Interactions between cigarette smoking and cognitive status on functional connectivity of the cortico‐striatal circuits in individuals without dementia: A resting‐state functional MRI study

Abstract Aims Cigarette smoking is a modifiable risk factor for Alzheimer's disease (AD), and controlling risk factors may curb the progression of AD. However, the underlying neural mechanisms of the effects of smoking on cognition remain largely unclear. Therefore, we aimed to explore the interaction effects of smoking × cognitive status on cortico‐striatal circuits, which play a crucial role in addiction and cognition, in individuals without dementia. Methods We enrolled 304 cognitively normal (CN) non‐smokers, 44 CN smokers, 130 mild cognitive impairment (MCI) non‐smokers, and 33 MCI smokers. The mixed‐effect analysis was performed to explore the interaction effects between smoking and cognitive status (CN vs. MCI) based on functional connectivity (FC) of the striatal subregions (caudate, putamen, and nucleus accumbens [NAc]). Results The significant interaction effects of smoking × cognitive status on FC of the striatal subregions were detected in the left inferior parietal lobule (IPL), bilateral cuneus, and bilateral anterior cingulate cortex (ACC). Specifically, increased FC of right caudate to left IPL was found in CN smokers compared with non‐smokers. The MCI smokers showed decreased FC of right caudate to left IPL and of right putamen to bilateral cuneus and increased FC of bilateral NAc to bilateral ACC compared with CN smokers and MCI non‐smokers. Furthermore, a positive correlation between FC of the NAc to ACC with language and memory was detected in MCI smokers. Conclusions Cigarette smoking could affect the function of cortico‐striatal circuits in patients with MCI. Our findings suggest that quitting smoking in the prodromal stage of AD may have the potential to prevent disease progression.


| INTRODUC TI ON
Alzheimer's disease (AD) is the leading cause of dementia, accounting for about 60%-80% of total dementia cases in the elderly people. [1][2][3] It has an insidious onset and is clinically characterized by progressive, irreversible cognitive decline. Mild cognitive impairment (MCI) is associated with a high risk of developing a variety of dementias, including AD, 4 vascular dementia, 5 and Parkinson's disease dementia. 6,7 The lack of effective treatment to prevent and reverse the course of AD 8 highlights the importance of controlling vascular risk factors in the early stage of AD. 3 Moreover, recent studies have emphasized that vascular dysfunction, such as the white matter hyperintensities 9 and blood-brain barrier breakdown, 10 play a crucial role in AD pathogenesis. Evidence from epidemiological studies and systematic reviews have indicated that cigarette smoking is significantly associated with a higher risk of AD and other forms of dementia, such as vascular cognitive impairment. 11,12 Therefore, exploring the effects of smoking on brain functional activity in MCI patients is of great significance in guiding early clinical intervention of AD.
Nicotine is the psychoactive component of cigarettes that contributes to the process of smoking addiction. It excites dopaminergic neurons in the mesencephalon by activating the nicotinic acetylcholine receptors(nAChRs) on the dopaminergic somata 13 to induce the release of dopamine from target regions, particularly the striatum. 14,15 Dysfunction of the striatal dopamine system, such as decreased dopamine transporter binding 16 and low dopamine receptors signaling, 17 has been described in nicotine addiction. To be specific, the striatum is comprised of the dorsal striatum (DS) and ventral striatum (VS). The DS (mainly the caudate and putamen) is involved in motor control and cognitive functions, whereas the VS (mainly the nucleus accumbens [NAc]) is the ventral extension of the DS and plays a central role in reward, the development of addictive behaviors, and habit formation. 18 Furthermore, the DS and VS showed extensive connections to cortical and limbic regions, such as the prefrontal cortex (PFC), orbital frontal cortex, anterior cingulate cortex (ACC), insula, and hippocampus, which constitute the close cortico-striatal circuits that contribute to the processes of addiction and cognition. 19,20 More importantly, recent studies have identified that cortico-striatal circuits may serve as the potential therapeutic targets for nicotine addiction, 21,22 which provides insight into the mechanisms of smoking-induced cognitive alterations in individuals without dementia.
Increasing evidence has suggested that functional connectivity (FC) disruption precedes structural atrophy, reflecting the underlying pathophysiological alterations. 23,24 Abnormal FC alterations of the cortico-striatal circuits have been observed in healthy smokers and AD/MCI patients. The FC of the striatum with dorsal ACC in healthy smokers was found to be negatively correlated with the severity of nicotine addiction, 25 while patients with AD and MCI showed abnormal connectivity between the striatum and cortical regions, including the PFC, medial frontal cortex, and middle temporal cortex. [26][27][28] Reduced FC of the striatum with precuneus was also found to be correlated with memory decline in patients with AD. 29 Nevertheless, the exact effects of smoking on FC alterations of cortico-striatal circuits in MCI patients remains unclear.
This study aimed to explore the interaction effects of smoking × cognitive status based on FC of the striatal subregions. Both DS and VS subregions (caudate, putamen, and NAc) were chosen as the seeds for FC analyses. Based on the role of cortico-striatal circuits in addiction and cognition, we assume that the functional changes in cortico-striatal circuits may be associated with the MCI in smoking patients.
Smoking was defined as the presence of any history of smoking and non-smoking was defined as participants who reported they never smoked cigarettes during their lifetime (Table S1). After the screening, 49 participants were excluded for excessive head motion (details later). Finally, 304 CN non-smokers, 44 CN smokers, 130 MCI nonsmokers, and 33 MCI smokers entered subsequent analyses. bilateral cuneus and increased FC of bilateral NAc to bilateral ACC compared with CN smokers and MCI non-smokers. Furthermore, a positive correlation between FC of the NAc to ACC with language and memory was detected in MCI smokers.

