Dopamine in the prefrontal cortex plays multiple roles in the executive function of patients with Parkinson’s disease

Zihang Zhou, Yalong Yan, Heng Gu, Ruiao Sun, Zihan Liao, Ke Xue, Chuanxi Tang

Abstract Parkinson’s disease can affect not only motor functions but also cognitive abilities, leading to cognitive impairment.One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive functioning.Executive functions help us plan, organize, and control our actions based on our goals.The brain area responsible for executive functions is called the prefrontal cortex.It acts as the command center for the brain, especially when it comes to regulating executive functions.The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine.However, little is known about how dopamine affects the cognitive functions of patients with Parkinson’s disease.In this article, the authors review the latest research on this topic.They start by looking at how the dopaminergic system, is altered in Parkinson’s disease with executive dysfunction.Then, they explore how these changes in dopamine impact the synaptic structure,electrical activity, and connection components of the prefrontal cortex.The authors also summarize the relationship between Parkinson’s disease and dopamine-related cognitive issues.This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson’s disease.

Key Words: dopamine; dopamine receptor; dopamine transporter; executive dysfunction; neural network; neural oscillation; prefrontal cortex; synaptic plasticity

Introduction

Parkinson’s disease (PD) is a complex neurodegenerative disease that seriously affects the lives of patients.In addition to its characteristic motor symptoms, PD can even have an impact on subtle neural activities, such as temporomandibular disorders (Minervini et al., 2023).At present, there is increasing evidence that early-stage PD can cause patients to produce non-motor symptoms such as cognitive decline (Biddiscombe et al., 2020).With the growing population of PD patients, research and understanding of cognitive impairments have become increasingly important.

The prefrontal cortex (PFC) plays a crucial role in cognitive function, mood,and affection (Moghaddam and Abbas, 2022).Dopamine, a dopamine is a neuromodulatory molecule, regulates the PFC (Ott and Nieder, 2019; Su et al., 2023).However, our current understanding of the role of prefrontal dopamine in cognitive regulation in PD, especially in the early stages, remains limited.This review aims to explore the role and mechanisms of prefrontal dopamine in cognitive regulation in PD.We review current research progress on cognitive impairments in PD and prefrontal dopamine and emphasize the importance of cognitive changes in the early stages.By filling this research gap, we hope to provide a deeper understanding of early diagnosis and treatment of PD, thus improving patients’ quality of life.

First, this review will introduce the manifestations of cognitive impairments in PD, with a focus on the PFC’s role in cognitive executive function.Next,we discuss the key role of dopamine in the PFC, including its impact on regional neuronal oscillations, synaptic plasticity, and neural microcircuits.Furthermore, we review the factors affecting PFC dopamine levels in PD and provide a summary of the clinical neuroimaging-neural network studies on cognitive impairments.Finally, we summarize existing evidence and propose future research directions to deepen our understanding of the role of prefrontal dopamine in cognitive regulation in PD.

Search Strategy

This narrative review assessed PubMed of the National Institute of Health(NIH), National Library of Medicine (https://www.ncbi.nlm.nih.gov/pubmed/),and Foreign Medical Literature Retrieval Service (https://www.metstr.com/)databases between January and May 2023.The search strategy and selection criteria used combinations of keywords such as Parkinson’s disease, prefrontal cortex, executive dysfunction, dopamine, dopamine transporter; neural network, neural oscillation, synaptic plasticity, dopamine receptor, and neural network.There was no limit on the year of publication, affiliation, authorship,or journal, but there was a preference for more recent research from 2017 to 2023.

The Epidemiological Research of Cognitive Abnormality in the Early Stage of Parkinson’s Disease

PD, a common neurodegenerative disease, was initially considered a type of dyskinesia owing to the symptoms of motor retardation, static tremor,postural instability, and rigidity (Erkkinen et al., 2018).In fact, with the indepth study of the disease’s characteristics, we corroborated that patients were always accompanied by 40–60% degenerated dopamine neurons when they were diagnosed (Fearnley and Lees, 1991; DeKosky and Marek, 2003).Clinically, PD with only non-motor symptoms is defined as the prodromal stage (Hustad and Aasly, 2020).From this point of view, PD is a complex disease affecting various systems and has a long latency period of its motor symptoms.Thus, the non-motor symptoms of PD have attracted more attention in recent years (Wang et al., 2022; Yuan et al., 2023).Typically,the non-motor symptoms of PD comprise cognitive decline; gastrointestinal symptoms (anosmia, constipation); sleep disorders (rapid eye movement sleep disorder, daytime sleepiness) (Seppi et al., 2019); and psychiatric symptoms(anxiety, depression) (Goldman and Postuma, 2014).Cognitive disorder,as one of the most common but essential early manifestations in motor symptoms, is reportedly pernicious because of the great burden imposed on patients and their families, the increasing risks of hospitalization, complicated nursing needs, and the prolonged length of hospital stay (Wilson et al., 2023).According to epidemiological statistics, about 36% of newly diagnosed PD patients have mild cognitive impairment (MCI), > 40% PD patients without cognitive impairment may develop MCI within 6 years, and > 80% PD patients develop PD with dementia (PD-D) within 20 years of onset.Compared with healthy controls, most PD patients show accompanying distinct functional retrogradation, particularly in executive function, attention, and visual-spatial ability (Fang et al., 2020).A cohort study showed that most patients develop PD-D 4–6-times faster than normal people after being diagnosed with PD(Hobson and Meara, 2004).The onset time of PD-D varies among patients.Patients with early-onset PD show a significantly faster rate of cognitive decline than those with delayed-type PD, which indicates an abbreviated time course of PD-D (Aarsland et al., 2004).PD shows a faster decline in symptoms of visual space and working memory abilities (Johnson and Galvin, 2011)than Alzheimer’s disease.Thus, to better differentiate the characteristics of cognitive impairment of PD from other diseases, the International Association of Parkinson’s Disease and Dyskinesia published the diagnostic criteria for PD accompanied by MCI and dementia (Litvan et al., 2012; Yu and Wu, 2022),which significantly alleviated the complexity of disease classification and the divergence caused by heterogeneity evaluation, and further improved the scientific accuracy and convenience of the clinical diagnosis.The cognitive abilities of PD patients always progress from normal cognition to slight decline (MCI), then to mild, moderate, and severe dementia.Hence, MCI is recognized as a transitional stage from normal cognitive aging to dementia(Yang et al., 2023); hence, the ability to focus on and intervene in cognitive ability in the early stage is the emphasis of disease research.Nowadays,classic neuropsychological evaluation methods have been set up for executive disorder, including Wisconsin Card Sorting (Cooper et al., 1992), Stroop Test(Gotham et al., 1988), Trail Making Test (Herrera et al., 2012), Verbal Fluency Test, and Tower of London test (TOL test).Meta-analyses have shown that the diagnosis of executive dysfunction in the early stage of PD, according to existing conditions, can be judged depending on the above-mentioned neuropsychological tests (Goldman and Sieg, 2020).

