Corticostriatal Circuits Research Articles

Cognitive training enhances growth mindset in children through plasticity of cortico-striatal circuits

Growth mindset, the belief that one’s abilities can improve through cognitive effort, is an important psychological construct with broad implications for enabling children to reach their highest potential. However, surprisingly little is known about malleability of growth mindset in response to cognitive interventions in children and its neurobiological underpinnings. Here we address critical gaps in our knowledge by investigating behavioral and brain changes in growth mindset associated with a four-week training program designed to enhance foundational, academically relevant, cognitive skills in 7–10-year-old children. Cognitive training significantly enhanced children’s growth mindset. Cross-lagged panel analysis of longitudinal pre- and post-training data revealed that growth mindset prior to training predicted cognitive abilities after training, providing support for the positive role of growth mindset in fostering academic achievement. We then examined training-induced changes in brain response and connectivity associated with problem solving in relation to changes in growth mindset. Children’s gains in growth mindset were associated with increased neural response and functional connectivity of the dorsal anterior cingulate cortex, striatum, and hippocampus, brain regions crucial for cognitive control, motivation, and memory. Plasticity of cortico-striatal circuitry emerged as the strongest predictor of growth mindset gains. Taken together, our study demonstrates that children’s growth mindset can be enhanced by cognitive training, and elucidates the potential neurobiological mechanisms underlying its malleability. Findings provide important insights into effective interventions that simultaneously promote growth mindset and learning during the early stages of cognitive development.

Neurexin1α knockout rats display oscillatory abnormalities and sensory processing deficits back-translating key endophenotypes of psychiatric disorders

Neurexins are presynaptic transmembrane proteins crucial for synapse development and organization. Deletion and missense mutations in all three Neurexin genes have been identified in psychiatric disorders, with mutations in the NRXN1 gene most strongly linked to schizophrenia (SZ) and autism spectrum disorder (ASD). While the consequences of NRXN1 deletion have been extensively studied on the synaptic and behavioral levels, circuit endophenotypes that translate to the human condition have not been characterized yet. Therefore, we investigated the electrophysiology of cortico-striatal-thalamic circuits in Nrxn1α−/− rats and wildtype littermates focusing on a set of translational readouts, including spontaneous oscillatory activity, auditory-evoked oscillations and potentials, as well as mismatch negativity-like (MMN) responses and responses to social stimuli. On the behavioral level Nrxn1α−/− rats showed locomotor hyperactivity. In vivo freely moving electrophysiology revealed pronounced increases of spontaneous oscillatory power within the gamma band in all studied brain areas and elevation of gamma coherence in cortico-striatal and thalamocortical circuits of Nrxn1α−/− rats. In contrast, auditory-evoked oscillations driven by chirp-modulated tones showed reduced power in cortical areas confined to slower oscillations. Finally, Nrxn1α−/− rats exhibited altered auditory evoked-potentials and profound deficits in MMN-like responses, explained by reduced prediction error. Despite deficits for auditory stimuli, responses to social stimuli appeared intact. A central hypothesis for psychiatric and neurodevelopmental disorders is that a disbalance of excitation-to-inhibition is underlying oscillatory and sensory deficits. In a first attempt to explore the impact of inhibitory circuit modulation, we assessed the effects of enhancing tonic inhibition via δ-containing GABAA receptors (using Gaboxadol) on endophenotypes possibly associated with network hyperexcitability. Pharmacological experiments applying Gaboxadol showed genotype-specific differences, but failed to normalize oscillatory or sensory processing abnormalities. In conclusion, our study revealed endophenotypes in Nrxn1α−/− rats that could be used as translational biomarkers for drug development in psychiatric disorders.

Acute Effects of Different Electroacupuncture Point Combinations to Modulate the Gut-Brain Axis in the Minipig Model.

