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Role of Dopamine in Attention Deficit Hyperactivity Disorder

Permission graciously given by the author to reproduce this paper: 

The Impact of Exposure to Methylmercury
on the Fetal Central Nervous System

Julie Fink


Attention is an aspect of cognitive psychology that has been extensively studied for many years.  It has become an important topic of research since the diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) has become widely known and more prominently diagnosed in the populations of children as well as adults.  Researchers have attempted to identify the causes as well as effective treatments for the disorder.  Although the exact mechanisms of the disorder have not been identified it has been apparent that the neurotransmitter dopamine plays a critical role in executive functions; including working memory, inhibition control, motor activity, and attention (Glickstein and Schmauss 2001).  Researchers have found many different effects of dopamine in different brain regions, genetic markers for ADHD, and researched the effectiveness of stimulants for the treatment of ADHD.  This progress in research has led to a better understanding of the disorder as well as more effective treatments.  With continued research a better understanding of how dopamine affects attention and attention deficit hyperactivity disorder can be discovered.  This is an important topic for researchers due to the prevalence of the disorder in children, adolescents, and adults; making it an important topic for society. 

Role of Dopamine in Attention Deficit Hyperactivity Disorder

Attention is an aspect of psychology that has been extensively studied in the domains of cognition, neuroscience, and education.  Attention is defined as the “cognitive process of selectively concentrating on one thing while ignoring other things” (Wikipedia, 2005).  It has become an important topic of research since the diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) has become widely known and more prominently diagnosed in the populations of children as well as adults.  Researchers have attempted to identify the causes as well as effective treatments for the disorder.  Although researchers have not yet identified the exact mechanisms of attention or ADHD it has been agreed upon that the neurotransmitter dopamine plays a critical role in both of their processes (Glickstein and Schmauss 2001).  Along with the neurotransmitter several distinct areas of the brain have also been identified as playing critical roles in different forms of attention.

Attention has been extensively studied for a hundred years.  One of the most famous definitions of attention was developed by a psychologist William James (Wikipedia, 2005).  He stated “Everyone knows what attention is. It is the taking possession by the mind in clear and vivid form, of one out of what seem several simultaneously possible objects or trains of thought...It implies withdrawal from some things in order to deal effectively with others." (Wikipedia, 2005)  During James’ time period the study of attention was conducted using introspection.  Although it was widely discussed by psychologists such as Sigmound Freud, Walter Benjamin, and Max Noordau, very little progress was made.  The study of attention slowed during the years of when behaviorism flurished because the study of cognitive processes such as attention were opposed.  Around the 1950 there was a cognitive boom, and the study of attention came back into focus.  Models of attention were developed and psychologists began developing methods of researching attention.  As the practice of medicine improved, it became popssible to also study attention using advanced imagining techniques.  (Wikipedia, 2005)

Attention Deficit Hyperactivity Disorder (ADHD) is a psychological disorder that is characterized by a dysfuction in attentional processes.  It is characterized by impulsivity, inattention, and hyperactivity.  ADHD is a childhood disorder that is divided into three categories: predominately inattentive type, predominately hyperactive, and a combination of the two (Nevid, Rathus, & Greene, 2003, p. 459).  It is often diagnosed in school settings due to the child having difficulties adjusting to school.  Attention Deficit Hyperactivity Disorder is the most commonly diagnosed pediatric disorder, and is the most common referral for of children to mental health agencies (Bradley & Golden, 2001).  It is believed to affect 5% to 10% of school children in the United States (Scahill, Carroll, & Burke, 2004).  Clearly this is a major public health problem that needs to be studied to idenfity the causes as well as a cure.  ADHD has some controversy due to differences in criteria for diagnosis between the United States and European countries (Biederman & Faraone, 2005). 

