The negative impact of chronic tobacco smoking on adult neuropsychological function: a case control study


 Background: The evidence on the effects of chronic tobacco smoking on neuropsychological functions is conflicting. The literature remains limited by inconsistent accounting for potentially confounding biomedical and psychiatric conditions. This study aimed to assess the neuropsychological functions of adult chronic tobacco smokers in comparison to healthy matched-subjects’ controls. Method: The study included 73 smokers and 84 matched-subject non-smoker controls. The data was collected during the year 2019. After an initial interview to collect demographics and smoking profile, the subjects undertook neuropsychological assessments that targeted a wide range of cognitive domains. Results: The performance of smokers was poorer on almost all neuropsychological domains, namely selective attention (p ≤ .001, p =.044), alternating attention (p = .002) working memory (p ≤ .001), Short-term memory (p = .006 and .003), Long-term memory (p ≤ .001), processing accuracy (p ≤ .001), and executive function (p = .011 and .026). Smokers were intact on processing speed. smoking accumulation and the age onset of regular smoking we negatively correlated with neuropsychological function. Conclusion: Our findings add to the growing body of evidence suggesting that chronic tobacco smoking impacts negatively on cognition.


Background
Tobacco smoking is a prevalent and serious problem across the world. In 2015, around a quarter (24.9%) of the global population were current users of some form of tobacco [1].
The harmful impact of chronic tobacco smoking on physical health is well documented and includes cardiovascular diseases, respiratory diseases, and various forms of cancer [2]. Additionally, chronic smoking is implicated in the pathogenesis of neuropsychological dysfunction and has been directly linked to increased risk of depression and cognitive impairment [1,3,4].
A large number of studies have examined the effects of smoking on neuropsychological function across multiple variables. Compared to healthy controls, chronic smoking was cumulatively reported to have detrimental effects on various neuropsychological domains, including general intellectual abilities, processing speed, attention, memory, cognitive exibility and executive functions [2,3,5]. The effects of nicotine on cognition are believed to vary based on the dose of nicotine used and the onset of regular use. Although the majority of studies provide evidence on the effect of chronic tobacco smoking on neuropsychological impairments, con icting evidence also exists. For example, a 10-year longitudinal study of 1436 older adults found that smokers were less likely to develop cognitive impairment than those who had never smoked [6].
Another study consisting of 2553 adults found smokers to have lower rates of cognitive impairment compared to non-smokers [7], and both studies concluded that smoking may be protective of cognitive function. Several other studies also support the notion that cigarette smoking seems not to affect cognition or to have a positive effect on some aspects of cognitive function of smokers [8,9,10,11].
Based on the current literature, it is di cult to draw solid conclusions on the impact of smoking on neuropsychological function [2]. The in uence of nicotine on speci c domains of cognition is complex and much remains to be known about the smoking impact on neuropsychology and cognition. The literature remains limited by inconsistent accounting for potentially confounding biomedical and psychiatric conditions. For example, many of the studies did not account for confounding variables such as psychiatric disorders and comorbid substance abuse (i.e., alcohol, cannabis, medications). In other studies, the severity of cognitive de cits was not correlated with the duration of tobacco use [12]. Other studies varied in terms of which subcategories of speci c neuropsychological domains were tested. Some controversy also remains regarding nicotine's effect on speci c cognitive functions, and individual differences in nicotine's cognitive effects. Consequently, it is essential to continue to investigate the association between chronic tobacco smoking and potential neuropsychological impairments while controlling for possible confounding variables. This cross-sectional study aimed to assess the neuropsychological functions of chronic tobacco smokers in comparison to healthy, matched-subjects' controls. It was hypothesized that chronic tobacco smokers would have signi cantly poorer global neuropsychological functions compared to healthy controls.