The Critical Modulatory Nucleus of Executive Function—Prefrontal Cortex

Cognitive disability in PD has become an increasingly investigated theme.It has been reported that about 15–20% people who are not diagnosed with PD according to their motor symptoms have MCI (Fang et al., 2020).As explained,MCI may be in a transitional stage.All cognitive domains could be involved in MCI, but the severity is not enough to influence daily functions.PD with MCI is a commonly used concept in the clinic, which bears a 75–95% chance of becoming PD-D with disease progression (Aarsland et al., 2010; Pedersen et al., 2017).Despite the significant discrepancy of cognitive dysfunction between different individuals, we could also discriminate MCI, based on the executive dysfunction caused by an impaired PFC, from dementia based on the extensive functional defect.The frontal-striatal dopamine disorder usually brings about the former, and the latter is often triggered by the disorder of all the neurotransmitter systems in the cortex (González-Usigli et al., 2023).The question then remains which cognitive categories are dominated by the frontal-striatal circuit? So far, the known frontal-striatal-modulated cognitions contain the plan execution, working memory, attention shifting, memory reidentification, and reinforcement learning (Menon and D’Esposito, 2022),which are just the core characteristics and aspects of executive function.What is executive function? It is a group of cognitive processes modulating goal-directed behavior, comprising goal setting, intention forming, execution,and results treatment (Cienfuegos et al., 2022).It involves several cognitive abilities, including resolving problems, scheduling, rules shifting/retaining,task switching, working memory, attention distribution, and reaction suppressing (Dirnberger and Jahanshahi, 2013; Adolphe et al., 2022).In this process, emotion regulation, intelligence, decision-making, perception, and metacognition are also involved (Godefroy et al., 2010).Given the significant enrichment and expansion of the executive function concept, the definition is never easy.Nonetheless, executive dysfunction in the clinic is still considered a characteristic of early-stage PD.It is an accepted predictor of later-stage dementia with high predictive value (Figure 1).

Figure 1 ｜The PFC is involved in the regulation of multiple subtypes of executive functions.

Several hypotheses exist about the mechanisms of cognitive executive dysfunction.From the perspective of clinical pathology, the deposition of Lewy bodies, neurofibrillary tangles, senile plaque formation, microvascular disease, and argyrophilic inclusion body aggregating could result in executive dysfunction (Sezgin et al., 2019).However, exceptions are also reported.From the genetic point of view, the mutation of several genes could aggravate the risk of cognitive dysfunction in PD, which include genes such as α-synuclein(SNCA), gamma-butyrolactone (GBA), apolipoprotein E4 (APOE4), and catecholamine O methyltransferase (COMT).It has been recently reported that genetic polymorphisms of COMT correlate with cognition in PD (Tang et al., 2019).Specifically, compared with Val/Val and Val/Met genotypes,patients with Met/Met type PD who show a more evident decline in the neural network activity in PFC have more severe cognitive dysfunction.Regarding neurobiology and anatomy, PD patients were found to show severe impairment in the dopamine neurons in the caudal lentiform nucleus, which was closely related to the executive dysfunction of spontaneous behavior.When the basal nucleus is impaired, the cortex has to work harder to control movement, and through this purposeful movement control, it can compensate for the deficiencies in execution and attention (Dirnberger and Jahanshahi,2013).The dopamine depletion in the part of the striatum appears to have a strong correlation with executive dysfunction (Stroop test; Kübler et al.,2017), which indicates that executive dysfunction may likely be caused by the diminishing dopamine inputs from the striatum to PFC.Functional magnetic resonance imaging (fMRI) has shown that when PD patients are performing a task, the activity of those regions descends evidently (Williams-Gray et al.,2007), and the frontal-parietal network is under-activated (Williams-Gray et al., 2008), both of which are reasons for such functional defects in earlystage PD patients (Williams and Goldman-Rakic, 1998).In a random number generation test task, PD patients with executive dysfunction showed a decline in medial PFC (mPFC) network activation (Friedman and Robbins, 2022).The same results were also identified in the timing and space-time perception tests (Harrington et al., 2011).Besides, the modulation of attention control and cognitive flexibility is also related to the frontal-striatal circuit (Ekman et al., 2012).Neuroimaging studies have reported consistent results, which show that working memory mainly involves the cortical-subcortical network,including the bilateral caudate nucleus, dorsal nucleus, ventral nucleus,and prefrontal and parietal cortex (Owen et al., 2005; Li et al., 2022).In the performing course of set-shifting (Jin Yoon et al., 2021) and working memory tasks (Bolkan et al., 2017), PD patients with cognitive impairment showed reduced activation of the circuit in the PFC, striatum, and thalamus.Imaging data also concludes that the lessening of mPFC networks is relevant to poor performance in cognitive tests (Müller et al., 2020).Nevertheless, positron emission tomography scanning demonstrates the functional impairment of the striatum, in which the dopamine neurons in the globus pallidus and caudate nucleus seem severely impaired.The impairment of those two areas could decrease the effective inputs from the globus pallidus to the PFC and further interrupt the frontal-striatal networks, which have a close relationship with the executive dysfunction of PD patients.Combined with transmitter analysis in the brain, the early appearance of nigrostriatal pathology in PD is often the dopamine depletion in the dorsal striatum, and the ventral part often remains comparatively intact (Jellinger, 2001).The connection of the dorsal striatum and dorsal lateral PFC (dlPFC) is involved in the modulation of executive function.The clinical cognitive appearance could not be expounded well when only considering the neuropathology and genetics.However,from the molecular and cytopathological perspectives, the mechanism of PD with cognitive dysfunction has dramatically progressed in recent years.In the following sections, we provide perspectives from neuropsychology,pharmacology, imaging, and electrophysiology.