This study aimed to compare the gut-brain axis responses to acute electroacupuncture (EA) at different acupoint combinations in the minipig model. Four adult Yucatan minipigs were subjected twice to four acute EA treatments (25-minute acute sessions) including sham (false acupoints) and control (no EA), during anesthesia and according to a Latin-square design paradigm. Acupoint combinations (4 loci each) are head-abdomen (#70 Dafengmen, #35 Sanwan), back (bilateral #27 Pishu, #28 Weishu), leg (bilateral #79 Hangou, #63 Housanli), and sham (2 bilateral points that are not acupoints). Electrocardiograms were performed to explore heart rate variability (HRV). Infrared thermography was used to measure skin temperature at the stimulation points. Saliva (cortisol) and blood samples (leptin, total/active ghrelin, insulin, and glucose) were collected for further analyses before and after acute EA. All animals were also subjected to BOLD fMRI to investigate the brain responses to EA. Acute EA significantly modulated several physiological and metabolic parameters compared to basal, sham, and/or control conditions, with contrasting effects in terms of BOLD responses in brain regions involved in the hedonic and cognitive control of food intake. The head-abdomen combination appeared to be the most promising combination in terms of brain modulation of the corticostriatal circuit, with upregulation of the dorsolateral prefrontal cortex, dorsal striatum, and anterior cingulate cortex. It also induced significantly lower plasma ghrelin levels compared to sham, suggesting anorectic effects, as well as no temperature drop at the stimulation site. This study opens the way to a further preclinical trial aimed at investigating chronic EA in obese minipigs.

Wireless charging-mediated angiogenesis and nerve repair by adaptable microporous hydrogels from conductive building blocks

Traumatic brain injury causes inflammation and glial scarring that impede brain tissue repair, so stimulating angiogenesis and recovery of brain function remain challenging. Here we present an adaptable conductive microporous hydrogel consisting of gold nanoyarn balls-coated injectable building blocks possessing interconnected pores to improve angiogenesis and recovery of brain function in traumatic brain injury. We show that following minimally invasive implantation, the adaptable hydrogel is able to fill defects with complex shapes and regulate the traumatic brain injury environment in a mouse model. We find that placement of this injectable hydrogel at peri-trauma regions enhances mature brain-derived neurotrophic factor by 180% and improves angiogenesis by 250% in vivo within 2 weeks after electromagnetized stimulation, and that these effects facilitate neuron survival and motor function recovery by 50%. We use blood oxygenation level-dependent functional neuroimaging to reveal the successful restoration of functional brain connectivity in the corticostriatal and corticolimbic circuits.

Connectivity of corticostriatal circuits in nonmanifesting LRRK2 G2385R and R1628P carriers.

Neuroimaging studies have shown that the functional connectivity (FC) of corticostriatal circuits in nonmanifesting leucine-rich repeat kinase 2 (LRRK2) G2019S mutation carriers mirrors neural changes in idiopathic Parkinson's disease (PD). In contrast, neural network changes in LRRK2 G2385R and R1628P mutations are unclear. We aimed to investigate the FC of corticostriatal circuits in nonmanifesting LRRK2 G2385R and R1628P mutation carriers (NMCs). Twenty-three NMCs, 28 PD patients, and 29 nonmanifesting noncarriers (NMNCs) were recruited. LRRK2 mutation analysis was performed on all participants. Clinical evaluation included MDS-UPDRS. When compared to NMNCs, NMCs showed significantly reduced FC between the caudate nucleus and superior frontal gyrus and cerebellum, and between the nucleus accumbens and parahippocampal gyrus, amygdala, and insula. We also found increased striatum-cortical FC in NMCs. Although the corticostriatal circuits have characteristic changes similar to PD, the relatively intact function of the sensorimotor striatum-cortical loop may result in less possibility of developing parkinsonian motor symptoms for the NMCs. This study helps explain why LRRK2 G2385R and R1628P mutations are risk factors rather than pathogenic mutations for PD and suggests that various LRRK2 mutations have distinct effects on neural networks.

