NEUROCHEMICAL DEFICITS AND DYSFUNCTION IN THE FRONTAL LOBE
By Lucinete Messina
In the late 60 much was known about ADHD, but the lack of new evidence linking the syndrome to the biological bases began to create discussions on the existence of the syndrome. Many believed that the disorder was an attempt to rid the country of the blame for spoiled and badly behaved children. After this period of uncertainty, new discoveries began to be made linking the problems associated with ADHD with certain types of neurotransmitters.
In 1970 apud Kornetsky of Stubbe, 2000 proposed the hypothesis that ADHD may be linked to problems with neurotransmitters such as dopamine and norepinephrine. More recently Carter, Kren, Chaderjian Nortycutt and Wolfe (1995), found that the regions that are closely associated with ADHD when studying the brain functioning pattern of distribution of the neurotransmitter dopamine includes the superior colliculus, the thalamus, the parietal lobe wolf frontal and anterior cingulate gyrus. For better understanding, Swanson, Posner, Cantwell, Wigal, Crinella, Filipek, Emerson, & Tiucker Nalcioglu (1998) developed a scheme that provides a simplified way the correlation between symptoms of ADHD and the brain areas involved (see Table 2).
Table 2. Correlation between ADHD symptoms and brain area involved.
symptoms
Neural Network
Difficulty sustaining attention
Right frontal lobe
It does not end tasks
Right posterior parietal lobe
Avoid tasks that require sustained mental effort
locus coeruleus
Easily distracted by extraneous stimuli
Bilateral parietal lobe
Seem not to hear
superior colliculus
Fail to maintain attention to detail
thalamus
responds precipitously
Anterior cingulate region
Interrupts or intrudes on others' affairs
Left lateral frontal region
Difficulty waiting turn
basal ganglia
symptoms
Neural Network
Difficulty sustaining attention
Right frontal lobe
It does not end tasks
Right posterior parietal lobe
Avoid tasks that require sustained mental effort
locus coeruleus
Easily distracted by extraneous stimuli
Bilateral parietal lobe
Seem not to hear
superior colliculus
Fail to maintain attention to detail
thalamus
responds precipitously
Anterior cingulate region
Interrupts or intrudes on others' affairs
Left lateral frontal region
Difficulty waiting turn
basal ganglia
Fonte: Swanson, J.; Posner, M.I.; Cantwell, D.; Wigal, S., Crinella, F., Filipek, P., Emerson, J., Tucker, D., Nalcioglu, O. 1998: Attention-Deficit/Hyperactivity Disorder: Symptom Domains, Cognitive Process, and Neural Networks. In: Parasuraman, R. (ed) The Attentive Brain, Massachusetts, A Bradford Book, p.455.
In the 1980s, several authors like Mattes, Gualtieri and Chelune (1984) cited in the Stubbe, speculated on the involvement of the frontal lobes in ADHD due to the similarity of symptoms presented by patients with ADHD and those who suffered damage to the frontal lobes due to accidents or other problems. In 1984, Lou, Henriksen, and Bruhn found evidence of a deficiency of blood flow in the frontal lobes and left hemisphere of people with ADHD. All these findings were confirmed in 1993 by Zametkin et al. through the development of new technologies such as PET (Positron Emission Tomography) which showed brain function in vivo. Through examination of PET comparing people diagnosed with ADHD and controls, Zametkin noted that the brains of people with ADHD had an energy about 8% lower than normal and that the areas most affected were the prefrontal lobes and pre-engines, which are responsible for regulating and controlling behavior, impulses and acts based on information received from more primitive areas of the brain as the thalamus and limbic system. As these new evidence was clear that ADHD was actually associated with changes in brain metabolism, finally ending with doubt about the real existence of the syndrome and its biological link.
Several studies using special techniques of neuroimaging have revealed an impairment of the frontal lobe and subcortical structures (caudate and putamen) relating thereto (Garmichael and Amen, 1997). Carter et. al. (1995) showed an asymmetry of the prefrontal cortex, which usually involves clarifying that the right prefrontal cortex is slightly larger than the left, and these patients would be a reduction in the right prefrontal cortex. This means that ADHD presents a hypo-functioning in the areas where the greatest concentration of dopamine, thus reflecting a likely decline in the action of the fronto-striatal catecholamine, mainly the right cerebral hemisphere (Garmichael and Amen, 1997).