Cognitive dysfunction is a disorder of multiple aspects, and the neural networks participating in various cognitive processes are affected by the dopaminergic transmitter.Thus, we wish to illuminate the generation and progress of cognitive dysfunction by focusing on the perspective of“transmitter imbalance-network imbalance.” What needs to be further emphasized is that cognitive networks interact and reciprocally overlap in a sophisticated manner.Although some neural networks are identified with more robust control on several cognitive dysfunctions than others, the portrayed neural networks can only be a conceptual and model definition for the discrepancy among individuals and behaviors.Presently, the accepted consensus is that PFC is, to a large extent, a “central executer” responsible for attention distribution, execution control, and cognitive resources allocation,and the basal ganglion acts as a “competitive dispatcher” specialized in the control of movement (Miller and Cohen, 2001; Popa et al., 2019).

Thus, it can be seen that early cognitive disorder of PD is often due to impairment of cognitive flexibility, which is generally called executive dysfunction, and is more because of the inability to adjust behavior for reaction-generated-goal-aimed and intelligent behavior, and involves working memory, attention distribution, and inhibitory modulatory.The control center of these functions is located in the PFC in the forepart of the telencephalon (Nyberg, 2018).PFC is responsible for receiving and integrating abstract sensory information and performing reactive treatment based on past experience and present needs, thus further delivering instructions to movement-related areas (Markowitz et al., 2015; Siegel et al., 2015).Multiple areas of PFC have a dopamine-dependent functional connection to various degrees (Middleton and Strick, 2000).The integrity and soundness of these circuits are essential for normal execution function.

Role of the Dopaminergic System in Cognitive Function

As mentioned earlier, PFC does not play a regulatory role within a single brain region, rather requires the coordination of multiple brain regions.There are two main areas in which the dopamine neurons connect with PFC: one is the substantia nigra, and the other is the ventral tegmental area (VTA).These two areas constitute the mesocortical dopamine pathway, but they are parallel and do not interact with each other (Williams and Goldman-Rakic, 1998).The dopamine projection from the VTA in the mesencephalon activates the anterior cingulate cortex (Brodmann area 24, BA 24) and mPFC (BA 14 and BA 32).The other dopamine projection originating from the substantia nigra projects to dlPFC (BA 12/47 and BA9/46) (Wise, 2008).Evidence suggests that dlPFC is a critical region in the frontal-striatal pathway, and the dopamine released in this pathway modulates multiple cognitive functions (Hertrich et al., 2021).As confirmed by clinical drug treatment, dopamine drugs could modestly improve cognitive abilities related to the pathway, such as working memory (Lewis et al., 2003).After treatment with levodopa, the bloodstream of dlPFC turned to normal, which is consistent with the conclusion that dopamine likely ameliorates the signal-to-noise ratio of PFC to improve cognition (Cools et al., 2002).Nevertheless, evidence also suggests that dopamine-based drugs could impair an advanced cognitive ability called reverse-order learning (Cools and Arnsten, 2022).In the early stage of PD,the dopamine loss in nigro-dlPFC is evident, but VTA-PFC dopaminergic loss is relatively low.However, after excess doses of dopamine is taken, the dopamine of VTA-PFC is abnormally elevated, which further worsens the cognitive function (Cools et al., 2001).This phenomenon gave rise to the hypothesis that dopamine is injurious to cognition (Oh et al., 2021).Thus, it can be concluded that the deviation of dopamine in the brain, whether it is elevated or decreased (Wang and Arnsten, 2015), is selectively harmful to the specific cognitive or motor abilities, which is consistent with the suggestion that a reverse U-shaped relationship exists between dopamine level and cognitive ability (Rowe et al., 2008).Another study pointed out that gene polymorphism ofCOMTcould influence the dopamine content, which may further play a role in the attention and planning tasks (Appleby et al., 2007),and is accompanied by the corticostriatal reactive change (Tang et al., 2019).Post-mortem reports found that the mesocortical networks of PD patients are degenerated (Scatton et al., 1983), and greater the loss of dopamine neurons in the VTA, more apparent the cognitive decline and dementia.