Hierarchical clustering optimizes the tradeoff between compositionality and expressivity of task structures for flexible reinforcement learning

A hallmark of human intelligence, but challenging for reinforcement learning (RL) agents, is the ability to compositionally generalise, that is, to recompose familiar knowledge components in novel ways to solve new problems. For instance, when navigating in a city, one needs to know the location of the destination and how to operate a vehicle to get there, whether it be pedalling a bike or operating a car. In RL, these correspond to the reward function and transition function, respectively. To compositionally generalize, these two components need to be transferable independently of each other: multiple modes of transport can reach the same goal, and any given mode can be used to reach multiple destinations. Yet there are also instances where it can be helpful to learn and transfer entire structures, jointly representing goals and transitions, particularly whenever these recur in natural tasks (e.g., given a suggestion to get ice cream, one might prefer to bike, even in new towns). Prior theoretical work has explored how, in model-based RL, agents can learn and generalize task components (transition and reward functions). But a satisfactory account for how a single agent can simultaneously satisfy the two competing demands is still lacking. Here, we propose a hierarchical RL agent that learns and transfers individual task components as well as entire structures (particular compositions of components) by inferring both through a non-parametric Bayesian model of the task. It maintains a factorised representation of task components through a hierarchical Dirichlet process, but it also represents different possible covariances between these components through a standard Dirichlet process. We validate our approach on a variety of navigation tasks covering a wide range of statistical correlations between task components and show that it can also improve generalisation and transfer in more complex, hierarchical tasks with goal/subgoal structures. Finally, we end with a discussion of our work including how this clustering algorithm could conceivably be implemented by cortico-striatal gating circuits in the brain.

Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study

Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships which may involve the impact of inflammation on synthesis and release of dopamine. To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable unmedicated adult MDD outpatients enrolled to have a range of inflammation (as indexed by plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (double-blind, randomized order ~1-week apart). The primary outcome of resting-state (rs)FC in a classic ventral striatum to ventromedial prefrontal cortex reward circuit was calculated using a targeted, a priori approach. Data available both pre- and post-challenge (n = 31/40) established stability of rsFC across visits and determined CRP > 2 mg/L as a cut-point for patients exhibiting positive FC responses (post minus pre) to L-DOPA versus placebo (p < 0.01). Higher post-L-DOPA FC in patients with CRP > 2 mg/L was confirmed in all patients (n = 40) where rsFC data were available post-challenge (B = 0.15, p = 0.006), and in those with task-based (tb)FC during reward anticipation (B = 0.15, p = 0.013). While effort-based motivation outside the scanner positively correlated with rsFC independent of treatment or CRP, change in anhedonia scores negatively correlated with rsFC after L-DOPA only in patients with CRP > 2 mg/L (r = -0.56, p = 0.012). FC in reward circuitry should be further validated in larger samples as a biomarker of target engagement for potential treatments including dopaminergic agents in MDD patients with increased inflammation.

Altered resting-state functional connectivity within corticostriatal and subcortical-striatal circuits in chronic pain

Brain corticostriatal circuits are important for understanding chronic pain and highly relevant to motivation and cognitive processes. It has been demonstrated that in patients with chronic back pain, altered nucleus accumbens (NAcc)—medial prefrontal cortex (MPFC) circuit fMRI-based activity is predictive of patient outcome. We evaluated the NAcc-MPFC circuit in patients with another chronic pain condition, fibromyalgia, to extend these important findings. First, we compared fMRI-based NAcc-MPFC resting-state functional connectivity in patients with fibromyalgia (N = 32) vs. healthy controls (N = 37). Compared to controls, the NAcc-MPFC circuit’s connectivity was significantly reduced in fibromyalgia. In addition, within the fibromyalgia group, NAcc-MPFC connectivity was significantly correlated with trait anxiety. Our expanded connectivity analysis of the NAcc to subcortical brain regions showed reduced connectivity of the right NAcc with mesolimbic circuit regions (putamen, thalamus, and ventral pallidum) in fibromyalgia. Lastly, in an exploratory analysis comparing our fibromyalgia and healthy control cohorts to a separate publicly available dataset from patients with chronic back pain, we identified reduced NAcc-MPFC connectivity across both the patient groups with unique alterations in NAcc-mesolimbic connectivity. Together, expanding upon prior observed alterations in brain corticostriatal circuits, our results provide novel evidence of altered corticostriatal and mesolimbic circuits in chronic pain.

