Predictors of Varenicline Adherence Among Cancer Patients Treated for Tobacco Dependence and its Association With Smoking Cessation.

INTRODUCTION: The degree to which smokers adhere to pharmacotherapy predicts treatment success. The development of interventions to increase adherence requires identification of predictors of treatment adherence, particularly among specific clinical populations. METHODS: Using data from a 12-week open-label phase of a clinical trial of varenicline for tobacco dependence among cancer patients (N = 207), we examined: (1) the relationship between self-reported varenicline adherence and verified smoking cessation and (2) demographic and disease-related variables, and early changes in cognition, affect, withdrawal, the reinforcing effects of smoking, and medication side effects, as correlates of varenicline adherence. RESULTS: At the end of 12 weeks, 35% of the sample had quit smoking and 52% reported taking ≥80% of varenicline. Varenicline adherence was associated with cessation (p < .001): 58% of participants who were adherent had quit smoking versus 11% of those who were not. Participants who experienced early reductions in depressed mood and satisfaction from smoking and experienced an increase in the toxic effects of smoking, showed greater varenicline adherence (p < .05); the relationship between greater adherence and improved cognition, reduced craving, and reduced sleep problems and vomiting approached significance (p < .10). CONCLUSIONS: Among cancer patients treated for tobacco dependence with varenicline, adherence is associated with smoking cessation. Initial changes in depressed mood and the reinforcing effects of smoking are predictive of adherence. IMPLICATIONS: The benefits of varenicline for treating tobacco dependence among cancer patients may depend upon boosting adherence by addressing early signs of depression and reducing the reinforcing dimensions of cigarettes.

Efficacy and safety of combination behavioral activation for smoking cessation and varenicline for treating tobacco dependence among individuals with current or past major depressive disorder: A 2 × 2 factorial, randomized, placebo-controlled trial.

BACKGROUND AND AIMS: Treatment of depression-related psychological factors related to smoking behavior may improve rates of cessation among adults with major depressive disorder (MDD). This study measured the efficacy and safety of 12 weeks of behavioral activation for smoking cessation (BASC), varenicline and their combination. DESIGN, SETTING, PARTICIPANTS: This study used a randomized, placebo-controlled, 2 × 2 factorial design comparing BASC versus standard behavioral treatment (ST) and varenicline versus placebo, taking place in research clinics at two urban universities in the United States. Participants comprised 300 hundred adult smokers with current or past MDD. INTERVENTIONS: BASC integrated behavioral activation therapy and ST to increase engagement in rewarding activities by reducing avoidance, withdrawal and inactivity associated with depression. ST was based on the 2008 PHS Clinical Practice Guideline. Both treatments consisted of eight 45-min sessions delivered between weeks 1 and 12. Varenicline and placebo were administered for 12 weeks between weeks 2 and 14. MEASUREMENTS: Primary outcomes were bioverified intent-to-treat (ITT) 7-day point-prevalence abstinence at 27 weeks and adverse events (AEs). FINDINGS: No significant interaction was detected between behavioral treatment and pharmacotherapy at 27 weeks (χ2 (1) = 0.19, P = 0.67). BASC and ST did not differ (χ2 (1) = 0.43, P = 0.51). Significant differences in ITT abstinence rates (χ2 (1) = 4.84, P = 0.03) emerged among pharmacotherapy arms (16.2% for varenicline, 7.5% for placebo), with results favoring varenicline over placebo (rate ratio = 2.16, 95% confidence interval = 1.08, 4.30). All significant differences in AE rates after start of medication were higher for placebo than varenicline. CONCLUSION: A randomized trial in smokers with major depressive disorder found that varenicline improved smoking abstinence versus placebo at 27 weeks without elevating rates of adverse events. Behavioral activation for smoking cessation did not outperform standard behavioral treatment, with or without adjunctive varenicline therapy.

Feasibility of implementing a novel behavioural smoking cessation intervention amongst human immunodeficiency virus-infected smokers in a resource-limited setting: A single-arm pilot trial.