Conclusions:
Cigarette smoking could affect the function of cortico-striatal circuits in patients with MCI. Our findings suggest that quitting smoking in the prodromal stage of AD may have the potential to prevent disease progression.

K E Y W O R D S
Alzheimer's disease, functional connectivity, magnetic resonance imaging, smoking, striatum scale-logical memory, WMS-LM, immediate and delayed recall), attention (Trail-Making Test, Part A, TMT-A), execution (Trail-Making Test, Part B, TMT-B), and language (Semantic Verbal Fluency, SVF).

| Imaging data acquisition
The structural and resting-state functional MRI (rsfMRI) images of all participants were scanned using a 3.0-Tesla Philips MRI scanner (Supplementary materials). Details of the ADNI neuroimaging acquisition protocol are publicly available on the Laboratory of Neuroimaging website (http://www.loni.ucla.edu/ADNI).

| Striatum-based resting-state FC analysis
The striatal subregions (caudate, putamen, and NAc) were chosen as the seeds for FC analyses according to Harvard-Oxford subcortical structural atlas. Dynamic brain connectome (DynamicBC) analysis toolbox (http://restf mri.net/forum/ Dynam icBC) 31 was used to create individual FC maps by calculating Pearson's correlations between the time course of striatal subregions and whole-brain areas, which were then transformed into Z maps.

| Propensity score matching
Propensity score matching (PSM) implanted in SPSS version 26 was performed to balance the differences in demographic features between non-smoking and smoking subgroups in CN and MCI. Specifically, a 1: 2 matching was used to pair CN smokers and MCI smokers based on age, sex, and education level. The clinical and striatal FC results were summarized in Tables S2, S3 and Figure S1.

| Statistical analysis
The statistical analyses of demographics and neuropsychological data were performed using IBM SPSS 26.0 statistical software.

| Demographics and clinical characteristics
The demographics and clinical characteristics of the four subgroups were summarized in Table 1 Figure 1D). The interaction regions of FC analyses were also summarized in Table 2.

