also evident in HIV+ adults when activation on the 2-back condition was compared to the extent of activation of the default mode network during periods of rest. Neural dynamic range was associated with both Stroop and HVLT-2 performance. These findings provide evidence that HIV-associated alterations in neural activation induced by VWM demands and during rest differentially predict executive-attention and verbal learning deficits. That the Stroop, but not Trail Making was associated with VWM activation suggests that attentional regulation difficulties in suppressing interference and/or conflict regulation are a component of working memory deficits in HIV+ adults. Alterations in neural dynamic range may be a useful index of the impact of HIV on functional brain response and as a fMRI metric in predicting cognitive outcomes.

A pilot investigation on the effects of combination transcranial direct current stimulation and speed of processing cognitive remediation therapy on simulated driving behavior in older adults with HIV.

Cognitive impairments seen in people living with HIV (PLWH) are associated with difficulties in everyday functioning, specifically driving. This study utilized speed of processing cognitive remediation therapy (SOP-CRT) with transcranial direct current stimulation (tDCS) to gauge the feasibility and impact on simulated driving. Thirty PLWH (M age = 54.53, SD = 3.33) were randomly assigned to either: sham tDCS SOP-CRT or active tDCS SOP-CRT. Seven indicators of simulated driving performance and safety were obtained. Repeated measures ANOVAs controlling for driver's license status (valid and current license or expired/no license) revealed a large training effect on average driving speed. Participants who received active tDCS SOP-CRT showed a slower average driving speed (p = 0.020, d = 0.972) than those who received sham tDCS SOP-CRT. Non-significant small-to-medium effects were seen for driving violations, collisions, variability in lane positioning, and lane deviations. Combination tDCS SOP-CRT was found to increase indices of cautionary simulated driving behavior. Findings reveal a potential avenue of intervention and rehabilitation for improving driving safety among vulnerable at-risk populations, such as those aging with chronic disease.

Fundamental dissipation due to bound fermions in the zero-temperature limit.

The ground state of a fermionic condensate is well protected against perturbations in the presence of an isotropic gap. Regions of gap suppression, surfaces and vortex cores which host Andreev-bound states, seemingly lift that strict protection. Here we show that in superfluid 3He the role of bound states is more subtle: when a macroscopic object moves in the superfluid at velocities exceeding the Landau critical velocity, little to no bulk pair breaking takes place, while the damping observed originates from the bound states covering the moving object. We identify two separate timescales that govern the bound state dynamics, one of them much longer than theoretically anticipated, and show that the bound states do not interact with bulk excitations.

Effects of Fermented Papaya Preparation (FPP) on Safety Outcomes in Older Adults - A Short Report of a Placebo-Controlled Clinical Trial.

Fermented Papaya Preparation (FPP®) has shown antioxidative and anti-inflammatory effects in preclinical and clinical aging studies. However, clinical trials are needed to fully evaluate the safety of FPP® in moderate-functioning, generally healthy older adults. In this randomized (9g/day of FPP® or placebo), crossover design study, we enrolled 30 older moderate-functioning older adults (70-100 years old). The participants completed both a treatment and a placebo condition. After eight (8) weeks on each of these regimens (with a 4-week wash-out period in between), participants had their venous blood drawn for assessment of blood chemistries, metabolic outcomes and inflammatory biomarkers. Participants were asked to report any adverse events during the course of the study and complete post-treatment outcome assessments for anthropometric and metabolic outcomes. The major finding related to safety was that there were no adverse changes in blood chemistries and few adverse events in the FPP® condition, which did not differ from placebo (p>0.05). There were no serious adverse effects in either condition. Twenty-nine (29) participants (mean age 78.2±5.3 yrs) completed the study with 94% adherence to the dosing regimen. There were no significant effects of FPP® on anthropometric and metabolic outcomes. In addition, no effects on markers of inflammation were observed. Our trial demonstrates FPP® supplementation is safe and feasible in adults ages 70 years and older. Based on these findings and the positive effects FPP has demonstrated in previous trials, future trials should examine the effects of FPP® in older adults with impaired health status and/or older adults who may have insufficient anti-oxidant protection due to their genetic background.

Dimensions of depressive symptoms and cingulate volumes in older adults.