BACKGROUND: Tobacco use is prevalent amongst individuals infected with human immunodeficiency virus (HIV). In resource-constrained settings, pharmacological smoking cessation interventions are unfeasible because of their high cost. There is a need to develop and evaluate behavioural interventions to address the unique challenges of tobacco use in the HIV-infected populations in these settings. OBJECTIVES: The authors aimed to assess the feasibility and acceptability of the Behavioural Activation/Problem Solving for Smoking Cessation (BAPS-SC) intervention programme to determine whether it should be tested in an adequately powered randomised controlled trial. METHOD: The authors merged behavioural activation therapy (BAT) with the principles of problem-solving therapy to create a novel five-session counselling model to address the unique challenges of tobacco cessation amongst those infected with HIV. Feasibility measures included the rate of enrolment amongst those eligible and the retention rate and descriptive analysis of intervention acceptability. The authors' secondary outcome was 7-day point smoking prevalence abstinence, confirmed with breath carbon monoxide. RESULTS: A total of 128 individuals were screened over 8 weeks with 50 deemed eligible and 40 enrolled (80%). Retention at week 12 was 53% (21/40). The 7-day point prevalence abstinence, co-confirmed, at week 12 was 37.5% (15/40). All respondents indicated that they would recommend BAPS-SC to other smokers who want to quit, and would be willing to participate in the programme again up to the point of exit if they did not stop smoking. CONCLUSION: A full-scale randomised control trial comparing BAPS-SC with usual practice is warranted to evaluate the efficacy of this novel intervention in these settings.

Electroreceptor neuron dynamics shape information transmission.

The gymnotiform weakly electric fish Apteronotus leptorhynchus can capture prey using electrosensory cues that are dominated by low temporal frequencies. However, conventional tuning curves predict poor electroreceptor afferent responses to low-frequency stimuli. We compared conventional tuning curves with information tuning curves and found that the latter predicted substantially improved responses to these behaviorally relevant stimuli. Analysis of receptor afferent baseline activity showed that negative correlations reduced low-frequency noise levels, thereby increasing information transmission. Multiunit recordings from receptor afferents showed that this increased information transmission could persist at the population level. Finally, we verified that this increased low-frequency information is preserved in the spike trains of central neurons that receive receptor afferent input. Our results demonstrate that conventional tuning curves can be misleading when certain noise reduction strategies are used by the nervous system.

Plastic and nonplastic pyramidal cells perform unique roles in a network capable of adaptive redundancy reduction.

Pyramidal cells show marked variation in their morphology, including dendritic structure, which is correlated with physiological diversity; however, it is not known how this variation is related to a cell's role within neural networks. In this report, we describe correlations among electrosensory lateral line lobe (ELL) pyramidal cells' highly variable dendritic morphology and their ability to adaptively cancel redundant inputs via an anti-Hebbian form of synaptic plasticity. A subset of cells, those with the largest apical dendrites, are plastic, but those with the smallest dendrites are not. A model of the network's connectivity predicts that efficient redundancy reduction requires that nonplastic cells provide feedback input to those that are plastic. Anatomical results confirm the model's prediction of optimal network architecture. These results provide a demonstration of different roles for morphological/physiological variants of a single cell type within a neural network performing a well-defined function.

Feedback and feedforward control of frequency tuning to naturalistic stimuli.

Sensory neurons must respond to a wide variety of natural stimuli that can have very different spatiotemporal characteristics. Optimal responsiveness to subsets of these stimuli can be achieved by devoting specialized neural circuitry to different stimulus categories, or, alternatively, this circuitry can be modulated or tuned to optimize responsiveness to current stimulus conditions. This study explores the mechanisms that enable neurons within the initial processing station of the electrosensory system of weakly electric fish to shift their tuning properties based on the spatial extent of the stimulus. These neurons are tuned to low frequencies when the stimulus is restricted to a small region within the receptive field center but are tuned to higher frequencies when the stimulus impinges on large regions of the sensory epithelium. Through a combination of modeling and in vivo electrophysiology, we reveal the respective contributions of the filtering characteristics of extended dendritic structures and feedback circuitry to this shift in tuning. Our results show that low-frequency tuning can result from the cable properties of an extended dendrite that conveys receptor-afferent information to the cell body. The shift from low- to high-frequency tuning, seen in response to spatially extensive stimuli, results from increased wide-band input attributable to activation of larger populations of receptor afferents, as well as the activation of parallel fiber feedback from the cerebellum. This feedback provides a cancellation signal with low-pass characteristics that selectively attenuates low-frequency responsiveness. Thus, with spatially extensive stimuli, these cells preferentially respond to the higher-frequency components of the receptor-afferent input.