ADHD was first discussed in 1845 by Dr. Heinrich Hoffman (NIMH, 2005).  He had published poems that described “Fidgety Philip”, a boy who would be diagnosed as ADHD.  Although Dr. Hoffman was the first to write a poem about a child with ADHD, it wasn’t until 1902 that Sir George F. Still published lectures about impulsive and hyperactive children that displayed significant behavioral problems.  He concluded that their behaviors were due to genetic dysfunction rather than child rearing practices.  (NIMH, 2005)

Inattention seems to be the most common feature, however other problems include inability to sit still for exptended periods of time, temper tantrums, and a failure to respond to punishment (APA, 2000).  The symptoms appear over many months, often with The symptoms of ADHD make it difficult for children to learn in classroom settings.  They fidget in their seats, butt into other’s conversations, throw temper tantrums, and can engage in dangerous behaviors (Nevid, Rathus, & Greene, 2003, p. 460).  Unlike your average child who can be labeled hyper ADHD children are unable to direct their behaviors, or conform to the demands of teachers and parents.  These children are usually of average intelligence, yet they often underachieve in school.  They may fail to follow directions, and can placed into special education classes and may repeat grades.  Although many of these symptoms tend to decrease with age, there is a milder form of ADHD seen in adolescents and adults (Biederman, Mick, & Faraone, 2000). 

Hyperactive children are always on the move and constantly in motion (NIMH, 2005).  They can be seen running around touching every object that is in sight.  Often they talk incessantly about many different topics at the same time.  In settings where they are required to sit for prolonged periods of time, you will see a hyperactive child squirming in his or her seat, and they often will stand and roam around the room.  As an adolescent or adult, hyperactive individuals feel restless and often report feeling the need to stay busy.

Impulsivity is slightly different than hyperactivity.  Impulsive children cannot withhold their reactions before they think about the situation (NIMH, 2005).  They can blurt out commonets, have strong changes in emotions, and act without any thought about the later consequences.  This can make it difficult for the child to wait for items that they want or take turns while playing a game.  For teenagers and adults, impulsivity is seen by individuals acting for small payoffs rather than participating in activities that produce greater rewards but with much larger delays. 

Children who are inattentive cannot concentrate for long periods of time (NIMH, 2005).  They often become bored with tasks shortly after beginning them.  Focusing their attention and completing tasks such as learning can be very taxing.  They can often become distracted by ouside stimuli (APA, 2000).  These children will fail to pay attention and make careless mistakes.  They can jump from one incompleted task to another without finishing any of their work.  These children often appear to be confused, lathargic, and often seen day dreaming (NIMH, 2005).  They have more difficulty processing information as quickly as other children. 

For many years it was blieved that children grew out of ADHD, however it is now believed that ADHD persists into adulthood in 10 %to 50% of childhood patients (Kryger, 2003).  Attention Deficit Hyperactivity Disorder is thought to be a life long affliction that decreases the ability to attend to complex tasks and successful completion of tasks (Paley, 2005).  There does appear to be an age-dependent decline in symptoms,; however even when the symptoms are not severe enough to warrant a diagnosis, they are often associated with impairments in social and behavioral contexts (Biederman & Faraone, 2005).  By the ages between thiry and forty, most individuals will no longer meat the diagnostic criteria for ADHD (Biederman & Faraone, 2005).  Although adults with ADHD are quite self sufficient, they often have poorer academic performance, poorer job performance, which often leads to lower socioeconomic status (Kryger, 2003).  These individuals are at a greater risk for divorce, job changes, change in living environments, and car accidents.  Reports have indicated that ADHD adults have higher levels of distress (79%) and interpersonal problems (Kryger, 2003). 

One of the first questions that many parents and teachers ask about children with Attention Deficit Hyperactivity Disorder is: what is the cause and how do I treat it?  Although there is currently no immediate cure or known cause, the understanding of ADHD is just around the corner due to advances in research, medicine, and neurology.  The past two decades have ushered in advances in noninvasive tools to gain a better understanding of psychological disorders, including ADHD.  The information that has been gained has provided evidence for dysfunction in anatomical and the functional aspects of the brain (Biederman & Faraone, 2005).

Although researchers have not identified the exact cause of ADHD there is significant support for a genetic or neurobiological link (NIMH, 2005).  Family, twin, and adoption studies have demonstrated high familiarity due to genetic links (Hechtman, 1996; Faraone & Biederman, 1998).  Studies have shown that 25% of parents with ADHD will have children with ADHD (Biederman, Faraone, Keenan, Knee & Tsuang, 1990).  This is significantly higher to the percentage in the normal population which is only 5%.   Studies with monozygotic and dizygotic twins have also suggested the strong relationship between genetics and Attention Deficit Hyperactivity Disorder (Faraone & Biederman, 1998).  Monozygotic twins have a significantly higher percentage rate compared to dizygotic twins. 