Dopamine, as an intermediate modulatory molecule, is synthesized by the given mesencephalic neurons and can be transmitted to multiple areas,including the PFC (Channer et al., 2023), which may indirectly enhance or inhibit synaptic transmission by influencing the information transmission in the synapse.When performing cognitive activities, dopaminergic terminals originating from the mesencephalon could release dopamine and regulate the activity of PFC neurons.A study showed that dopaminergic neurons from the VTA or substantia nigra could modulate learning ability by “reward prediction” (Geisler and Hayes, 2023).For example, when test animals make a presented behavior, a kind of reward stimulation such as food will be provided.Here, the dopaminergic neurons will show short-term periodic activity.Once the animal relates the associated behavior with a reward,i.e., “l(fā)earning”, dopaminergic neurons thus shift from activating when the original reward stimulus appears to activate by predicting the reward appearance.If the predicted reward is lacking, dopaminergic neurons would be accordingly inhibited.The critical values of dopaminergic neurons in the learning process can therefore be shown.Physiologically, released dopamines could combine with D1–D5 receptors on the membrane and give rise to a cascade effect rather than stimulate postsynaptic neurons directly (Jackson and Westlind-Danielsson, 1994; Seamans and Yang, 2004).According to the structure and pharmacological characteristics, dopamine receptors can be divided into two types: D1 receptor (D1R) (D1, D5) and D2R (D2, D3, D4).D1R is extensively expressed in primate PFC, where the expression level of D1R is 10-times that of D2R (Lidow et al., 1991).D1R and D2R are expressed in both pyramidal neurons and intermediate inhibitory neurons.The final enhancing or inhibitive effects of dopamine depend on receptor subtype,cell type, synaptic characteristics, and interaction between transmitters(Cools and Arnsten, 2022).Research corroborates that dopamine released from the midbrain may modulate the activity of D2R in PFC and play a role in cognitive flexibility (Festucci et al., 2022).Positron emission tomography imaging shows that D1R-predominated PFC participates in the regulation of working memory (Abi-Dargham et al., 2002; Schneider et al., 2019).When a receptor antagonist is used for locally shutting offD1R in PFC, the activity of single neurons that encode working memory will be suppressed (Yang et al.,2022b).Simultaneously, dopamine levels in the mPFC of PD patients will be reduced (Kaasinen et al., 2000).Moreover, in rodent experiments, selective blocking of D1R in PFC is identified with impaired cognitive functions such as interval sequence judgment (Yin et al., 2022) and working memory abilities(Yang et al., 2022a).Nevertheless, what is interesting is that immoderate D1R stimulation will still result in cognitive impairment.For example, a D1R agonist infused into PFC or just exposed to pressure causes a tremendous elevation of DA in the PFC, and the cognitive status also declines.However, the cortical structure is not purely composed of a single cell type.It is constructed by cells with different dopamine receptors in different layers, and the projecting area is also different.If each kind of projection neuron in each layer has a unique influence on behavioral cognition (Jenni et al., 2017), then the dopamine regulation in PFC from the midbrain is critical; hence, this research is important.Thus, regardless of whether it is the dopamine transmitter system or local regions that have disordered dopamine levels, cognition will inevitably be impaired.However, different modulatory effects will appear with the involved dopamine receptor differs (Figure 2).At the clinical level, distinguishing cognitive impairments in the early stages of PD from progressive supranuclear palsy with predominant parkinsonism(PSP-P) poses challenges (Alster et al., 2020).The compromised dopamine in the PFC may impact patients’ cognitive function, emotional regulation,and motor control.Particularly in PSP-P, involvement of the PFC can lead to cognitive impairments and emotional issues, potentially contributing to partial clinical overlap between the early stages of PD and PSP-P.

Figure 2 ｜Different dopaminergic receptors mediate different aspects of executive function regulation.

It should be noted that these two diseases exhibit distinct pathological and symptomatic differences, as they involve different brain regions and neuronal populations.PD primarily entails the degeneration of midbrain dopamine neurons.In the early stages, the degeneration of the substantia nigra may not yet significantly affect motor function, but the reduction in dopamine in the targeted PFC could have some impact on cognitive function.Patients may experience mild impairments in executing cognitive tasks, attention concentration, decision-making, and other aspects.

On the other hand, PSP-P is a rare neurodegenerative disease characterized by the formation of neurofibrillary tangles, primarily composed of tubulinassociated unit (Tau), in specific regions of the cerebral cortex and brainstem(Steele et al., 1964; Jellinger, 2008).Tau is a microtubule-associated protein expressed mainly in brain cells, and its role is to stabilize axonal microtubules(Kovacs et al., 2020).These tangles mainly accumulate in the frontal cortex,supranuclear area, and basal ganglia.

Furthermore, the affected brain areas and types of neurons are different in these diseases.For example, in PSP-P patients, the frequency of alexithymia diagnosis was higher than in PD (Assogna et al., 2019), leading to variations in disease progression and symptom presentation.Therefore, in the early stages of both diseases, although there is dopamine loss in the PFC, there is undoubtedly a significant presence of Tau tangles in the PFC of PSP-P patients, whereas deposition of α-synuclein appears to be the main feature in PD patients (Zhao et al., 2022).

Participation of the Prefrontal Cortex in Cognitive Modulation

Planning decisions, attention, and working memory are essential for guiding people’s behaviors.As mentioned earlier, the release amount and availability of dopamine in the PFC and basal ganglia modulate these cognitive courses.The precise relationship between dopamine increasing or descending with cognitive improvement or exacerbation could not be defined, which depends on multiple factors, including the local or global status of dopamine utilization,gene discrepancy, and disparate cognitive dimensions (Floresco, 2013).As far as PFC is concerned, dopamine released from mesencephalic dopaminergic terminals plays a neuromodulatory role in this area.The postsynaptic bioelectric effects originate from the transduction system of chemical signals,which consist of corresponding neurotransmitter receptors and the following downstream molecules.Different postsynaptic receptor types could project long-range inputs to other regions, which contain activating or inhibitory abilities, to modulate cognition (Anastasiades et al., 2018).The cognitive course is modulated by transmitter activity, and the morphologic change of synapse essentially determines this activity (Tang et al., 2023).In the dopamine neurons branching into the PFC, only 39% generate synapses.In PFC, the dopamine terminals are connected predominantly with the cervical part of the distal dendritic spines in pyramidal neurons and sparsely with the dendritic axis in gamma-aminobutyric acid (GABA)-ergic intermediate neurons (Smiley and Goldman-Rakic, 1993).The symmetrical synapses and asymmetrical excitatory synapses on the dendritic spines finally converge and thus modulate the excitability of glutamatergic neurons (Macht and Reagan,2018).This modulation may be achieved by influencing the construction or electroactive patterns of postsynaptic neurons, thereby regulating cognitive functions related to learning and memory.