Altered resting-state functional connectivity of default mode network in brachioradial pruritus.

Patients with chronic pruritus (CP) have a low quality of life, thus it is important to gain a better understanding of the underlying processes. Previous functional magnetic resonance imaging studies at rest (rsfMRI) have shown that mainly areas associated with the default mode network (DMN), sensorimotor (SMN), frontoparietal (FPN) and salience networks (SN) are involved in the processing of itch in patients with chronic pruritus (CP), as well as the cortico-striatal circuit, which is involved in the motoric preparation of scratching. rsfMRI studies on functional connectivity (FC) patterns of resting-state networks (RSNs) in patients with inflammatory atopic dermatitis (AD) or with neuropathic brachioradial pruritus (BRP) compared with healthy controls (HC) are lacking. The main goals of this study were to investigate whether functional connectivity within networks and areas associated with itch detection and processing are altered in patients with AD and BRP compared with matched healthy controls by rsfMRI, respectively. Patients with AD (n = 28) and with BRP (n = 28) were compared with corresponding matched healthy controls by rsfMRI. Group-specific RSNs were identified by independent component analysis (ICA) and between-group differences in the RSNs were analysed by dual regression technique. Seed-based functional connectivity was analysed in several itch-related brain regions belonging to the DMN, SN and FPN, respectively. ICA and seed-based analyses revealed decreased functional connectivity in BRP compared with HC specially within the DMN including the precuneus and cingulate cortex. For AD patients in comparison with HC, as well as when BRP and AD patients were compared directly, no significant FC differences at rest were seen. Our findings point towards decreased FC particularly in the DMN at rest in patients with BRP. These results seem to indicate that central connectivity patterns at rest differentially encode itch in BRP and AD.

Oscillation/Coincidence-Detection Models of Reward-Related Timing in Corticostriatal Circuits

Abstract The major tenets of beat-frequency/coincidence-detection models of reward-related timing are reviewed in light of recent behavioral and neurobiological findings. This includes the emphasis on a core timing network embedded in the motor system that is comprised of a corticothalamic-basal ganglia circuit. Therein, a central hub provides timing pulses (i.e., predictive signals) to the entire brain, including a set of distributed satellite regions in the cerebellum, cortex, amygdala, and hippocampus that are selectively engaged in timing in a manner that is more dependent upon the specific sensory, behavioral, and contextual requirements of the task. Oscillation/coincidence-detection models also emphasize the importance of a tuned ‘perception’ learning and memory system whereby target durations are detected by striatal networks of medium spiny neurons (MSNs) through the coincidental activation of different neural populations, typically utilizing patterns of oscillatory input from the cortex and thalamus or derivations thereof (e.g., population coding) as a time base. The measure of success of beat-frequency/coincidence-detection accounts, such as the Striatal Beat-Frequency model of reward-related timing (SBF), is their ability to accommodate new experimental findings while maintaining their original framework, thereby making testable experimental predictions concerning diagnosis and treatment of issues related to a variety of dopamine-dependent basal ganglia disorders, including Huntington’s and Parkinson’s disease.

Hiding in plain sight: how the COVID-19 pandemic unmasked the autoinflammatory PFAPA syndrome lurking in our midst

The striatum has important roles in motor control and action learning and, like many brain regions, receives multiple monoaminergic inputs. We have examined serotonergic modulation of rat and mouse corticostriatal...