Clinical depression and subthreshold depressive symptoms in older adults have been linked to structural changes in the cingulate gyrus. The cingulate comprises functionally distinct subregions that may have distinct associations with different types, or symptom dimensions, of depression. This study examined the relationship between symptom dimensions of depression and gray matter volumes in the anterior cingulate, posterior cingulate and isthmus of the cingulate in a nonclinical sample. The study included 41 community-dwelling older adults between the ages of 55 and 81. Participants received a structural magnetic resonance imaging scan and completed the Center for Epidemiologic Studies Depression Scale. Subscale scores for depressed mood, somatic symptoms and lack of positive affect were calculated, and Freesurfer was used to extract cingulate gray matter volumes. Regression analyses were conducted to examine the relationship between depressive symptoms and volumes of cingulate subregions while controlling for sex, age and estimated total intracranial volume. Higher scores on the depressed mood subscale were associated with larger volumes in the left posterior cingulate and smaller volumes in the isthmus cingulate. Higher scores on the somatic symptoms subscale were significantly related to smaller volumes in the posterior cingulate. A trend was observed for a positive relationship between higher scores on the lack of positive affect subscale and larger volumes in the anterior cingulate cortex. These results are consistent with previous findings of altered cingulate volumes with increased depressive symptomatology and suggest specific symptom dimensions of depression may differ in their relationship with subregions of the cingulate.

A technical guide to tDCS, and related non-invasive brain stimulation tools.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.

The effect of the NK1 receptor antagonist CP-99,994 on emesis and c-fos protein induction by loperamide in the ferret.

The site of the anti-emetic action of the neurokinin1 receptor antagonist CP-99,994 was studied in the ferret using the centrally acting opiate receptor agonist loperamide at a dose (0.5 mg/kg s.c.) which induced emesis in all animals tested. CP-99,994 (1 mg/kg, s.c.x2) abolished the emetic response (retching and vomiting) and the behaviours (licking, wet dog shakes, mouth scratching and gagging) induced by loperamide over a 2-h observation period. The enantiomer of this compound CP-100,263 (1 mg/kg, s.c.x2) did not have any significant effect on emesis or related behaviours. Loperamide (0.5 mg/kg s.c.) administration (but not its vehicle) resulted in dense fos-like immunoreactivity (FLI) mainly throughout the rostro-caudal extent of the nucleus tractus solitarius but not the area postrema. Although CP-99,994 (1 mg/kgx2) abolished the loperamide-induced emesis, it did not have any statistically significant effect on FLI in the brainstem. In loperamide and CP-100,263 (1 mg/kg, s.c.x2) treated animals FLI was comparable to that in animals treated with loperamide and CP-99,994. The results from this study taken together with those from previous studies indicate that loperamide exerts its emetic effect via nucleus tractus solitarius dendrites projecting into the area postrema. The lack of significant effect of CP-99,994 on the FLI induced by loperamide in this nucleus suggests that it is acting at a site "deep" in the nucleus tractus solitarius or elsewhere. The marked reduction in behaviours associated with loperamide administration by CP-99,994 provides a preliminary indication that NK1 receptor antagonist (as represented by CP-99,994) may in the clinic have effects on behaviours induced by emetic agents in addition to their previously described effects on retching and vomiting.

The emetic and anti-emetic effects of the capsaicin analogue resiniferatoxin in Suncus murinus, the house musk shrew.

1. In SUNCUS: murinus the ultrapotent capsaicin analogue resiniferatoxin (RTX) induced an emetic response in the dose range 1 - 1000 microg kg(-1), s.c. The latency was inversely related to dose and ranged from 41.2+/-4.4 min. (1 microg kg(-1), s.c.) to 2.7+/-0.6 min. (1000 microg kg(-1), s.c.). 2. The emetic response to RTX (10 or 100 microg kg(-1), s.c.) was blocked or markedly reduced by pre-treatment with RTX (100 microg kg(-1), s.c.), 8-OH-DPAT (100 microg kg(-1), s.c.), morphine (2 mg kg(-1), s.c.), neonatal capsaicin (100 mg kg(-1), s.c.) and the NK(1) receptor antagonist CP-99,994 (10 - 20 mg kg(-1), s.c.) but not by the 5-HT(3) receptor antagonist tropisetron (200 microg kg(-1), s.c.). 3. RTX (100 microg kg(-1), s.c.) induced c-fos-like immunoreactivity in the area postrema and parts of the nucleus tractus solitarius. This pattern is consistent with the proposal that the emetic effect is mediated via one or both of these structures and an involvement of substance P is discussed. 4. RTX (10 and 100 microg kg(-1), s.c.) had broad-spectrum antiemetic effects in Suncus as indicated by its ability to block or markedly reduce the emetic response to motion (1 Hz, 4 cm lateral, 10 min.), cisplatin (20 mg kg(-1), i.p.), intragastric copper sulphate (40 mg kg(-1), p.o.), nicotine (10 mg kg(-1), s.c.) and RTX (100 microg kg(-1), s.c.) itself. 5. It is proposed that the site of the anti-emetic effect is in the nucleus tractus solitarius and mechanisms involving the modulation of substance P release are discussed. 6. The general utility of SUNCUS: for investigations of vanilloid receptors is reviewed in the light of the exquisite sensitivity of the emetic reflex in this species to resiniferatoxin.

