The Effects of Smoking Abstinence on Incentivized Spatial Working Memory

Background and Objective: Reward processing and working memory (WM) underlie value-based decision-making; consequently, joint examination of these systems may further our understanding of why smokers choose to smoke again following a quit attempt (relapse). While previous studies have demonstrated altered reward and WM function associated with nicotine exposure, little is known about the effects of abstinence on the joint function of these systems. The current study aims to address this gap. Method: Eighteen daily smokers were tested on a monetarily incentivized memory guided saccade (MGS) task on two separate, counterbalanced occasions, an abstinent and a non-abstinent session. The MGS task is a widely used metric of spatial working memory and enables precise quantification of the effects of rewards and nicotine exposure on behavior. Results: During the non-abstinent session, participants showed increased accuracy of the initial saccade towards the remembered target location on reward vs. neutral trials. Participants also showed increased accuracy of the final saccade towards the target, across incentive types, only during the non-abstinent condition. Discussion and Conclusions: Our observation that rewards improve the accuracy of the initial memory guided saccade during the non-abstinent but not abstinent condition extends a growing literature indicating reduced motivation towards monetary rewards during abstinence. Further, differences in the accuracy of the final corrective saccade during the non-abstinent but not the abstinent condition suggests smoking abstinence-related effects on WM precision beyond those related to incentive motivation (e.g., sustained attention). Significance: This work extends our fundamental understanding of smoking's effects on core affective and cognitive processes.     

Smoking and cognitive decline

The decline in cognitive functioning over a 7-year period in long-term regular smokers over the age of 50 was compared with that of lifelong non-smokers. The data comes from the Health and Lifestyle Survey, a longitudinal study of a representative sample of adults living in private households in England, Scotland and Wales. Four cognitive tests (memory, reasoning, simple reaction time and choice reaction time) were administered to participants in 1984–1985 and again in 1991–1992. Odds ratios for large falls in the respective scores of smokers relative to non-smokers, adjusted for age, education and lung function, and with or without adjustment for baseline score, were calculated, separately for males and females. There were no significant differences between smokers and non-smokers. For all adult smokers, change scores were not systematically related to time since they last smoked at the times of the tests. At baseline, cognitive scores of non-smokers who became regular smokers did not differ from those of non-smokers who remained non-smokers. Proportionally more regular smokers than non-smokers died in the 3 years following the second survey. © 1997 John Wiley & Sons, Ltd.     

Prefrontal Cortical GABA Modulation of Spatial Reference and Working Memory

Background:

Dysfunction in prefrontal cortex (PFC) GABA transmission has been proposed to contribute to cognitive dysfunction in schizophrenia, yet how this system regulates different cognitive and mnemonic functions remains unclear.

Methods:

We assessed the effects of pharmacological reduction of GABA_A signaling in the medial PFC of rats on spatial reference/working memory using different versions of the radial-arm maze task. We used a massed-trials procedure to probe how PFC GABA regulates susceptibility to proactive interference. Male rats were well-trained to retrieve food from the same 4 arms of an 8-arm maze, receiving 5 trials/day (1–2min intervals).

Results:

Infusions of the GABA_A receptor antagonist bicuculline (12.5–50ng) markedly increased working and reference memory errors and response latencies. Similar treatments also impaired short-term memory on an 8-baited arm task. These effects did not appear to be due to increased susceptibility to proactive interference. In contrast, PFC inactivation via infusion of GABA agonists baclofen/muscimol did not affect reference/working memory. In comparison to the pronounced effects on the 8-arm maze tasks, PFC GABA_A antagonism only causes a slight and transient decrease in accuracy on a 2-arm spatial discrimination.

Conclusions:

These findings demonstrate that prefrontal GABA hypofunction severely disrupts spatial reference and short-term memory and that disinhibition of the PFC can, in some instances, perturb memory processes not normally dependent on the frontal lobes. Moreover, these impairments closely resemble those observed in schizophrenic patients, suggesting that perturbation in PFC GABA signaling may contribute to these types of cognitive deficits associated with the disorder.     