Many researchers believe that ADHD is a problem of chemical imbalance in the brain and a recent study added to the apparent improvement achieved by psychopharmacology seem to confirm this hypothesis (Castellanos, Giedd, Ellia al. Et al. 1997b; Faraone al. Et al. 1998; Swanson al. et al., 1998).
Of the various known neurotransmitters believed to be involved in ADHD dopamine and norepinephrine. Speaks in favor of this hypothesis the fact that the drugs can lessen the symptoms of ADHD (especially psychic stimulants such as methylphenidate and d-amphetamine) are substances that increase the amount of available dopamine and norepinephrine in the brain (Castellanos, Giedd, Ellia, Marsh, Ritchie, Hamburger, Rapport 1997b; Comings, Wu, Chiu, Ring, Gad, Ahn, Macmurray, Dietz, Muhleman 1996).
Some molecular studies focusing on the neurotransmitter dopamine found that impulsive and compulsive behaviors especially in people with Tourette Syndrome and ADHD are associated with the gene for dopamine type "a" and "two" (D1 and D2) (Knell and Comings 1993; Correia and Rohde, 1998; Swanson, Sunohara, Kennedy, Regino, Fineberg, Wigal, 1998). These genes (D1 and D2) were candidates for initial investigations, as the carrier protein is inhibited by stimulants used to treat ADHD. Another gene in the dopaminergic system investigated in this disorder is the gene for dopamine D4 receptor (DRD4), was observed at 7-repeat allele of the DRD4 gene may be associated with the change of personality (humor) and "novelty seeking" . In addition, the product of this gene is concentrated in areas of the brain whose functions are implicated in disease symptoms. Children with repetition of this allele can easily feel bored in the absence of highly stimulating conditions, with an aversion to protracted situations and do not like to wait (Faraone, Biederman, Weiffenbach, Keith Chu, Weaver 1999; Jesena, 2000, Swanson et al. al., 2000, Swanson et al. al., 1998). Comings et al. (1996) and Comings, Gade-Andavolu, Gonzalez, Blake, Wu, Macmurray (1999), found that the gene for dopamine b-hydroxylase (DBH) (noradrenergic system genes) has been associated with social problems and learning disabilities, oppositional defiant and aggressive behavior often observed in subjects with ADHD.
The gene DBH converts dopamine to norepinephrine and low levels of this enzyme in the blood have been associated with ADHD and conduct disorder. These studies have to confirm that no evidence of an involvement of serotonin in ADHD. So is that the serotonergic agents, such as fluoxetine and other, although they may be useful in treating co-morbid conditions such as anxiety and depressive disorders, have no effect on the core symptoms of ADHD (Anderson, Dover, Yang 2000).
To better understand this study will be necessary to review the paradoxical aspects of the disorder ADHD, and there are several among them two prominent it should be noted: the fact is not necessarily the sign marked inattention (may be maladaptive, anti-sociability and aggressiveness); as well as being a psychostimulant (methylphenidate and pemoline that's not available in Brazil) that has the best drug treatment outcomes. The psychostimulant that acts preferentially in the increased activity of dopamine, could be responsible for activating circuits linked to attention and synchronization of the thalamus to the frontal cortex, the general mechanism of attention / concentration voluntary.
However, both the lack of attention may not be the predominant element, as well as the use of psychostimulants can trigger a calming effect and not exciting, as one would expect. Methylphenidate and other stimulant drugs of its kind, act by blocking the reuptake of dopamine, which in principle has the effect of enhancement of motor activity and / or intellectual and hardly calming or antidepressant (typically tied to action in two other classes of neurotransmitters: norepinephrine and serotonin) (Bennett, Brown, Graver, 1999 Anderson, Berman, Douglas, Barr, 1999; Biederman, Faraone, Mick Moore, Lelon, 1996; Buitelaar, Van Der Gaag, Swaab-Barneveld, Kuiper 1995, 1998 Carom, Zrull 1967, Zrull, Posnansky 1970).