Tracheal epithelial damage alters tracer fluxes and effects of tracheal osmolaity in sheep in vivo.

Tracheal osmolaity affects blood flow and the flux of a tracer, technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA), from tracheal lumen to venous blood in anesthetized sheep. Hyperosmolar liquids increase blood flow and slightly decrease 99mTc-DTPA flux, whereas hyposmolar liquids have no effect on blood flow and greatly increase 99mTc-DTPA flux. We have now investigated whether epithelial damage induced by exposure of the tracheal lumen to a detergent (0.2% Triton X-100) alters these effects. A tracheal artery was perfused, and tracheal venous blood was collected. The initial tracheal volume was 12.8 +/- 0.7 ml. Triton X-100 greatly increased the permeability coefficient for 99mTc-DTPA from -2.1 x 10(-7) to -240 x 10(-7) cm/s. Hyperosmolar Krebs-Henseleit solution (KH; 739 +/- 6 mosmol/kg) increased arterial (+14.3%) and venous (+21.5%) flows and decreased 99mTc-DTPA output by 51.7%. Water flux into the lumen (+0.3 +/- 0.1 ml) was not significant, and the osmolality decreased by 99 +/- 9 mosmol/kg. Hyposmolar KH (124 +/- 2 mosmol/kg) had no effect on arterial and venous flows (-1.3% for both), and the increase in 99mTc-DTPA output (+8.3%) was small and not significant. The volume decreased by 0.4 +/- 0.1 ml, and the osmolaity increased by 36 +/- 4 mosmol/kg. Thus epithelial damage greatly increases the baseline permeability of the tracheal wall to 99mTc-DTPA. It does not alter the qualitative effects of hypersomolar KH on blood flow and 99mTc-DTPA output but does reduce the effect of hyposmolar KH on 99mTc-DTPA output. The latter effect may be a consequence of the reduced net water movement in response to non-isosmolar solutions after epithelial damage.

Effects of central injection of glucose on thermogenesis in normal, VMH-lesioned and genetically obese rats.

Intra-cerebroventricular (i.c.v.) injection of glucose (0.1-1.0 mumol) caused dose-dependent increases in resting oxygen consumption (Vo2) of conscious rats (maximum increase of 15.4 +/- 2% at 0.5 mumol). These effects were significantly attenuated by peripheral (i.p.) pretreatment with the beta-adrenoceptor propranolol, indicating the importance of the sympathetic nervous system (SNS) in the response. Plasma glucose concentrations were elevated (11%) 30 min after central injection of glucose, but intravenous glucose (0.5 mumol) did not affect resting Vo2. Animals which had been fasted for 12 h prior to Vo2 measurement exhibited reduced basal Vo2 values, but the nutritional state of the animal did not affect the metabolic response to central injections of glucose (0.5 mumol). Rats exhibiting genetic (fa/fa Zucker rats) and hypothalamic (VMH-lesioned) obesity showed similar thermogenic responses to centrally administered glucose, to their lean counterparts. These data suggest a dual action of central glucose in the regulation of energy balance, involving stimulation of energy expenditure in addition to its reported inhibition of energy intake. The defective diet-induced thermogenesis associated with VMH and genetic obesities does not appear to result from an inability to respond to changes in intracerebroventricular glucose concentrations.

Cisplatin acutely reduces 5-hydroxytryptamine-induced vagal depolarization in the rat: protective action of dexamethasone.

The effect of the anti-cancer cytotoxic drug cisplatin on KCl and 5-hydroxytryptamine (5-HT)-induced depolarization in the rat isolated cervical vagus nerve was investigated using the 'grease gap' extracellular recording technique. KCl (10 mM) perfused onto the isolated nerve previously incubated for 2 h in 10 microM cisplatin initiated a d.c. potential of 1.06 +/- 0.09 mV compared to a potential of 1.29 +/- 0.13 mV in control nerves. Perfusion with 5 microM 5-HT produced a markedly reduced depolarization (0.23 +/- 0.02 mV) in cisplatin-treated nerves compared with control nerves (0.42 +/- 0.04 mV, P = 0.005). This effect was enhanced when 5-HT was reapplied 30 min later (0.19 +/- 0.02 mV in cisplatin-treated compared with 0.42 +/- 0.03 mV in controls, P < 0.0001). The inhibitory effect of cisplatin on 5-HT-induced depolarization was found to be significantly (P = 0.004) reduced by the addition of dexamethasone (10 microM) to the incubation buffer (0.34 +/- 0.04 mV). These results are discussed in the light of the emetic and neurotoxic effects of cisplatin and the protective effects of dexamethasone.