Effects of Cigarette Smoking on Psychopathology Scores in Patients With Schizophrenia: An Experimental Study

Cigarette smoking and/or nicotine administration have been shown to transiently ameliorate several psychophysiological deficits in patients with schizophrenia such as indicators of deficient sensory gating and attention, but acute effects of smoking on positive and negative symptoms in schizophrenia have not been evaluated in experimental paradigms. The current study assessed whether smoking of cigarettes, after 6–12 h abstinence, transiently alters the expression of negative and/or positive symptoms in patients with schizophrenia who have a history of regular smoking. In a double-blind, placebo controlled study patients with schizophrenia participated in two sessions in which they smoked either cigarettes moderately high in nicotine content or denicotinized cigarettes. They were interviewed pre-and postsmoking to obtain ratings of PANSS and SANS scales, and had blood pressure and pulse serially recorded before and after smoking. Pulse rate and blood pressure were slightly higher after smoking in the high nicotine cigarette session. Negative symptom scores on both scales were significantly lower after cigarette smoking compared to same-day predrug baseline, but there were no differences in active versus denicotinized cigarette drug effects. These results suggest that acute smoking of cigarettes reduces negative symptoms in patients with schizophrenia in this experimental paradigm. Future work needs to identify the mechanism responsible for this behavioral effect.     

Genetics of Smoking and Schizophrenia

ABSTRACT

Schizophrenia is a common mental illness with a high prevalence of smoking. More than 80% of schizophrenics smoke compared to 25% of the general population. Both schizophrenia and tobacco use have strong genetic components, which may overlap. It has been suggested that smoking in schizophrenia may be a form of self-medication in an attempt to treat an underlying biological pathology. Smoking normalizes auditory evoked potential and eye tracking deficits in schizophrenia, as well as improving cognitive function. Nicotine acts through a family of nicotinic receptors with either high or low affinity for nicotine. The loci for several of these receptors have been genetically linked to both smoking and to schizophrenia. Smoking changes gene expression for more than 200 genes in human hippocampus, and differentially normalizes aberrant gene expression in schizophrenia. The α7? nicotinic receptor, linked to schizophrenia and smoking, has been implicated in sensory processing deficits and is important for cognition and protection from neurotoxicity. Nicotine, however, has multiple health risks and desensitizes the receptor. A Phase I trial of DMXB-A, an α7? agonist, shows improvement in both P50 gating and in cognition, suggesting that further development of nicotinic cholinergic drugs is a promising direction in schizophrenia research.     

Working Memory Impairment in Cannabis- and Opioid-Dependent Adolescents

ABSTRACT. Background: Cannabis and opioid use are associated with cognitive impairment, whether preexisting or substance-induced, but there have been few substance-specific assessments of cognitive functioning in adolescent substance users. Working memory impairment may be particularly important, as it has been linked to poorer performance in substance abuse treatment. Methods: Working memory (Wechsler Intelligence Scale for Children-IV or Adult Intelligence Scale-IV) and baseline substance use were assessed in 42 youth (mean age = 17.9 years, SD = 1.3, range: 16–20; 65% Caucasian, 30% female) 1–2 weeks after admission to residential treatment with supervised abstinence, 19 for primary cannabis dependence and 23 for primary opioid dependence. Results: There were substantial deficits in working memory in both groups, with significant differences (P < .001) between the opioid (M = 39.1th%ile, SD = 25.6) and cannabis (M = 16.3th%ile, SD = 13.6) groups. The primary opioid group had high rates of cannabis use, with no significant difference in past-month days of cannabis use from the primary cannabis group. The opioid group was older and had completed more years of formal education. Seventy-nine percent of the cannabis group had public health care coverage (mostly Medicaid), compared with 24% of the opioid sample. Conclusions: Working memory impairment was substantial in treatment-seeking youth with primary cannabis and opioid dependence (the latter actually having comparable rates of cannabis use), and significantly more pronounced in the primary cannabis-dependent group. Without an assessment of working memory prior to substance exposure, the differential contributions of substance-induced vs. preexisting impairment are unclear. Lower scores in the cannabis group may reflect lower socioeconomic status (SES), which is typically correlated with cognitive performance. These findings highlight underrecognized cognitive impairment in youth with SUDs, especially inner-city cannabis-dependent youth. Modification of treatments to account for cognitive capacity and/or cognitive remediation interventions may be indicated to improve treatment outcomes.     