Molecular genetic studies are being used to explain the complex genetics of ADHD (Biederman & Faraone, 2005).  Genome scans have been run on individuals with ADHD and have searched for regions of the gene that may be linked to Attention Deficit Hyperactivity Disorder (Bakker, van der Meulen, & Buitelaar, 2003).  These researchers found possible genetic links with the chromosomes 7p and 15q.  Another genome study was conducted and it was determined that there were a possible genetic link found with loci 4q13.2, 5q33.3, 11q22, and 17p11 (Acros-Burgos, Castellanos, & Pineda, 2004).  It has been determined that currently there is no strong evidence for a single gene related to the effects of ADHD. 

Along with the genetics researchers are also trying to locate areas within the brain that appear to be related to attention and ADHD.  A single pathway is not expected to be identified, but studies have implicated dysregulations in fronto-subcortical pathways (Levy & Swanson, 2001).  Due to dysfunctions in executive functioning in individuals with ADHD research has looked into frontal subcortical circuits, because it is believed that these areas are involved in inhibition, working memory, interference control, planning, and attention (Barkley, Edwards, Laneri, Fletcher, & Metevia, 2001).  These patterns have led to hypotheses related to neurological dysfunctions and Attention Deficit Hyperactivity Disorder.  However, no single theory is able to account for all of the symptoms found in individuals with ADHD. 

A study using Magnetic Resonance Imaging (MRI) showed that boys with ADHD had distinct areas of the brain that were smaller than aged norms (Asher, 1996).  The three areas that were significantly smaller all occurred on the right side of the brain.  Those three areas were prefrontal cortex, caudate nucleus, and globus pallidus.  The right hemisphere of the brain is believed to perform executive functions, making the connection between the lack of inhibitory behaviors with Attention Deficit Hyperactivity Disorder and the smaller brain regions.

Another study using quantitative MRI with adults with ADHD found differences in the total cerebral volume between the ADHD group and norms (Castellanos, Giedd, & Marsh, 2001).  Individuals with ADHD had a lower total cerebral volume and had less asymmetry in the size of the caudate nucleus.  Besides the total volume, the researchers also found decreased volumes in the right globus pallidus, right anterior frontal region and cerebellum.

Along with actual differences in size of ADHD brains, studies have also found differences in activation and functioning of different areas of the brain.  One area within the brain that has been greatly studied is the prefrontal cortex (Chevins, 2001).  Imaging studies have found this area to be underactive in children with ADHD compared to normal children.  Along with the prefrontal cortex, researchers have also found differences in the activation of the caudate nucleus and globis pallidus (Chevins, 2001).  Both the caudate nucleus and the globis pallidus are located near the center of the brain. They are believed to control the incoming information to the prefrontal cortex.  This under activation could produce the impulsivity seen in many individuals with Attention Deficit Hyperactivity Disorder.

PET studies allow for researchers to measure the activation of different areas within the brain during cognitive tasks.  Adults with ADHD were compared to normal adults during a conflict task (Bush, Frazier, & Rauch, 1999).  The normal adults showed more activation in the anterior cingulate cortex compared to the ADHD adults.  The ADHD individuals showed activation in a different area of the brain, the anterior insula, which is associated with more routine tasks.  In a follow up study by Bush, Spencer, and Holmes (2003) PET scans were used to look at the effects of methylphenidate on the brain.  They found that after administration of methylphenidate the brains of ADHD patients showed activation of the anterior cingulated cortex similar to that of healthy adults.

Dopamine was first discovered in the late 1950s (Scahill, Carroll, & Burke, 2004).  Since its discovery much research has gone into understanding the effects that dopamine has on human behavior and mood.  The role of dopamine in ADHD was first addressed after the beneficial affects of drugs used to treat this disorder (Biederman & Faraone, 2005).  There have been several lines of research and evidence that implicated the neurotransmitter dopamine in the pathogenesis of Attention Deficit Hyperactivity Disorder (DiMaio, Grizenko & Joober, 2003).  Neurotransmitters are chemical signals that pass information to and from neurons within the brain (Chevins, 2001).  Disruptions in any of the neurotransmitter systems can greatly affect mood and behaviors in individuals. 