Thermoregulatory effects of resiniferatoxin in the rat.

When administered acutely, the vanilloid (capsaicin) receptor agonist resiniferatoxin induces marked hypothermia in the ferret, rat and mouse. The aim of this study was to further characterise the thermoregulatory effects of resiniferatoxin in the rat in an attempt to understand the mechanism by which resiniferatoxin induces this hypothermic effect. Three doses of resiniferatoxin were administered (50, 100, 200 micrograms/kg s.c.) in separate animals at an ambient temperature (Ta) of 20 degrees C but there was no apparent dose-related effect on the decrease in colonic temperature over this range. Resiniferatoxin (50 micrograms/kg s.c.) decreased whole body oxygen consumption when measured below thermoneutrality (Ta = 20 degrees C) but not at thermoneutrality (Ta = 29 degrees C); likewise there was no hypothermic response to resiniferatoxin when measured at a Ta of 29 degrees C. Operant responding for radiant heat in a cold environment (-8 degrees C) was also measured in resiniferatoxin-treated (50 micrograms/kg s.c.) rats. These experiments showed that resiniferatoxin-treated rats attempted to defend body temperature by lever pressing for more radiant heat. However, this was not sufficient to reverse the hypothermia. Two repeat doses, 1 week apart, had little or no effect on colonic temperature, oxygen consumption or operant responding in the cold. Resiniferatoxin (50 micrograms/kg s.c.) also produced hypothermia (Ta = 20 degrees C) in neonatally capsaicinized adult rats. The exact site and mode of action is still under investigation, but it is postulated that resiniferatoxin activates, and then destroys or desensitizes warm thermoreceptors.

The development of the emetic reflex in the house musk shrew, Suncus murinus.

The emetic (retching and vomiting) reflex is an important component of the body's defence system against accidentally ingested toxins and emesis is also a common symptom of disease and a side-effect of a number of pharmacological therapies. The development of the reflex has been the subject of few systematic studies. The aim of this study was to characterise the development of the emetic reflex in Suncus murinus (the house musk shrew) using emetic stimuli acting via three different afferent pathways: motion via the vestibular system, pyrogallol via abdominal vagal afferents and resiniferatoxin (a capsaicin analog) via the brainstem. The emetic reflex was not present to any stimulus prior to postnatal day 10 but the onset of the response to motion lagged behind that to the other stimuli in not being present until postnatal day 15. Body weight was not a determinant of the presence of the reflex. It is proposed that the delayed presence of the emetic reflex in Suncus makes it an ideal species in which to investigate factors regulating its development.

An electrophysiological investigation of the effects of cisplatin and the protective actions of dexamethasone on cultured dorsal root ganglion neurones from neonatal rats.

In this study we have investigated the acute and chronic effects of cisplatin on whole cell currents in cultured dorsal root ganglion neurones. Consistent with effects on action potentials measured under current clamp, acute (5 min) application of cisplatin (5 microM) attenuated voltage-activated potassium, and mixed cation currents by approximately 50% in both cases. Chronic treatment (5-7 days) of cultured neurones with 5 microM cisplatin also resulted in greatly reduced voltage-activated potassium currents (by 50%) and calcium currents (by 60%) compared to events recorded from neurones not treated with cisplatin. In contrast, the amplitude of inward cation current activated by hyperpolarization was doubled by 5-12 days treatment with cisplatin. Studies on action potential after-depolarizations and calcium-activated chloride currents suggest that cisplatin disturbs calcium homeostatic mechanisms. These observations may account for anode break spike excitation and the low efficiency with which cells buffer intracellular calcium following cisplatin treatment. Dexamethasone has been found to enhance the anti-emetic effects of 5-HT3 receptor antagonists in patients treated with cisplatin. For this reason the actions of dexamethasone were studied in combination with cisplatin treatment. Although acute application of dexamethasone (1-10 microM) produced transient depolarizations and bursts of action potentials, after 5 minutes application it had no effect on membrane potential, input resistance, or the properties of action potentials evoked by depolarizing current commands.(ABSTRACT TRUNCATED AT 250 WORDS)