Neuronal Communication by Oscillations Depends on Dopamine

As mentioned above, when confronted with enormous pressure, the topdown modulatory circuit of PFC would be apparently “off-line,” and the individual’s cognition would be grievously impaired.It has been reported that high levels of dopamine and norepinephrine released during stress can combine respectively with dopamine D1R and α1 adrenergic receptor rapidly and directly, thus activating intracellular Ca2+-cyclic adenosine monophosphate signals, opening potassium channels, weakening synaptic connectivity, and further causing significant depression of cell discharges in PFC (Datta and Arnsten, 2019).In the rat model of PD, the discharge frequency of pyramidal neurons in PFC increases obviously, and the discharge pattern tends to be in burst, and the discharge interval is delayed (Fan et al., 2019).Yet there is no direct evidence in this study to confirm that those phenomena are caused by the change of dopamine content in PFC.Other studies suggest that the fluctuation of dopamine levels is inevitably related to the firing patterns of pyramidal neurons in PFC.It is well known that activities of different neurotransmitters can change the firing patterns of neurons,which means that in different circumstances, the brain could process information by equilibrating transmitter activity to maintain the interaction balance between the individual, the physical environment, and psychology.In this dimension, we would find that incoordination of cognition would appear when the equilibration collapses.Consequently, behavioral disorders are formed, and the adjustive abilities based on circumstantial judgment become impaired.Evidence shows a linear relationship between the input dopamine of PFC and PFC activity, which, in other words, means that variation of dopamine input may change the firing rates of PFC neurons that ultimately leads to a regional hybrid effect (Lapish et al., 2007; Ottand Nieder, 2019).Facts also show that cognitive behaviors need highly associated space-time activities of the neural network, which requires synchronous oscillation of coherent membrane potentials both in and between the local networks, as different network oscillation frequencies may bring about different cellular activities and functional changes of the systems (Hudson and Jones, 2022).Nevertheless, dopamine influences multiple oscillation frequencies of the PFC network (Kim and Narayanan, 2019), especially the γ oscillation (Lohani et al., 2019).In earlier years, many researchers suggested that in goal-aimed activities, mesencephalic-cortical dopamine neurons are related to the activities of PFC.However, many confounders exist in these studies, and the cognitive behaviors are intricate.Therefore, the direct function of dopamine neurons remains equivocal.Nevertheless, recent research has revealed the causal relationship between dopamine neurons from the mesencephalon and behaviors dominated by PFC.In this study, optogenetic methods are introduced to rule out the interference of individual behaviors and tasks, and the phased activation of dopamine neurons in VTA is confirmed, which could lead to a synergistic change of single neurons, neuron coherence, and local field potential (Lohani et al., 2019).Interestingly, the effect of dopamine on the firing rate of a single neuron is weak and uneven in the dimension of time.However, the effect of synergetic neural clusters, regional γ oscillation, and γ-θ coupling is intense and persistent, which indicates the regulation of dopamine on PFC is at the level of long-term cognitive behavior rather than of transient and instantaneous chemical signals (Ellwood et al., 2017).

Considering the fact that the effect of dopamine on single neurons in PFC is difficult to measure, wherein this regulation has different excitation/inhibition effects on different types of neurons, and that its duration fluctuates from milliseconds to minutes, we did not review the effects of the firing pattern on a single neuron and that of neuron clusters.The peak vector counting method is used to count the activity changes of PFC neuron clusters at different time points or under different stimulation conditions (Stopfer et al.,2003).Research shows that in about 5 minutes after dopamine neurons are stimulated, neuron clusters in PFC appear in a persistently activated phase and evidently increased fast spikes (Westbrook and Braver, 2016).The PFC activity regulated by dopamine is important for maintaining cognitive flexibility(Ellwood et al., 2017).It is reported that dopamine activity in VTA has a causal relation to γ oscillation in mPFC (Park and Moghaddam, 2017).It has been widely established that γ oscillation is vital to working memory and attention,and dopamine has an even more intense influence on the high-frequency component.For example, in psychiatric patients, high-frequency γ oscillation is found to be severely impaired, and impulsive activity of dopamine neurons in the PFC could effectively activate and strengthen high-frequency γ oscillation to modulate cognition (Lohani et al., 2019).The oscillation of local field potential can synchronize spike signals of clusters so that they can reach the postsynaptic area simultaneously (Fries, 2005) and further lead to the effective transmission of messages.In addition to enhancing the communication between specific frequency neuron clusters, the oscillation could also modulate the coupling of cross-frequency oscillation between different clusters (Liu et al., 2022) to form a dependence on dopamine and further regulate cognitive functions (Bastos et al., 2018).Specifically, one of the possibilities is that dopamine can independently regulate high frequency γ oscillation to envelop θ oscillation, which is the key to working memory(Semprini et al., 2021).Furthermore, when individuals perform working memory tasks, the δ and θ oscillation is apparent in PFC (Parto Dezfouli et al., 2021).In PD, since the δ and θ oscillation in PFC, which is regulated by DA and its receptor D1R, are attenuated (Kim et al., 2017; Albeely et al., 2023),the individuals appear to have weakened cognitive flexibility and degraded clue-behavior-aimed cognition (Kim and Narayanan, 2019).This phenomenon appears to involve the variation of D1R-mediated regional glutamate level,which affects the activity and coordination of glutamate neurons (Smiley et al., 1994).Therefore, we can see that dopamine level in PFC is of critical importance for the regulation of local potential oscillation and the regulation and maintenance of normal cognition.

Alteration of Synaptic Plasticity and Microcircuits

The imbalance of dopamine input in the PFC may result in cognitive degradation, such as a disorder of working memory and social activity.Furthermore, in those courses, the heterocyclics and dendritic morphology of subcortical structure are considerably altered, which may result from the chronic change of dopamine level.It is known that each region of PFC has a clear division of labor and interactive regulation in working memory, attention control, behavioral inhibition, emotion and social interaction, and other highlevel cognition.This phenomenon depends, to some extent, on synapse modification, among which the modification of dopaminergic synapses projected from the midbrain participates in the modulation of several types of information encoding.For example, in spatial cognitive memory research, the dopaminergic system’s modulation is first confirmed.Then, by the proteomics analysis of PFC, the changed expression of proteins related to dopamine receptors are validated, among which many proteins are involved in cognitive regulation.Furthermore, after being grouped by function, those proteins are predominantly involved in the modulation of synaptic transmission, synaptic remodeling, and dendritic spine morphology (Daba Feyissa et al., 2019).The results have showed that the alteration of dopamine level would further mediate the intracellular effect through the receptor and give rise to largescale synaptic reorganization to change the former synaptic structure and connection and affect cognitive ability.For instance, in the analysis of mPFC of depressive mice, it is found that the mRNAs responsible for encoding neural activities are down-regulated, which contain mRNAs of dopaminergicsynaptic-structure-associated proteins, vesicle-associated proteins, and axon-forming proteins.In the study of dopamine transporter (DAT) knockout mice, the dendritic spine density of pyramidal neurons in the mPFC and hippocampal CA1 decreased, and a large-scale decrease in dendritic spines may lead to behavioral abnormality and cognitive defect (Kasahara et al.,2015).In addition, after D1R is knocked out in mPFC, inhibitory postsynaptic currents mediated by dopamine-D1R path are found to be impeded, and regulation of dopaminergic synapse is significantly destroyed, accompanied by the translation impedance of dendritic-spine-structural-associated mRNA,all of which further lead to the regional destruction of synaptic plasticity and synaptic transmission, finally resulting in mental retardation, cognitive impairment, and autism (Paul et al., 2013).Another study confirms that after long-term cognitive training, working memory is evidently improved, and with the D1R density in PFC and parietal cortex enhancement (McNab et al., 2009),D1R-mediated cognitive protection effects also recover.Furthermore, anin vitrostudy showed that after the addition of exogenous dopamine to the PFC slice, extracellular signal-regulated kinase, a postsynaptic kinase, is activated,and long-term potentiation is successfully induced, which is the physiological basis of executive function (Kolomiets et al., 2009).As mentioned above, the DAT is responsible for regulating regional dopamine content, and D1R could mediate the transduction of dopamine.Moreover, the content alteration of dopamine could be an initial factor that brings about cognitive defects.Furthermore, in the research related to DAT and glutamate release in PFC,functional change of DAT appears to play an essential role in regulating glutamate release in PFC (Illiano et al., 2021), and thus influences cognition,which is consistent with the notion mentioned above that dopamine may affect local field potential to regulate the cognitive abilities.