Common and Unique Biological Pathways Associated with Smoking Initiation/Progression, Nicotine Dependence, and Smoking Cessation

Twin and family studies reveal a significant genetic contribution to the risk of smoking initiation and progression (SI/P), nicotine dependence (ND), and smoking cessation (SC). Further, numerous genes have been implicated in these smoking-related behaviors, especially for ND. However, no study has presented a comprehensive and systematic view of the genetic factors associated with these important smoking-related phenotypes. By reviewing the literature on these behaviors, we identified 16, 99, and 75 genes that have been associated with SI/P, ND, and SC, respectively. We then determined whether these genes were enriched in pathways important in the neuronal and brain functions underlying addiction. We identified 9, 21, and 13 pathways enriched in the genes associated with SI/P, ND, and SC, respectively. Among these pathways, four were common to all of the three phenotypes, that is, calcium signaling, cAMP-mediated signaling, dopamine receptor signaling, and G-protein-coupled receptor signaling. Further, we found that serotonin receptor signaling and tryptophan metabolism pathways were shared by SI/P and ND, tight junction signaling pathway was shared by SI/P and SC, and gap junction, neurotrophin/TRK signaling, synaptic long-term potentiation, and tyrosine metabolism were shared between ND and SC. Together, these findings show significant genetic overlap among these three related phenotypes. Although identification of susceptibility genes for smoking-related behaviors is still in an early stage, the approach used in this study has the potential to overcome the hurdles caused by factors such as genetic heterogeneity and small sample size, and thus should yield greater insights into the genetic mechanisms underlying these complex phenotypes.     

Pattern Classification of Working Memory Networks Reveals Differential Effects of Methylphenidate, Atomoxetine, and Placebo in Healthy Volunteers

Stimulant and non-stimulant drugs can reduce symptoms of attention deficit/hyperactivity disorder (ADHD). The stimulant drug methylphenidate (MPH) and the non-stimulant drug atomoxetine (ATX) are both widely used for ADHD treatment, but their differential effects on human brain function remain unclear. We combined event-related fMRI with multivariate pattern recognition to characterize the effects of MPH and ATX in healthy volunteers performing a rewarded working memory (WM) task. The effects of MPH and ATX on WM were strongly dependent on their behavioral context. During non-rewarded trials, only MPH could be discriminated from placebo (PLC), with MPH producing a similar activation pattern to reward. During rewarded trials both drugs produced the opposite effect to reward, that is, attenuating WM networks and enhancing task-related deactivations (TRDs) in regions consistent with the default mode network (DMN). The drugs could be directly discriminated during the delay component of rewarded trials: MPH produced greater activity in WM networks and ATX produced greater activity in the DMN. Our data provide evidence that: (1) MPH and ATX have prominent effects during rewarded WM in task-activated and -deactivated networks; (2) during the delay component of rewarded trials, MPH and ATX have opposing effects on activated and deactivated networks: MPH enhances TRDs more than ATX, whereas ATX attenuates WM networks more than MPH; and (3) MPH mimics reward during encoding. Thus, interactions between drug effects and motivational state are crucial in defining the effects of MPH and ATX.     