Receptive field organization determines pyramidal cell stimulus-encoding capability and spatial stimulus selectivity.

Sensory systems must operate over a wide range of spatial scales, and single neuron receptive field (RF) organization may contribute to the ability of a neuron to encode information about stimuli having different spatial characteristics. Here we relate the RF organization of sensory neurons to their ability to encode time-varying stimuli, using linear stimulus estimation, measures of information transfer, and more conventional analysis techniques. The electrosensory systems of weakly electric fish are recognized as very tractable model systems for studies of sensory processing because behaviorally relevant stimuli are generated easily and related to known behaviors and because a detailed anatomical database is available to guide the design and interpretation of experiments. Receptive fields of neurons within the first central electrosensory-processing region have an antagonistic center-surround organization; the RF area varies with cell type, with dendritic morphology, and with the spontaneous activity patterns of the cell. Functional consequences of variations in center-surround organization were assessed by comparing responses to two spatial stimulus patterns that mimic naturalistic stimuli and that provide input to the center alone or to the center plus surround. Measures of the quality of stimulus estimation (coding fraction) and information transmission (mutual information) as well as traditional measures of responsiveness consistently demonstrate that, for cells having large surrounds, the activation of both receptive field components degrades the ability to encode time-varying stimuli. The loss of coding efficiency with center-surround stimulation probably results from cancellation of balanced excitatory and inhibitory inputs. However, cells with small surrounds relative to centers perform well under all spatial stimulus regimes.

Parallel processing of sensory input by bursts and isolated spikes.

Burst firing is commonly observed in many sensory systems and is proposed to transmit information reliably. Although a number of biophysical burst mechanisms have been identified, the relationship between burst dynamics and information transfer is uncertain. Electrosensory pyramidal cells have a well defined backpropagation-dependent burst mechanism. We used in vivo, in vitro, and modeling approaches to investigate pyramidal cell responses to mimics of behaviorally relevant sensory input. We found that within a given spike train, bursts are biased toward low-frequency events while isolated spikes simultaneously code for the entire frequency range. We also demonstrated that burst dynamics are essential for optimal feature detection but are not required for stimulus estimation. We conclude that burst and spike dynamics can segregate a single spike train into two parallel and complementary streams of information transfer.

Population coding by electrosensory neurons.

Sensory stimuli typically activate many receptors at once and therefore should lead to increases in correlated activity among central neurons. Such correlated activity could be a critical feature in the encoding and decoding of information in central circuits. Here we characterize correlated activity in response to two biologically relevant classes of sensory stimuli in the primary electrosensory nuclei, the electrosensory lateral line lobe, of the weakly electric fish Apteronotus leptorhynchus. Our results show that these neurons can display significant correlations in their baseline activities that depend on the amount of receptive field overlap. A detailed analysis of spike trains revealed that correlated activity resulted predominantly from a tendency to fire synchronous or anti-synchronous bursts of spikes. We also explored how different stimulation protocols affected correlated activity: while prey-like stimuli increased correlated activity, conspecific-like stimuli decreased correlated activity. We also computed the correlations between the variabilities of each neuron to repeated presentations of the same stimulus (noise correlations) and found lower amounts of noise correlation for communication stimuli. Therefore the decrease in correlated activity seen with communication stimuli is caused at least in part by reduced noise correlations. This differential modulation in correlated activity occurred because of changes in burst firing at the individual neuron level. Our results show that different categories of behaviorally relevant input will differentially affect correlated activity. In particular, we show that the number of correlated bursts within a given time window could be used by postsynaptic neurons to distinguish between both stimulus categories.

Temporal processing across multiple topographic maps in the electrosensory system.