It is believed that there are currently five different subtypes of dopamine receptors within the brain (Scahill, Carroll, & Burke, 2004).  The dopamine receptors are found on both presynaptic and postsynaptic locations.  The receptors on the presynaptic locations are involved in the production and release of dopamine into the synapse.  The receptors on the postsynaptic locations are responsible for removing the dopamine from the synapse.

Animal lesion studies have also provided evidence for the role of dopamine in Attention Deficit Hyperactivity Disorder.  One animal lesion study showed that rats with lesions in their dopamine pathways developed ADHD symptoms (Shaywitz, Cohen, & Shaywitz, 1978).  Another study that provided further evidence for the dopamine hypothesis is an animal model for a spontaneously hyperactive rat (Sagvolden, 2000).  Using in vivo measures this rat showed dopamine release dysfunctions in subcortical structures.

Many psychotropic medications, such as amphetamine and methylphenidate (Ritalin), which increase the amount of dopamine in the synapse, effectively control the symptoms of ADHD.  This make a strong proposal for a dopamine deficiency and the unset of symptoms of ADHD.  Stimulants are effective in 80% to 90% of children with Attention Deficit Hyperactivity Disorder, and it is considered a first line treatment for the disorder (Scahill, Carroll, & Burke, 2004). 

Methylphenidate is a stimulate that promotes the release of stored dopamine and also prevents the reuptake of dopamine into the presynaptic nerve endings (Scahill, Carroll, & Burke, 2004).  One imaging study found that when healthy adults were given an oral administration of methylphenidate (5mg) they had an average of 12% of the dopamine transporter filled with the drug after two hours; and 74% when given a dosage of 60mg of methylphenidate (Scahill, Carroll, & Burke, 2004).  Amphetamines have a slightly different role on dopamine neurons.  Amphetamines also block the reuptake of dopamine like methylphenidate, but they are more selective in the synthesis of new dopamine. 

Methylphenidate (Ritalin) is the most commonly prescribed medication for children with ADHD (Volkow, Wang, Fowlers, Logan, Gerasimov, Maynard, Ding, Gatley, Gifford, & Franceschi, 2001).  Researchers have recently discovered the mechanisms behind the therapeutic benefits of this medication.  One study used positron emission tomography (PET) scan to determine if oral administration of methylphenidate increases the synaptic dopamine.  The findings proved that oral administration of the medication is able to increase the dopamine levels within the brain to significantly affect the symptoms of ADHD.  The increase in dopamine is achieved by methylphenidate blocking the dopamine transporters.  The researchers postulated that the normally weak signal from dopamine is enhanced by methylphenidate, thus improving attention and decreasing the individual’s distractibility. 

In another study using a positron emission tomography (PET) scan and the effects of methylphenidate on the brain were studied (Paley, 2005).  The study reported that methylphenidate increases dopamine within the synapse of neurons by increasing the secretion of the neurotransmitter.  The researchers were able to measure the dopamine release while individuals performed complex tasks, or simply stared at pictures.  The task involving viewing the pictures did not increase brain dopamine, but the task that involved the complex mathematical problems increased dopamine significantly in both the drug and placebo group.  Treatment with Ritalin increased the dopamine flow as well as improved the patients’ concentration. 

Along with studies involving psychotropic medications, different functional neuro-imagining studies have shown that children with ADHD have abnormalities in areas within the brain that are rich with dopamine neurons, or dopamine projections.  Also, numerous animal studies have shown a connection between ADHD and abnormalities of the dopamine neurotransmitter system (Goldman-Rakic, Muly, & Williams, 2000).  Deficiencies in the neurotransmitter system for dopamine would create a need for individuals with ADHD to seek chemicals or behaviors that would help to elevate the dopamine levels, such as attention seeking behaviors and drug addiction (Chevins, 2001). 