Clozapine-Induced Chemogenetic Neuromodulation Rescues Post-Stroke Deficits After Chronic Capsular Infarct

Long-term disabilities induced by stroke impose a heavy burden on patients, families, caregivers, and public health systems. Extensive studies have demonstrated the therapeutic value of neuromodulation in enhancing post-stroke recovery. Among them, chemogenetic neuromodulation activated by clozapine-N-oxide (CNO) has been proposed as the potential tool of neuromodulation. However, recent evidence showed that CNO does not cross the blood − brain barrier and may in fact have low binding affinity for chemogenetic tool. Thus, clozapine (CLZ) has been suggested for use in chemogenetic neuromodulation, in place of CNO, because it readily crosses the blood–brain barrier. Previously we reported that low doses of CLZ (0.1 mg/kg) successfully induced neural responses without off-target effects. Here, we show that low-dose clozapine (0.1 mg/kg) can induce prolonged chemogenetic activation while avoiding permeability issues and minimizing off-target effects. In addition, clozapine-induced excitatory chemogenetic neuromodulation (CLZ-ChemoNM) of sensory-parietal cortex with hsyn-hM3Dq-YFP-enhanced motor recovery in a chronic capsular infarct model of stroke in rats, improving post-stroke behavioral scores to 56% of pre-infarct levels. Longitudinal 2-deoxy-2-[18F]-fluoro-D-glucose microPET (FDG-microPET) scans showed that a reduction in diaschisis volume and activation of corticostriatal circuits were both correlated with post-stroke recovery. We also found c-Fos increases in bilateral cortices and BDNF increases in the cortices and striatum after CLZ-ChemoNM, indicating an increase in neural plasticity. These findings suggest the translational feasibility of CLZ-ChemoNM for augmenting recovery in chronic stroke.

Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons

Learning and consolidation of new motor skills require plasticity in the motor cortex and striatum, two key motor regions of the brain. However, how neurons undergo synaptic changes and become recruited during motor learning to form a memory engram remains unknown. Here, we train mice on a motor learning task and use a genetic approach to identify and manipulate behavior-relevant neurons selectively in the primary motor cortex (M1). We find that the degree of M1 engram neuron reactivation correlates with motor performance. We further demonstrate that learning-induced dendritic spine reorganization specifically occurs in these M1 engram neurons. In addition, we find that motor learning leads to an increase in the strength of M1 engram neuron outputs onto striatal spiny projection neurons (SPNs) and that these synapses form clusters along SPN dendrites. These results identify a highly specific synaptic plasticity during the formation of long-lasting motor memory traces in the corticostriatal circuit.

A corticostriatal pathway mediating self-efficacy enhancement

Forming positive beliefs about one’s ability to perform challenging tasks, often termed self-efficacy, is fundamental to motivation and emotional well-being. Self-efficacy crucially depends on positive social feedback, yet people differ in the degree to which they integrate such feedback into self-beliefs (i.e., positive bias). While diminished positive bias of this sort is linked to mood and anxiety, the neural processes by which positive feedback on public performance enhances self-efficacy remain unclear. To address this, we conducted a behavioral and fMRI study wherein participants delivered a public speech and received fictitious positive and neutral feedback on their performance in the MRI scanner. Before and after receiving feedback, participants evaluated their actual and expected performance. We found that reduced positive bias in updating self-efficacy based on positive social feedback associated with a psychopathological dimension reflecting symptoms of anxiety, depression, and low self-esteem. Analysis of brain encoding of social feedback showed that a positive self-efficacy update bias associated with a stronger reward-related response in the ventral striatum (VS) and stronger coupling of the VS with a temporoparietal region involved in self-processing. Together, our findings demarcate a corticostriatal circuit that promotes positive bias in self-efficacy updating based on social feedback, and highlight the centrality of such bias to emotional well-being.

Pathological gambling and impulsivity related to Huntington's disease

Patients with Huntington's disease are a risk group for developing problematic gambling, which is characterised by subjects’ inability to stop gambling despite financial, personal or professional problems. Predisposition to pathological gambling and other addictions involves disturbances in the same corticostriatal circuits that are affected in Huntington's disease, and displays similar disinhibition‐related symptoms. The authors present a case of long‐standing pathological gambling, impulsivity and organic mood disorder related to Huntington's disease.