Besides affecting synaptic structural remodeling, dopamine modulates neural microcircuits and even the whole neural network.Researchers are now proposing that working memory is essentially the periodic activation of pyramidal neurons in the PFC, which, in other words, could be understood as the electrical conduction enhancement after formation of local neural microcircuits.As one of the neuromodulators, dopamine could regulate the switch state of the ion channel to swiftly and flexibly change the connective efficiency of those synaptic circuits, which is the so-called dynamic network connection.Those networks appear in an ever-changing and intricate activating mode, which is the basis of cognition and offers a hierarchical regulation for attention, behaviors, and motions (Fuster, 2009; Ottand Nieder,2019).Under the premise that the basic synaptic structure will not change,the regulation could, based on the excitatory state, make the synapse “online”or “offline” in the neural network and further harmonize neural systems for the regulation of behavior, mind, and emotion.Among the neurons that constitute the networks, there is one type called “delay cells,” which can save the working memory information for subsequent calling and responding.For example, in a visuospatial delay reactive task, delay cells fire continuously in the delay stage and could project to aimed areas even without visual stimulus (Glantz and Lewis, 2000); thus, we could see their importance in cognitive modulation.From the above, it is informed that dynamic network connection is the basis of cognitive ability.Through electrophysiological and anatomical research on tasks of spatial working memory, we know that the parietal association cortex projects sensory inputs to the PFC, and the repeated excitation of glutamate pyramidal neurons microcircuits could result in the persistent firing of delay cells (Kritzer and Goldman-Rakic, 1995).A further study showed that adjacent neurons with similar functions could keep persistent firing by reciprocal stimulation through connections between their dendritic spines, thus independent of the repeated stimulation of visual sense(Glantz and Lewis, 2000).This obviously strengthens the maintenance of memory.Nevertheless, in the research on dopamine’s role in those courses,it is seen that the dopamine stimulation of D1R bears an inverted U-shape relationship with neuron firing in PFC and working memory performance.That means a high dose of dopamine may reduce cellular firing and impair working memory (Arnsten et al., 1994), whereas a low dose of dopamine or treatment with the D1R antagonist may result in the inability of persistent firing of delay cells and thus, impairment of working memory (Williams and Goldman-Rakic, 1995).Only an appropriate dopamine dose can stabilize the firing pattern of neurons, optimize firing orientation, lessen firing in the nonpreferred direction, and improve the oscillatory coordination of delay cells to make strong responses to stimuli (Sarno et al., 2022), and further strengthen the working memory.This course is mediated by D1R, which first activates the intracellular cyclic adenosine monophosphate/protein kinase A, followed by activation of the hyperpolarized-activated cyclic nucleotide-gate cation channel (Kr?ner et al., 2007; Arnsten et al., 2021), and enhancement of ion channels; finally, the rhythmic activities of clustered neurons is regulated.In addition, the activation of cyclic adenosine monophosphate/protein kinase A could also enhance the function of N-methyl-D-aspartate receptor.Until enough N-methyl-D-aspartate receptor is evoked, a persistent firing would be generated, which plays a critical role in the formation and activation of neural microcircuits (Dallérac et al., 2021).Except that dopaminergic synapses directly regulate the glutamate pyramidal neurons, there is also regulation for fast-spiking interneurons.Dopamine could directly enhance the excitability of fast-spiking neurons so that even a single excitatory postsynaptic potential could locally initiate a spike with high time accuracy (Suarez et al., 2020).From the above, it can be seen that dopaminergic terminals can form a local microcircuit with interneurons and pyramidal neurons.A moderate content of dopamine can regulate the electroactivity of the microcircuit and ensure normal cognitive function.

Synaptic functional disability also broadly impacts the functional connection between cerebral regions, that may change neural networks.Resting-state fMRI has become a widely used technique that can map the functional cerebral networks and improve visualization.Numerous facts confirm that this technique can provide a novel perspective for studying brain network destruction in various neurological and mental diseases.In an rs-fMRI scanning study of 6-hydroxydopamine modeled rats, PD rats were confirmed to contain a change of cerebral functional connection and an evident reduction of cortical functional connection, especially in the FPC.In mPFC, the local efficiency and agglomeration coefficient was significantly reduced, which is consistent with the disconnection of subcortical and cortical dopaminergic neurons (Westphal et al., 2017; Figure 3).

The Factors that Regulate Dopamine Levels in the Prefrontal Cortex

There are many known reasons for regulating dopamine levels in the brain,including age, genetic susceptibility, history of drug abuse, and mental status (Ashby et al., 1999).As the brain undergoes aging, the dopamine level reduces by about 7% every 10 years, and in PD patients, that is at least 70% (Ashby et al., 1999).Owing to the death of dopaminergic neurons in the substantia nigra and VTA, the dopamine level of PFC and striatum gets significantly reduced.However, the question remains whether there are any others that regulate the dopamine level in the physiological state except for the above-stated reasons.After release, the dissociative dopamine will be either reabsorbed into the presynaptic membrane for recycling or decomposed by enzymes.