Method Participants and procedure
We recruited the participants via social medial and local adverts during the year 2019. The participants were interviewed regarding cigarette smoking and use of other tobacco products. We excluded participants who reported current use of other substances that are known to affect cognition (i.e., alcohol, cannabis, and psychotropic medications, except for caffeine) up to three months prior to study enrollment. Since psychiatric illness is strongly correlated to cognitive impairment, we excluded subjects with any known psychiatric problems or mental diseases. Participants with any medical condition or history of serious head injury that are known to in uence cognition were also excluded. To be included in the smoking group, the participant must have been a smoker for at least ten years and smoked a minimum of one pack per day. The healthy controls were matched with the smoking group for age, sex, ethnicity, educational, and socioeconomic status.
For the non-smokers' group, the participant must not have been a smoker before and is not currently a second-hand smoker.
The study was approved by the Institutional Review Board, and all participants signed a written consent form to participate in the study before data collection. An initial interview collected information related to sociodemographic, health, and smoking pro les. After the interview session, all participants completed a comprehensive battery of outcome measures assessing neuropsychological functions that target a wide range of cognitive domains. All the measures used in this study have well-established and comprehensive psychometric properties, and were used in other studies on neuropsychological function (a brief description of each measure is provided in Table 1). In addition to the neuropsychological measures, we used the Grooved Pegboard as a measure of ne motor dexterity, which requires visual-spatial and motor coordination.
The test battery was administered by a trained researcher, and the entire battery required about 60-70 minutes to complete. The participants were allowed short breaks between tests, and smokers were free to Page 4/23 smoke during the breaks if desired. The sequence of outcome measures was administered consistently across all participants.    [1] World Health Organization, "WHO global report on trends in prevalence of tobacco use 2000-2025," 2019.
After completion of all measures, the participants were presented with two questions which they were required to answer by "Yes" or "No". 1) ''Do you believe that smoking increases the risk of physical health problems, such as getting heart disease, lung disease, stroke and cancer?", and 2) ''Do you believe that smoking increases the risk of cognitive health problems, such as reduced memory, attention, and

Results
The nal sample included 73 smokers (M = 52.1 years, SD = 7.2) and 84 non-smokers (M = 51.7 years, SD = 8.1). Independent t-tests showed that both groups were comparable across participant socio-demographic and health characteristics. Table 2 shows the general characteristics of the study population.   When asking the participants about the effects of smoking on health, 100% of non-smokers and 92% of smokers believe that smoking has negative effects on physical health, while 37% of non-smokers and 19% of smokers believed that smoking has negative effects on cognitive health.