| Smoking ×cognitive status interaction on FC of the striatal subregions
Then, post-hoc analyses were performed for interaction regions of the four subgroups ( Figure 2

| Correlation between FC of the striatal subregions and cognition
We investigated the relationships between FC values of the interaction regions (left IPL, bilateral cuneus, and bilateral ACC) and different cognition domains (Table 3)

| DISCUSS ION
In this study, our main goal is to explore the interaction effects of smoking × cognitive status based on FC of the striatal subregions.
Our findings showed that regions with interaction effects were primarily located in the IPL, cuneus, and ACC. Specifically, the CN smokers had increased FC between the DS and parietal region compared with non-smokers, while the MCI smokers showed decreased FC between the DS and parieto-occipital regions and increased FC between the VS and frontal cortex compared with CN smokers and MCI non-smokers. Furthermore, FC between the NAc and ACC in MCI smokers was positively correlated with language and memory.
This study indicates that cigarette smoking influences the function of cortico-striatal circuits in patients with MCI.
First, we found that the IPL served as an essential interaction region showing different functional changes in CN smokers and MCI smokers. There is growing evidence that habitual mechanism plays a vital role in addiction. 33,34 Individuals with higher levels of nicotine addiction have increased engagement of motor preparation circuits, suggesting increased dependence on habitual behavior. 35 Interestingly, the IPL is the key brain region that controls the conscious motor intention "wanting to move" by specifying a general goal to be reached before movement planning. 36 Findings from fMRI studies demonstrated smoking cue-induced activation in the IPL was associated with the severity of nicotine dependence. 37,38 Thus, our result of higher FC of the caudate to IPL in CN smokers indicates intense motor intentions of smokers on smoking before they smoke.
Besides the function of motor intention, the IPL is also a functional core of the default mode network (DMN) that plays a crucial role in episodic memory retrieval. 39 Disrupted FC of the IPL/DMN has been widely reported in MCI and AD patients, which is associated with memory decline. [40][41][42] A progressive decline of structural and functional connections within the DMN has also been observed from CN to MCI and then to AD patients. 43 To be noted, the accumulation of β-amyloid (Aβ), which is the pathological hallmark of AD, appears predominantly within the DMN in the early stages. 44,45 Animal studies also proved that smoking-related oxidative stress could facilitate Aβ aggregation. 46  consequence on memory, 49 and memory decline might stem from the early deteriorations in attention which influences the later memory. 50 Chronic smoking had a negative influence on cognitive function, including attention and memory, 51 which are also the common cognitive impairment in the progression of AD. 52 Meanwhile, evidence from other fMRI studies has consistently elaborated aberrant functional activity in cerebral networks related to the above cognitive domains in MCI and AD patients. [53][54][55] Taken together, we speculate that smoking affects visual attention through the cortico-striatal circuits, which further causes memory decline in MCI patients.
In addition, FC between the NAc and ACC was modulated by the smoking ×cognition interactions and correlated with language and fronto-striatal circuit in information integration between addiction and cognition. The ACC is a part of the brain's limbic system that is involved in various cognitive functions, such as memory retrieval, language preparation, executive control, and visuospatial processing. [56][57][58] ACC also shows specific interconnections with other PFC and striatal subregions, especially the NAc, constituting the frontostriatal reward circuit that plays a key role in nicotine addiction. 59 Reduced FC of the fronto-striatal circuit has been observed in cigarette smokers and is negatively correlated with the severity of nicotine dependence. 60,61 Similarly, in a multicenter large sample study, patients with MCI also showed decreased FC between regions of the fronto-striatal circuits. 27 Whereas, we found higher FC between the NAc and ACC in MCI smokers than non-smokers indicating that smoking might exert some compensatory effects on cognitive impairment, supported by previous work on increased intrinsic brain activity in MCI smokers. 62 Although smoking is a risk factor for dementia, few studies indicated a protective effect of nicotine on cog-

| CON CLUS ION
In this study, we detected the interaction effects of smoking ×cognitive status on FC of the striatal subregions in the IPL, cuneus, and ACC. Our findings indicate that smoking can affect the function of cortico-striatal circuits, which is associated with cognitive impairment. This study suggests that quitting smoking in the prodromal stage of AD may have the potential to prevent disease progression. W81XWH-12-2-0012).

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflict of interest.

AUTH O R S' CO NTR I B UTI O N S
Author contributions included conception and study design (TTQ,

E TH I C A L A PPROVA L
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

CO N S ENT TO PA RTI CI PATE
Written informed consent was obtained from all participants and/ or authorized representatives and the study partners before any protocol-specific procedures were carried out in the ADNI study.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data used in the preparation of this article were obtained from the Alzheimer's disease Neuroimaging Initiative (ADNI) database: http://adni.loni.usc.edu/.