Corticostriatal circuits in the transition to chronic back pain: The predictive role of reward learning

SummaryConnectivity between the nucleus accumbens (NAc) and ventromedial prefrontal cortex (vmPFC) and reward learning independently predict the transition from acute to chronic back pain (CBP). However, how these predictors are related remains unclear. Using functional magnetic resonance imaging, we investigate NAc- and vmPFC-dependent reward learning in 50 patients with subacute back pain (SABP) and follow them over 6 months. Additionally, we compare 29 patients with CBP and 29 pain-free controls to characterize mechanisms of reward learning in the chronic stage. We find that the learning-related updating of the value of reinforcement (prediction error) in the NAc predicts the transition to chronicity. In CBP, compared with controls, vmPFC responses to this prediction error signal are decreased, but increased during a discriminative stimulus. Distinct processes of reward learning in the vmPFC and NAc characterize the development and maintenance of CBP. These could be targeted for the prevention and treatment of chronic pain.

Value representations: Fast and slow

Corticostriatal circuits represent value and choice during value-guided decision making. In this issue of Neuron, Balewski etal. (2022) show that caudate nucleus and orbitofrontal cortex use distinct value signals during choice, which are consistent with two parallel valuation mechanisms, one fast, one slow.

Misconfigured striatal connectivity profiles in smokers

Dysregulation of frontal cortical inputs to the striatum is foundational in the neural basis of substance use disorder (SUD). Neuroanatomical and electrophysiological data increasingly show that striatal nodes receive appreciable input from numerous cortical areas, and that the combinational properties of these multivariate “connectivity profiles” play a predominant role in shaping striatal activity and function. Yet, how abnormal configuration of striatal connectivity profiles might contribute to SUD is unknown. Here, we implemented a novel “connectivity profile analysis” (CPA) approach using resting-state functional connectivity data to facilitate detection of different types of connectivity profile “misconfiguration” that may reflect distinct forms of aberrant circuit plasticity in SUD. We examined 46 nicotine-dependent smokers and 33 non-smokers and showed that both dorsal striatum (DS) and ventral striatum (VS) connectivity profiles with frontal cortex were misconfigured in smokers—but in doubly distinct fashions. DS misconfigurations were stable across sated and acute abstinent states (indicative of a “trait” circuit adaptation) whereas VS misconfigurations emerged only during acute abstinence (indicative of a “state” circuit adaptation). Moreover, DS misconfigurations involved abnormal connection strength rank order arrangement, whereas VS misconfigurations involved abnormal aggregate strength. We found that caudal ventral putamen in smokers uniquely displayed multiple types of connectivity profile misconfiguration, whose interactive magnitude was linked to dependence severity, and that VS misconfiguration magnitude correlated positively with withdrawal severity during acute abstinence. Findings underscore the potential for approaches that more aptly model the neurobiological composition of corticostriatal circuits to yield deeper insights into the neural basis of SUD.

Fast and slow contributions to decision-making in corticostriatal circuits

We make complex decisions using both fast judgments and slower, more deliberative reasoning. For example, during value-based decision-making, animals make rapid value-guided orienting eye movements after stimulus presentation that bias the upcoming decision. The neural mechanisms underlying these processes remain unclear. To address this, we recorded from the caudate nucleus and orbitofrontal cortex while animals made value-guided decisions. Using population-level decoding, we found a rapid, phasic signal in caudate that predicted the choice response and closely aligned with animals' initial orienting eye movements. In contrast, the dynamics in orbitofrontal cortex were more consistent with a deliberative system serially representing the value of each available option. The phasic caudate value signal and the deliberative orbitofrontal value signal were largely independent from each other, consistent with value-guided orienting and value-guided decision-making being independent processes.

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.

AimsCigarette 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.MethodsWe 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]).ResultsThe 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.ConclusionsCigarette 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.