Discussion
The current study aimed to assess the neuropsychological functions of chronic tobacco smokers in comparison to healthy matched-subjects' controls. As hypothesized, the results indicated that chronic tobacco smokers had signi cantly poorer neuropsychological functions compared to their matched healthy controls. The poorer performance was apparent in almost all cognitive domains, namely attention, memory, processing accuracy, and executive function, but not processing speed.
With respect to global neuropsychological function, the performance of smokers in the Montreal Cognitive Assessment (MoCA) was not impaired since they scored within the "normal" range. Nonetheless, their performance was signi cantly weaker compared to their matched non-smoker controls. Despite the "normal" results of the MoCA, the more dedicated measures in this study clearly revealed a sub-optimal neuropsychological performance of our smokers' group.
The effects of smoking on memory performance is inconsistent in the literature, with studies reporting signi cant differences between smokers and non-smokers in some memory measures [4,13,14,15,16,17] while others reporting insigni cant differences [13,18,14,19,20,10]. Our results showed the neuropsychological domain of memory to be affected in our smoking sample and with group differences of moderate to strong effect sizes, as our non-smokers control outperformed the smokers in all components of memory measures. Our non-smokers had better short-term and long-term memory as indicated by their superior capacity to recall information in the Contextual Memory Test, which involves visual presentation of pictures, as well as the Digit Span Task, which involves auditory and verbal presentation of numbers. Working memory was particularly compromised by our chronic tobacco smokers, as evident by the largest effect size (d = .75) amongst the neuropsychological measures employed in this study. Similar results for working memory impairments were found in middle-aged adults [21,14], young adults [22,23,24,25] and even adolescent smokers [26]. Based on the compromised overall memory performance of smokers, it is plausible to state that chronic tobacco smoking may predispose the development of dementia.
While the effects of tobacco smoking on memory have been widely studied, their effects on attention have been less investigated. Attention is central for learning and memory since encoding information requires attention in the rst place. The smokers in our study were less able to block irrelevant information and focus their selective attention on the task at hand. This was strongly demonstrated in the Stroop Color and Word Test and less signi cantly demonstrated in the d2 Test of Attention. Alternating attention was also affected in our smokers' CTMT test, indicating more di culty to disengage and reengage the focus of attention in response to environmental stimuli, in comparison to their non-smokers' control group. Our ndings on the domain of attention are consistent with the literature where attention was found to be affected in smokers [23,20], but contrasted several other studies where attention was not affected [18,26,25,10]. Given the intertwined relationship between attention and memory, it is reasonable to suggest that smoking may diminish memory as a result of decreasing attentional capacities, re ected in reduced ability to resist distraction and blocking irrelevant stimuli.
Executive function involves the simultaneous use of a set of cognitive abilities to allow the individual to perform higher-level complex tasks. The ndings in our study detected a signi cant executive function difference in favor of the non-smokers' control group, who performed better in both subtests of the WCST-64.
These results are consistent with previous literature ndings of executive function limitation among smokers [27,23,18,14,15,9,10,17], indicating that chronic tobacco smokers have inferior mental exibility and abstract thinking compared to non-smokers.
Interestingly, processing speed was not signi cantly affected in the smoking group across all the four subtests we used in this study, albeit two of the subtests were statistically borderline (p = .052, .055). These ndings agree with few studies [23,18,25,10], but contrast with most other studies that assessed processing speed for their smoking participants [28,4,13,29,14,30]. Despite this nding, the processing accuracy of our smokers' sample was signi cantly lower than non-smokers (p ≤ .001). That is, the smokers' processing speed matched that of non-smokers, but with a signi cantly higher number of errors. The substandard performance of smokers on measures of processing accuracy, as evident by a signi cantly higher number of cognitive errors, should be added to a growing list of neuropsychological sequelae associated with persistent smoking.
Within the smoker group, smoking onset was negatively associated with poorer performance on working memory, selective attention, alternating attention, and the number of errors made. This means that individuals who start smoking at a younger age are at a greater risk of developing neuropsychological dysfunction. The impairments appear to manifest very early in smokers, as demonstrated in the inferior working memory of adolescents with a mean of only 4 years of smoking [26]. Additional support on the effects of smoking on the young brain was objectively shown in functional magnetic resonance imaging where young adult smokers had reduced prefrontal cortex activation during attentional tasks when compared with nonsmoking controls [31]. This pronounced negative effects of smoking on the young brain might be explained by the fact that the prefrontal cortex has not completed its maturation, as the prefrontal cortex is one of the last brain areas to mature and is still developing during adolescence and early adulthood [32]. This stage of ongoing development makes the brain more susceptible to the in uence of nicotine and other psychoactive substances [32].