DAT is a dopamine transporter located in the presynaptic membrane of dopamine neurons that acts as a terminal DA concentration regulator(Giros et al., 1996; Erdozain et al., 2018).DAT provides a rapid and effective mechanism for the reuptake of dopamine in the synaptic cleft, which is highly important for regulating dopamine neurotransmission.A faster reuptake of dopamine, which results in the limited diffusion of dopamine, and a weaker function of receptors are both reasons for weak dopamine effects.A study reported that when dopamine neurons are suddenly activated, the released dopamine could trigger intracellular Rho-GTPase and further result in the internalization of terminal DAT (Lohani et al., 2018).Later, after the task is completed, dopamine would be released at a lower rate.However,because of the internalization of DAT, dopamine can only be recycled at a meager rate, and thus the extracellular dopamine gets accumulated.The persistence of this DA effect results in an ability of slow diffusion to outer areas (Rice and Cragg, 2008), under which premise the activity of more presynaptic and postsynaptic sites in the PFC region could be modulated through spatial transport (Grace et al., 2007).The diffuse dopamine signals can maintain and consolidate the network activated by learning and working memory (Lohani et al., 2018).In addition, the persistent dopamine signal could reduce the threshold of the long-term potentiation of all synapses (Bin Ibrahim et al., 2022) for the adaptive modulation of memory encoding.In the research on working memory related to psychosis, it is also confirmed that individuals, who were bullied in adolescence, are often mentally abnormal and accompanied by working-memory defects.Further exploration also confirmed a severe degradation of dopamine-associated functions in their mPFC, which pertains to the enhancement of DAT expression in this area(Novick et al., 2015).Moreover, DAT knockout mice have poor cognitive flexibility and executive ability (Mallien et al., 2022), which indicates that the presence and functional status of DAT closely influence extracellular dopamine levels and are critical factors that dominate cognitive ability.In that case, the question remains what likely influences DAT status.As mentioned above, the first step is the activation of Ca2+/calmodulin-dependent protein kinase II or intracellular G protein-coupled receptors (Jayaramayya et al.,2020; Underhill and Amara, 2021), which induces the Rho path, leading to internalization of DAT and the alternation of reuptake function.The second candidate is the level of drugs or hormones such as excessive ketamine or androgen (Du et al., 2019) that may reduce DAT expression in PFC and further change mental behavior and cognition (Sun et al., 2019).Although the research focus on this candidate is not purely inclined to advanced cognition like executive ability, they have confirmed the cognitive change followed by the alteration of DAT.The third candidate is the level of protective factors,including brain-derived neurotrophic factors and glial-derived neurotrophic factors.Considerable evidence indicates that brain-derived neurotrophic factor pertains to the plasticity of the synapse and cognition, which is closely related to the dopaminergic path and has extensive influence on neural networks.This suggests that dopamine mediates the regulation of brainderived neurotrophic factor in the cognitive function of the PFC (Koo et al., 2019; Ismail et al., 2020).In addition, another research focusing on the dopaminergic projection in PFC reported that neuregulin1/Erb-B2 receptor tyrosine kinase 4 modulates the DAT on the presynaptic membrane, and activating this path significantly reduces the DAT-dependent uptake of dopamine and thus enhances the extracellular dopamine level (Skirzewski et al., 2018).With another research confirming that glial-derived neurotrophic factor can stimulate axon expression of neuregulin-1 (Esper and Loeb, 2004),there is a possibility that the initial factor is the change of neurotrophic factors.

In PFC, astrocytes play a critical role in regulating dopamine homeostasis.Specifically, the extracellular dopamine is first transported into cells via organic cation transporter 3 (OCT3), later packed into vesicles via vesicle monoamine transporter 2, and finally, metabolized via monoamine oxidase B and COMT to maintain the balance of dopamine in vesicles and cytoplasm,and further maintain a stable level of extracellular dopamine for the stability of neural circuits.The conditional absence of vesicle monoamine transporter 2 in astrocytes may give rise to the loss of dopamine balance in PFC, which leads to the deficiency of vesicles, redundancy of cytoplasmic dopamine,and the activation of dopamine degradative path.The low intracellular dopamine level could further activate DAT on the membrane of astrocytes to take in more dopamine (Mosharov et al., 2003; Karakaya et al., 2007).Finally, because of the low extracellular level of dopamine, the excitability of glutamate neurons is reduced, and the synaptic plasticity is hindered.The number of dendritic spines of pyramidal cells in layer VI is enhanced (which is not conducive to establishing remote connections) (Jia et al., 2013), and these differences result in cognitive disorders (Petrelli et al., 2020) including executive dysfunction.Additionally, the loss of dopamine synapses in the PFC may also be influenced by inflammation.During the course of PD, patients often display a state of low-grade inflammation activation, characterized by abnormal central microglial activation, which further exacerbates dopamine neurodegeneration (McGeer and McGeer, 2004; Madetko et al., 2022).

Figure 3 ｜A series of changes in neural activity including synaptic plasticity, neural microcircuits, oscillations, and neural network connectivity are induced by the weakening of dopamine transmission in the PFC.