The Effects of CACNA1C Gene Polymorphism on Spatial Working Memory in Both Healthy Controls and Patients with Schizophrenia or Bipolar Disorder

CACNA1C gene polymorphism (rs1006737) is a susceptibility factor for both schizophrenia (SCZ) and bipolar disorder (BP). However, its role in working memory, a cognitive function that is impaired in both diseases, is not clear. Using three samples, including healthy controls, patients with SCZ, and patients currently in manic episodes of BP, this study tested the association between the SNP rs1006737 and spatial working memory as measured by an N-back task and a dot pattern expectancy (DPX) task. Among SCZ patients and healthy controls, the clinical risk allele was associated with impaired working memory, but the association was either in opposite direction or non-significant in patients with BP. These results indicated that rs1006737 may have differential effects on working memory in different disease populations and pointed to the necessity for more studies in different patient populations.     

The Prevalence of Cigarette Smoking in an Acute Inpatient Physical Medicine and Rehabilitation Population

The purpose of this study was to determine the prevalence of cigarette smoking among patients before and after discharge from an acute inpatient physical medicine and rehabilitation unit and to assess smokers' interest in and desire for smoking cessation. A consecutive sample of inpatients (n = 233) admitted over a 5-month period to a regional rehabilitation inpatient center for acute rehabilitation treatment was surveyed for their smoking patterns. Ten percent of patients admitted to rehabilitation were active smokers prior to their hospitalization. In spite of reporting high motivation to stop smoking, half were not interested in participating in a smoking cessation program if one were offered to them. Following discharge from inpatient rehabilitation, 54% of a small sample of patients who could be contacted had resumed smoking (all within 4 weeks of being home). Given the prevalence of smoking in this population and its adverse consequences on health and quality of life, we suggest that rehabilitation professionals actively address this health problem during the patient's hospitalization.     

The Effects of Nicotine Replacement on Cognitive Brain Activity During Smoking Withdrawal Studied with Simultaneous fMRI/EEG

Impaired attention (‘difficulty concentrating'') is a cognitive symptom of nicotine withdrawal that may be an important contributor to smoking relapse. However, the neurobiological basis of this effect and the potentially beneficial effects of nicotine replacement therapy both remain unclear. We used functional MRI with simultaneous electroencephalogram (EEG) recording to define brain activity correlates of cognitive impairment with short-term smoking cessation in habitual smokers and the effects of nicotine replacement. We found that irrespective of treatment (ie nicotine or placebo) EEG α power was negatively correlated with increased activation during performance of a rapid visual information processing (RVIP) task in dorsolateral prefrontal, dorsal anterior cingulate, parietal, and insular cortices, as well as, caudate, and thalamus. Relative to placebo, nicotine replacement further increased the α-correlated activation across these regions. We also found that EEG α power was negatively correlated with RVIP-induced deactivation in regions comprising the ‘default mode'' network (ie angular gyrus, cuneus, precuneus, posterior cingulate, and ventromedial prefrontal cortex). These α-correlated deactivations were further reduced by nicotine. These findings confirm that effects of nicotine on cognition during short-term smoking cessation occur with modulation of neuronal sources common to the generation of both the blood oxygen-level-dependent and α EEG signals. Our observations thus demonstrate that nicotine replacement in smokers has direct pharmacological effects on brain neuronal activity modulating cognitive networks.     