Correspondingly, smoking accumulation in this study similarly affected neuropsychological function, meaning the longer an individual smoked during their lifetime, the more prone they become to cognitive dysfunction. These results are consistent with other studies that reported total lifetime years of smoking to be correlated with inferior neuropsychological e ciency [14] and executive function [19]. Interestingly, the dose of nicotine consumed (cigarette per day or pack-years) were not associated with neuropsychological performance in this study, contrasting the main ndings of a recent review conducted by Conti et al (2019), in which several studies included in their review reported a negative link between the number of pack-years and neuropsychological function [2]. This discrepancy in results may be confounded by the considerable variations in the number of pack-years reported across studies (ranging from 4.26 to 73.73) [2].
The magnitude of differences between smokers and non-smokers in this study extend beyond neuropsychological function to include the psychomotor domain as well. Our non-smoking group outperformed the smoking group in the Grooved Pegboard test of ne motor dexterity, albeit with a relatively small effect size of .37. Durazzo et al [14] also reported signi cantly poorer ne motor dexterity performance in their smoking sample, but with much larger effect sizes (i.e., .72). The psychomotor function was also negatively correlated with smoking accumulation, where longer lifetime smoking was associated with reduced ne motor dexterity.
The question arises related to the reasons for heterogeneity in study outcomes between studies of comparable designs? Processing speed, for example, was largely affected by some studies [28,13,29,4,14,30] but not in others [23,18,25,10]. The same question can be raised for memory and attention. Several reasons could explain such variations in the performance; 1) The assessments used to assess the target variable (i.e., processing speed) are different across studies, which may vary in their sensitivity and other psychometric properties. 2) Some studies did not report which version of the tests they used (e.g., original version, modi ed version, pen and paper, or electronic version). Depending on the assessment used, it could involve a visual task, an auditory task, or even a motor task. An assessment that involves the use of pen and paper will recruit a variety of motor and cognitive pathways in the brain to facilitate writing or tracing, while an electronic version of the same assessment will involve different brain pathways. Such variations in assessment components could yield different results. These factors make it less accurate to perform crossstudy comparisons or to compare the study scores with normative data. A possible solution to help make the results more comparable across studies, and thus more clinically meaningful, is to use complete reporting of the speci c testing procedures (e.g., test version, subtests used, and scoring methods) and to use consistent and systematic data collection and analysis procedures.
When asking the participants about the effects of smoking on physical health, 100% of non-smokers and 92% of smokers believe that smoking has negative effects on physical health. When asked about neuropsychological health, however, only 37% of non-smokers and 19% of smokers believed that smoking has negative effects on cognition. This very low awareness of the negative consequences of smoking on neuropsychological function among smokers and non-smokers is a major public health issue that should be properly addressed.
Since tobacco smoking remains highly prevalent across the globe and is known to be in uenced by public perception of risk and associations with negative outcomes [23], it is imperative to invest further in policy initiatives to control smoking. The emphasis of public health campaigns primarily focuses on physical health, and less commonly address neuropsychological health. Increasing public awareness should go beyond the already established physical health consequences to include the negative impact of smoking on neuropsychological function. We hope that raising awareness about the wider effects of tobacco smoking on cognition could help encourage people to stop smoking.

Limitations and future research
A notable strength of our study is the prospective matched control design. Still, there are several limitations and areas for improvement in future research. Although we attempted to control for demographics and health variables by group matching, self-reported health & medical pro le can be problematic due to matters of the accuracy of some participants. Future research should adopt standardized screening measures to provide accurate objective measures. The scope of neuropsychological impairment associated with chronic cigarette smoking has yet to be fully delineated. Large-scale prospective studies with more consistent, highly sensitive, and robust cognitive outcome measures are required to determine the true links between smoking and neuropsychological dysfunction.

Conclusion
Chronic tobacco smoking seems to be a prospective risk factor for neuropsychological impairment, as expressed in our data by reduced attention, memory, executive function, and processing accuracy of smokers compared to their healthy matched controls. The cognitive performance of participants decreased as the number of years smoking increased. Similarly, the younger the age when regular smoking started, the lower was the cognitive performance. The consequences of smoking go beyond neuropsychological performance to encompass ne motor dexterity tasks as well. Declarations Ethics approval and consent to participate: The study was approved by Kuwait University Health Sciences Center Ethical Committee. All participants signed a written consent form to participate in the study before data collection.

Consent for publication: Not applicable
Availability of data and materials: The datasets used during the current study are available from the corresponding author on reasonable request.