Multiple topographic representations of sensory space are common in the nervous system and presumably allow organisms to separately process particular features of incoming sensory stimuli that vary widely in their attributes. We compared the response properties of sensory neurons within three maps of the body surface that are arranged strictly in parallel to two classes of stimuli that mimic prey and conspecifics, respectively. We used information-theoretic approaches and measures of phase locking to quantify neuronal responses. Our results show that frequency tuning in one of the three maps does not depend on stimulus class. This map acts as a low-pass filter under both conditions. A previously described stimulus-class-dependent switch in frequency tuning is shown to occur in the other two maps. Only a fraction of the information encoded by all neurons could be recovered through a linear decoder. Particularly striking were low-pass neurons the information of which in the high-frequency range could not be decoded linearly. We then explored whether intrinsic cellular mechanisms could partially account for the differences in frequency tuning across maps. Injection of a Ca2+ chelator had no effect in the map with low-pass characteristics. However, injection of the same Ca2+ chelator in the other two maps switched the tuning of neurons from band-pass/high-pass to low-pass. These results show that Ca2+-dependent processes play an important part in determining the functional roles of different sensory maps and thus shed light on the evolution of this important feature of the vertebrate brain.

Non-classical receptive field mediates switch in a sensory neuron's frequency tuning.

Animals have developed stereotyped communication calls to which specific sensory neurons are well tuned. These communication calls must be discriminated from environmental signals such as those produced by prey. Sensory systems might have evolved neural circuitry to encode both categories. In weakly electric fish, prey and communication signals differ in their spatial extent and frequency content. Here we show that stimuli of different spatial extents mimicking prey and communication signals cause a switch in the frequency tuning and spike-timing precision of electrosensory pyramidal neurons, resulting in the selective and optimal encoding of both stimulus categories. As in other sensory systems, pyramidal neurons respond only to stimuli located within a restricted region of space known as the classical receptive field (CRF). In some systems, stimulation outside the CRF but within a non-classical receptive field (nCRF) can modulate the neural response to CRF stimulation even though nCRF stimulation alone fails to elicit responses. We show that pyramidal neurons possess a nCRF and that it can modulate the response to CRF stimuli to induce this neurobiological switch in frequency tuning.

Oscillatory activity in electrosensory neurons increases with the spatial correlation of the stochastic input stimulus.

We present results from a novel experimental paradigm to investigate the influence of spatial correlations of stimuli on electrosensory neural network dynamics. Further, a new theoretical analysis for the dynamics of a model network of stochastic leaky integrate-and-fire neurons with delayed feedback is proposed. Experiment and theory for this system both establish that spatial correlations induce a network oscillation, the strength of which is proportional to the degree of stimulus correlation at constant total stimulus power.

Inhibitory feedback required for network oscillatory responses to communication but not prey stimuli.

Stimulus-induced oscillations occur in visual, olfactory and somatosensory systems. Several experimental and theoretical studies have shown how such oscillations can be generated by inhibitory connections between neurons. But the effects of realistic spatiotemporal sensory input on oscillatory network dynamics and the overall functional roles of such oscillations in sensory processing are poorly understood. Weakly electric fish must detect electric field modulations produced by both prey (spatially localized) and communication (spatially diffuse) signals. Here we show, through in vivo recordings, that sensory pyramidal neurons in these animals produce an oscillatory response to communication-like stimuli, but not to prey-like stimuli. On the basis of well-characterized circuitry, we construct a network model of pyramidal neurons that predicts that diffuse delayed inhibitory feedback is required to achieve oscillatory behaviour only in response to communication-like stimuli. This prediction is experimentally verified by reversible blockade of feedback inhibition that removes oscillatory behaviour in the presence of communication-like stimuli. Our results show that a sensory system can use inhibitory feedback as a mechanism to 'toggle' between oscillatory and non-oscillatory firing states, each associated with a naturalistic stimulus.

Especificidade das descargas do órgão elétrico em espécies de Gimnotóides simpátricos do rio Negro

Summary Electric organ discharges (EODs) of six sympatric, mud-dwelling gymnotoid fish species of the Rio Negro occupy non-overlapping ranges of peak power frequencies and repetition rates (fig. 4). Since electro-receptors are known to be most sensitive at the species' peak power frequency the evolution of EODs with species specific spectra should minimize species "cross talk" in social communication.

Resumo Descargas do órgão elétrico (EODs) de seis espécies simpátricas, habitantes de lama de gimnotóides do rio Negro ocupam áreas não sobrepostas de picos de freqüência e taxa de repetição. Como os eletrorreceptores são conhecidos como os mais sensíveis dentro do pico de freqüência da espécie, a evolução da EODs com espectros específicos para espécie minimizaria a conversação cruzada das espécies na comunicação social.