Current and Emerging Pharmacotherapies for Cessation of Tobacco Smoking

Tobacco use disorder is a chronic illness. With its high comorbidity rate, it is a major cause of years of life lost or years lived with disability; however, it is also considered the most preventable cause of death in developed countries. Since the development of nicotine replacement therapy (NRT) in 1978, treatment options have continued to evolve and expand. Despite this, currently available treatments remain insufficient, with less than 25% of smokers remaining abstinent 1 year after treatment. In this article, we review existing and emerging smoking cessation pharmacotherapies, with a special emphasis on the most promising agents that are currently being investigated. A search of the Cochrane Database of Systematic Reviews and the PubMed, Ovid, and ClinicalTrials.gov databases (August 2 to September 1, 2017) was undertaken for articles on smoking cessation pharmacotherapies, applying no language restrictions. More than 40 pharmacotherapies were reviewed including conventional pharmacotherapies—NRT, bupropion, and varenicline (all approved by the U.S. Food and Drug Administration as first‐line treatment of smoking cessation)—and novel therapies: cytisine, N‐acetylcysteine, cycloserine, memantine, baclofen, topiramate, galantamine, and bromocriptine. Studies of combination NRT and varenicline showed the greatest smoking cessation rates. Clonidine and nortriptyline are second‐line treatments used when first‐line treatments fail or are contraindicated, or by patient preference. Some novel therapies, especially acetylcholinesterase inhibitors, cytisine, and N‐acetylcysteine, display promising results. Because the results of randomized clinical trials were reported using varied end points and outcome measures, direct comparisons between different pharmacotherapies cannot easily be evaluated. Additional high‐quality randomized double‐blind placebo‐controlled trials with long‐term follow‐up, using validated sustained abstinence measures, are needed to find more effective smoking cessation aids.     

Dual Tasking and Working Memory in Alcoholism: Relation to Frontocerebellar Circuitry

Controversy exists regarding the role of cerebellar systems in cognition and whether working memory compromise commonly marking alcoholism can be explained by compromise of nodes of corticocerebellar circuitry. We tested 17 alcoholics and 31 age-matched controls with dual-task, working memory paradigms. Interference tasks competed with verbal and spatial working memory tasks using low (three item) or high (six item) memory loads. Participants also underwent structural MRI to obtain volumes of nodes of the frontocerebellar system. On the verbal working memory task, both groups performed equally. On the spatial working memory with the high-load task, the alcoholic group was disproportionately more affected by the arithmetic distractor than were controls. In alcoholics, volumes of the left thalamus and left cerebellar Crus I volumes were more robust predictors of performance in the spatial working memory task with the arithmetic distractor than the left frontal superior cortex. In controls, volumes of the right middle frontal gyrus and right cerebellar Crus I were independent predictors over the left cerebellar Crus I, left thalamus, right superior parietal cortex, or left middle frontal gyrus of spatial working memory performance with tracking interference. The brain–behavior correlations suggest that alcoholics and controls relied on the integrity of certain nodes of corticocerebellar systems to perform these verbal and spatial working memory tasks, but that the specific pattern of relationships differed by group. The resulting brain structure–function patterns provide correlational support that components of this corticocerebellar system not typically related to normal performance in dual-task conditions may be available to augment otherwise dampened performance by alcoholics.     

Effects of Negative Affect,Urge to Smoke,and Working Memory Performance (n-back) on Nicotine Dependence

Background: Three key domains including negative emotionality, incentive salience, and executive function form the core functional elements of addictive behaviors. Variables related to these broader domains have been studied extensively in relation to one another; however, no studies to date, have examined models including variables from all three domains, in relation to nicotine dependence. Method: Smokers (N = 117), 65.8% female, 78% white, mean age of 44.4 (SD = 10.8), enrolled in a smoking cessation program completed measures of negative affect (a component of negative emotionality), urge to smoke (incentive salience), and working memory (WM; a core executive function), during a baseline assessment period prior to initiating treatment. Results: Negative affect was associated with greater urge to smoke, and this elevated urge to smoke was associated with higher levels of nicotine dependence. Further, a significant moderated mediation indicated that WM moderated the relationship between increased urge to smoke and nicotine dependence. For those with low to average WM, urge to smoke was significantly related to nicotine dependence; however, for those with higher WM (+1 SD), urge to smoke stemming from negative affect was not associated with nicotine dependence. Conclusions: To our knowledge, this is the first reported relationship between negative affect, urge to smoke, WM, and nicotine dependence. Although preliminary, results indicate that WM may moderate the relationship between urge to smoke associated with negative affect and nicotine dependence. Treatments targeting WM may be particularly useful for individuals with average to low WM who experience urge to smoke related to negative affect.     