Clinical Imaging-Neural Network Studies of Parkinson’s Disease

In recent years, with the increasing popularity of the connectome, brain function studies are becoming more and more diverse.As noted earlier,synaptic dysfunction will have a wide range of effects on functional connections between brain regions in the long run, which could result in a change in neural networks.A previous study recognized PD as a network disease (Kulkarni et al., 2022).fMRI, as a popular technology in cognitive neuroscience, uses MRI to measure hemodynamic changes caused by neuronal activity.Another study showed that there are connective changes in the cerebral network of PD patients, wherein the network connectivity of the frontal cortex and cerebellum reduces, but that of the basal ganglion increases (Sala et al., 2017).In addition, there is an extensive reduction of long-distance connections inside the frontal cortex, all of which suggest connectivity resetting on a scale of the whole brain.In the past few years,more and more neuroimaging researchers have reported the network change in the brain of PD patients.They consistently indicate that diffusion tensor imaging and resting fMRI have confirmed the change in striatal-cortical connectivity.In combination with studies on cognitive function status, it is found that, the connectivity of the default mode network is reduced,which pertains to working memory and visuospatial disorder.Moreover,as fMRI shows that executive disorder of PD patients in working memory tasks is relevant to insufficient activation (Lewis et al., 2003) of the circuits that connect the dorsolateral and ventral PFC, striatum, and thalamus, the relationship of attention network, frontal-parietal network, and execution is confirmed (Lebedev et al., 2014).There is also compensation for excessive activation in other brain regions to maintain the normal working memory in PD patients (Hattori et al., 2022).These indicate that the abnormal neural network connection is a significant factor of cognitive impairment.Therefore,is dopamine abnormal in these networks? Or can it be said that DA affects these networks? An fMRI result showed that the frontal-striatal circuit appears to have reduced activity.However, in this research, no patient appears to have executive dysfunction, which is one of the reasons for the highly activated island and the frontal and parietal lobes that compensate for the loss of dopamine in other circuits (Au et al., 2012).In another research, fMRI was performed, when making working memory tasks, to scan 31 PD patients who did not take dopamine drugs and had normal cognition.The results were compared respectively with the results of drug-treated PD patients and normal individuals, for the validation of whether there is a compensative degeneration of neural network connectivity after treatment with dopamine drugs.The results show that PD patients with normal cognition and without taking drugs have compensative overactivation in the bilateral putamen nucleus and posterior insular lobe, and PD patients with dopamine drug treatment have decreased compensation.Interestingly, the deficiency of this compensation pertains closely to the slow-motion appearance in working memory tasks and the poor cognitive rate in numerical modal tests (Poston et al., 2016), indicating that dopamine-based drugs can change the activation network and modulate working memory ability.Similarly, in studies of brain activation patterns during movement in PD, we describe a consistent diseasespecific pattern of putaminal hypoactivation during motor tasks that appears reversed by dopamine replacement.This also suggests an effect of dopamine on the activity of regions in the neural network (Xing et al., 2020).

Taken together, all the symptom changes of PD have the corresponding network connective changes.The degradation of dopaminergic neurons can result in neural dysfunction and impedance of axonal transport, which causes disorders of transmission release modulation and furthers the disconnection of synapses, thereby ensuring network collapse (Bellucci et al., 2016).In addition, the appropriate and timely supplement could compensate for the loss of network activity.

Conclusion and Perspectives

We summarized the possible manifestations of cognitive impairment in the early stage of PD and introduced the function of the PFC in terms of the neuroanatomy of executive function.In addition, the important effects of dopamine, as a neuromodulator in the PFC, on cluster discharge oscillation,synaptic plasticity, and neuronal microcircuits were analyzed, and the mechanism of dopamine regulation was briefly summarized.We also made a brief summary of the regulation mode of dopamine content and the research of PD clinical neural network, which helps to understand the possible role of dopamine in advanced cognition, helps to explain the mechanism of advanced cognition from the biological point of view, and also provides several hints regarding how dopamine participates in cognitive regulation.

Currently, the clinical classification of PD subtypes primarily relies on the presence of motor impairments.In other words, PD patients with subtypes such as tremor, rigidity, and bradykinesia may also exhibit executive function impairments, but they often show deficits in specific aspects of executive function.For instance, there might be a connection between postural instability and executive control, or executive function could worsen with bradykinesia.

In various PD subtypes, executive function impairments encompass difficulties in higher-level cognitive processes, including planning,decision-making, attention control, and working memory.These cognitive deficits may manifest differently in different subtypes, underscoring the importance of comprehending the heterogeneity of PD presentations.In conclusion, cognitive impairments, especially executive function deficits,warrant thorough investigation across different PD subtypes.Identifying and addressing cognitive deficits in the early stages of PD can facilitate comprehensive management and enhance the quality of life for PD patients.Finally, we expound on the shortcomings of the full paper and the future research focus of the hint as follows: In future, human studies, especially longitudinal studies and long-term follow-up studies, should be strengthened to understand the dynamic changes of PFC dopamine in cognitive regulation of PD.Such studies could provide a more accurate understanding of the association between cognitive impairment and prefrontal dopamine levels, as well as its role in disease progression.Strengthening multimodal neuroimaging research: combining a variety of neuroimaging techniques such as fMRI, electroencephalography, and magnetic encephalography to explore the neural mechanism of dopamine in PFC involved in cognitive regulation.By integrating multimodal information, the role of dopamine in the PFC can be more fully revealed.To study the molecular mechanism of PFC dopamine involved in cognitive regulation, including the role of dopamine receptor subtypes in cognitive function, the regulation of dopamine synthesis and metabolism pathways, etc.These studies contribute to further understanding of the cellular level mechanisms by which PFC dopamine participates in cognition.More attention should be paid to disease subtypes to study the molecular mechanism of PFC dopamine involved in cognitive regulation.Based on the role of PFC dopamine in cognitive regulation this review explores the development of new therapeutic strategies targeting this mechanism.These strategies may include drug therapy, non-invasive brain stimulation, and cognitive training to improve cognitive function in PD patients.Enhanced cooperation and interdisciplinary research: The role of PFC dopamine in cognitive regulation is a complex research field that requires interdisciplinary cooperation, including experts from neuroscience, neurology,cognitive psychology, imaging, and other disciplines.Collaborative research could advance this field and provide a more comprehensive view of our understanding of cognitive dysfunction in PD.

In conclusion, future research directions should focus on strengthening human research, multimodal neuroimaging research, in-depth study of molecular mechanisms, and focus on the differences of disease subtypes.At the same time, it is necessary to develop more effective treatment strategies and comprehensive assessment tools to promote early intervention and treatment of cognitive impairment in PD (Table 1).Interdisciplinary collaboration is an important means to advance this field, and by working together, we can better understand the role of PFC dopamine in cognitive regulation in PD.

Author contributions:Literature search and manuscript writing:ZZ,YY,CTand RS;figure preparation:ZZ,YY,HG and ZL;manuscript revision:CT,HG and KX;review supervision and outline design:CT.All authors approved the final version of the manuscript.

Conflicts of interest:All authors claim that there are no conflicts of interest.

Data availability statement:Not applicable.

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