Researchers have used single-photon emission computed tomography (SPECT) to look at dopamine neurons within the brains of ADHD individuals.  One study looked at the dopamine transporters (Paley, 2005).  The role of the transporters is to remove dopamine from the synapse of neurons within the brain.  The more transporters in the brain, the less dopamine is found within the synapses.  Individuals with ADHD were found to have significantly more dopamine transporters compared to norms when visualized under SPECT.
 In another neuron-imaging study children with ADHD were monitored during a steady state condition (Teicher, Polcari, & Anderson, 2003).  This study used a T2 relaxometry measure (fMRI procedure) to measure the blood flow in the caudate and the putamen.  Boys with ADHD had significantly higher T2 relaxation times compared to norms.  This relaxation time was correlated with the amount of time the child was able to remain seated and still during the procedure.  When the boys were treated with methylphenidate their relaxation times increased.

In a similar study conducted by Anderson, Polcari, and Lowen (2002), they reported that methylphenidate significantly decreased cerebral blood flow in the cerebellar vermis of objectively hyper ADHD boys.  The drug had the opposite effect on boys who were not objectively hyper.  The study reported that the higher the dosage of methylphenidate, were rate dependent with the child’s cerebral blood flow and objective hyperactivity. 

Due to the increasing evidence that Attention Deficit Hyperactivity Disorder has a genetic basis, many scientists have tried to identify the gene that is responsible for this disorder.  It is also believed that more than one gene could regulate this disorder, especially since there are three different types of ADHD (Chevins, 2001).  One gene that has been studied is the dopamine transporter gene (SLC6A3) (Giros, Jaber, Jones, Wightman, & Caron, 1996).  This gene has been studied because it is theorized to be inhibited by methylphenidate.  Giros et al. (1996) developed a knock out mouse that displayed behaviors similar to ADHD characteristics.  Those mice were more hyperactive and displayed higher levels of motor activity compared to wide type mice.  When the knock out mice were treated with amphetamine or methylphenidate, their behaviors calmed.  Also they found that the knock out mice had higher levels of extracellular dopamine than the wide type mice. 

Xu, Moratalla, Gold, Hiroi, Koob, and Graybiel (1994) looked at the association between the dopamine receptor 1 (D1R1) and attention deficit hyperactivity disorder.  The researchers used mutant D1R1 mice in the study.  The D1R1 mice exhibited heightened locomotor activity compared to wild type mice used as a norm.  Unlike the previous study though, these mice did not respond to dopamine agonists or antagonists.  This indicated that the D1 receptors need to be unaltered to function properly in the expression of normal motor activity.  Another study that also looked at the D1 receptors found that the receptors in the prefrontal cortex are also associated with attention (Goldman-Rakic, Muly, & Williams, 2000).  They also reported that the D1 receptors in the prefrontal cortex were also associated with deficits in working memory, which have been associated with ADHD. 

Other researchers interested in the genetics of Attention Deficit Hyperactivity Disorder have looked at the role of the dopamine D3 receptor (DRD3).  One study with animals showed that the DRD3 mRNA is overly expressed in the ventral striatum (Sokolof, Giros, Martres, Bouthenet, & Schwartz, 1990).  This expression is believed to play a role in the control of motor behavior.  This role could be linked to the excessive motor activity that is seen in individuals with ADHD.  Another animal model of the DRD3 gene used mutant mice that were lacking this gene (Accili, Fishburn, & Drago, 1996).  These mice displayed hyperactive behaviors in numerous settings.  Another supporter for dysfunction in the DRD3 gene is the treatment of ADHD with 7-OH-DPAT, a dopaminergic agonist that binds to the D3 receptors (Lundstrom & Turpin, 1996).  When this medication is administered it decreases motor activity and hyperactivity. 

Other researchers have looked at the dopamine D4 receptor (DRD4) in the implication of ADHD symptoms (Faraone & Biederman, 1998).  The dopamine D4 receptors are prevalent in the frontal-subcortical networks of the brain that have been implicated in ADHD.  It has been identified that the DRD4 receptors have variations with the 7 repeat allele.  This difference produces a blunted response to dopamine within the brain.  This difference was also found more often in family studies compared to case controls.

There have been many different theories proposed for attention deficit hyperactivity disorder.  One such theory states that individuals with ADHD have problems with inhibition of irrelevant information (Casey, Castellanos, & Giedd, 1997).  They found that children with ADHD showed differences in their performance on response inhibition tasks.  While completing these tasks the researchers also recorded MRI measures from the front-striatal circuitry.  They found a role for inhibitory effects in the right prefrontal cortex, and the basal ganglia to be involved in the execution of responses. 