High Suicide Risk After the Development of Cognitive and Working Memory Deficits Caused by Cannabis,Cocaine and Ecstasy Use

ABSTRACT

We report the case of attempted suicide by a 30-year-old man who had significant cognitive deficits that developed after at least three years of polysubstance use with cannabis, methylenedioxymethamphetamine (MDMA, “ecstasy”) and cocaine. The patient reported increasing difficulties in his professional and interpersonal life which may have been associated with his cognitive dysfunction caused by his poly-drug use. In this setting, the patient complained of increasing symptoms of depression, including feelings of hopelessness and helplessness, and multi somatic complaints (based on DSM-IV criteria). These depressive symptoms led to the development of active suicidal ideation and ultimately to a suicide attempt. We propose that the patient's cognitive deficits resulted directly from his polysubstance use and contributed to his depression, suicide attempt and current serious suicidal ideation.     

Relationships Between Trait Urgency,Smoking Reinforcement Expectancies,and Nicotine Dependence

Urgency (i.e., the tendency to act rashly during negative/positive affect) may increase vulnerability to a variety of risky behaviors. This cross-sectional study of nontreatment-seeking smokers examined the relationship between urgency, level of nicotine dependence, and smoking reinforcement expectancies. Both positive and negative urgency were associated with nicotine dependence. Mediational analyses illustrated that smoking reinforcement expectancies significantly accounted for urgency-dependence relations, with negative reinforcement expectancies displaying incremental mediational effects. If replicated and extended, these findings may support the use of treatments that modify beliefs regarding smoking reinforcement outcomes as a means of buffering the risk of nicotine dependence carried by urgency.     

Working Memory Training for Adolescents With Cannabis Use Disorders: A Randomized Controlled Trial

Adolescent cannabis use is associated with working memory impairment. The present randomized controlled trial assigned adolescents ages 14 to 21 enrolled in cannabis use treatment to receive either working memory training (experimental group) or a control training (control group) as an adjunctive treatment. Cognitive function, drug use, and other outcomes were assessed before and after training. We observed few differences in cognitive, functional, or self-reported drug use outcomes as a function of training group, although tetrahydrocannabinol (THC) urinalysis results favored the experimental group. These findings are similar to previous studies in substance users, which have shown limited transfer effects for working memory training.     

CYP2A6 Genotype and Smoking Behavior in Current Smokers Screened for Lung Cancer

Functional CYP2A6 genetic variation partially determines nicotine metabolism. In 2005, we examined functional CYP2A6 variants associated with reduced metabolism (CYP2A6*2, CYP2A6*9, CYP2A6*4), smoking history, and change in smoking in 878 adult smokers undergoing lung cancer screening in an urban setting. At one year, 216 quit smoking for more than 30 days while 662 continued smoking. Compared to subjects who smoked 30 cigarettes per day at baseline, the odds of a reduced metabolism genotype was 52% higher in subjects smoking 20–29 cigarettes per day and 86% higher in subjects smoking less than 20 cigarettes per day (p-trend = 0.016). Reduced metabolism genotypes appeared unrelated to quitting. Though related to smoking dose, CYP2A6 may not influence cessation.     

神经生长因子在豚鼠形觉剥夺性近视中的作用

目的探讨NGF（神经生长因子）在豚鼠形觉剥夺性近视中的作用。方法一周龄健康3色豚鼠50只随机分为ABC 3组,A（n=10）组半透明罩单纯遮盖右眼,B（n=20）组半透明罩遮盖右眼＋玻璃体腔注射NGF,C（n=20）组半透明罩遮盖右眼＋玻璃体腔注射生理盐水。结果 ABC 3组中遮盖眼与对照眼在眼轴长度,屈光度上相比差异有显著性（P〈0.05）,视网膜细胞凋亡明显,Caspase-3表达上升,而BC两组中遮盖眼比较,眼轴长度,屈光度无显著性差异,B组遮盖眼视网膜细胞凋亡率最低。结论细胞凋亡是形觉剥夺性近视形成的病理学原因之一,而NGF能部分地阻止这些改变。