Another theory, that is similar to the one previously stated, involves the right sided frontal-striatal dysfunction (Heilam, Kytja, Voeller, & Nadeau, 1991).  The theory proposed by Heilam, Kytja, Voeller, and Nadeau (1991) stated that the dysfunctions found in ADHD are due to impairments in the mesocortical dopamine system.  The researchers proposed that the impulsivity and hyperactivity that are found in ADHD are related to low thresholds for gating behavior.  Due to this the researchers believed that methylphenidate relieves the systems of ADHD by interceptive stimuli relevant to the task being performed at that time. 

Even though researchers can agree that dopamine appears to play a critical role in attention and thus ADHD, they cannot agree upon the exact mechanisms of the neurotransmitter.  Currently there are two theories: a hyper-dopaminergic and hypo-dopaminergic theory (Levy & Swanson, 2001).  The hypo-dopaminergic theory states that there are lower than normal concentrations of dopamine in the synapses of the brain.  One example to support the hypo-dopaminergic theory was a study conducted by Levy and Hobbes (1996).  The have shown that haloperidol is able to block the normalizing effects of methylphenidate in children diagnosed with ADHD using a continuous performance test. 

Also supporting the hypo-dopaminergic theory is research conducted by LeMoal and Herve (1991).  These researchers have stated that ADHD is likely to be linked to low concentrations of dopamine, because dopamine is responsible for the temporal integration of external cues and motor performance.  Low levels of dopamine would produce increased motor activity and reactivity to external cues.  They also postulated that it is involved in the functions of working and spatial short term memory.  They believe that the dopamine neurons act as a filtering process for signals from the ventral and dorsal striatum to the neocortex.  When there is not enough presynaptic dopamine these signals cannot be transferred as well, providing evidence for the disinihibition of ADHD symptoms. 

More support for the hypo-dopaminergic theory is the idea that Attention Deficit Hyperactivity Disorder results from abnormally low tonic levels of dopamine activity (Grace, 2001).  These low levels of tonic dopamine in the ventral striatum and nucleus accumbens lead to abnormally high phasic dopamine response.   To provide support for this it is believed that the dorsolateral prefrontal cortex projects to the striatum and is responsible for the proper functioning of working memory.  Thus, a decrease in tonic dopamine would be consistent with the working memory deficits seen in ADHD individuals.

Additionally Sagvolden, Aase, and Johnasen (2000) proposed a hypo functioning dopamine system.  They stated that a hypo functioning mesocortical dopamine system would produce frontal cortical hypo functioning.  This would in turn create a cognitive impulsiveness.  Also it would produce a shorter delay of reinforcement gradient producing decreases in attention, along with hyperactivity and motor impulsiveness.  They also stated that a hypo functioning nigro-striatal dopamine system can cause dysfunctions in motor control. 

Other researchers proposed that there is a hyper-dopaminergic theory to ADHD in which there is an excessive level of dopamine in the synapses.  One study created mutant mice that reduced the expression of the dopamine transporter (DAT) (Zhaung, Oosting, Jones, Gainetdinov, Miller, Caron, & Hen, 2001).  In vivo microdialysis studies indicated that these mice had higher levels of extracellular dopamine within their brains compared to wild type rats.  These rats displayed hyperactivity and impaired response habituation to new stimuli.  Also when these rats were treated with stimulants their motor activity became more inhibited, still providing evidence for the effectiveness of stimulants for the treatment of ADHD. 

ADHD has become a highly studied psychological disorder in the 20th century due to its prevalence and recent media coverage.  Although much research has gone into the understanding and development of Attention Deficit Hyperactivity Disorder, researchers still have not identified clear mechanisms for the disorder.  Researchers have linked several brain areas including the prefrontal cortex, caudate nucleus, and globus pallidus in the regulation of executive functions including working memory, inhibition, attention, and motor activity.   Researchers have also implemented the neurotransmitter dopamine in the regulation of attention and ADHD.  While much has been learned through functional neuron-imaging studies, animal models, and psychotropic medications, continued research still needs to be conducted to gain a more accurate understanding of this disorder.  ADHD can affect children, adolescents, and adults, making this a health concern for everyone.  Gaining a better understanding of the mechanisms can improve treatments and also assist in preventing Attention Deficit Hyperactivity Disorder.


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