Given these many apparent paradoxes lies a consideration of the brain and complexity. Higher nervous functions, among which stands out behavior, learning, sociability, mood, thinking and values and tend to interconnect so that punctual and linear reasoning can commit adultery and impoverish the clinic and research. Because it is strongly non-linear dynamics of interaction of neuronal populations responsible for higher functions, paradoxes are not always scary, but only evidence of complexity and interaction between different systems and different brain neurotransmitters (Carom 1998, Popper 1997).
Confirming this feature multiconectado a brain and complex, which sometimes scares us in the face of so-called "paradoxical reactions", a recent article on ADHD has shed light on the role of methylphenidate and other psychostimulants in the treatment of similar problems.
Gainetdinov (1999) published the article "Role of Serotonin in the Paradoxical Calming Effect of Psychostimulants on Hyperactivity" (The role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity). The researchers, in a brilliant series of experiments, rats are able to select a substance that does not have the DAT (dopamine transporter), which carries the dopamine neuron to the synapse and thence back to the neuron that produced it. DAT-deficient mice, which can be obtained through genetic manipulation laboratory, exhibit features markedly similar to those of ADHD, including hyperactivity and different reactions in the face of new environments that require conditioning, operation and faster response time after learning.
Although mice with DAT exhibit high concentrations of dopamine in the striatum cortex (primarily responsible for motor skills), it is shown through a series of experiments, that the action of methylphenidate and other psychostimulants has no role in dopamine and serotonin but in the would explain its role soothing. Is not the place to report the complexity of the methods employed, although it should be noted its elegance and consistency.
Given this fact, one could point to another role of methylphenidate in the treatment of ADHD, which would be better replaced by direct action of drugs on serotonin (fluoxetine, paroxetine, clomipramine, sertraline, etc..) Which is not totally true in clinical terms. These substances tend to have poor results compared to the results of psychostimulants. A possible compromise comes from the fact that there are many subtypes of serotonin receptors in the brain, which could explain the fact that a drug acting on some of them and one other, and therefore, the first effective for the control of hyperactivity and another for the treatment of anxiety or binge eating (sibutramine case).
Although the data of these investigations are not yet definitive, they are consistent with the idea that dopaminergic and noradrenergic changes have an important role in the pathophysiology of ADHD. Barkley (1997) proposes a unifying theory for such systems, the central deficit in ADHD would be a failure of behavioral inhibition and, consequently, the other executive functions.
This failure would cause the symptoms seen in patients, such as hyperactivity, inattention and impulsivity. That is, the above experiments suggest new directions for research and pharmacotherapy in the treatment of ADHD, and shows that rather than being a disorder of attention or hyperactivity, which is at stake, says Barkley, one of the world's authorities on the problem, is a disorder of resource allocation and cognitive self-monitoring. In this sense, it is difficult to complete that therapy is limited to pharmacological intervention, should be added the psychotherapeutic process.
The brain is so complex shows, in this case ADHD in two directions: either that in which the neurotransmitters and their subtypes interact in a way that may seem paradoxical, but in need of assistance being focussed on the individual and on their environment in order to remedy the problem or at least understand it in its entirety and undertake all actions that reduce the consequences of poor performance functional.
Several studies using special techniques of neuroimaging have revealed an impairment of the frontal lobe and subcortical structures (caudate and putamen) relating thereto (Garmichael and Amen, 1997). Carter et. al. (1995) showed an asymmetry of the prefrontal cortex, which usually involves clarifying that the right prefrontal cortex is slightly larger than the left, and these patients would be a reduction in the right prefrontal cortex. This means that ADHD presents a hypo-functioning in the areas where the greatest concentration of dopamine, thus reflecting a likely decline in the action of the fronto-striatal catecholamine, mainly the right cerebral hemisphere (Garmichael and Amen, 1997).
Many researchers believe that ADHD is a problem of chemical imbalance in the brain and a recent study added to the apparent improvement achieved by psychopharmacology seem to confirm this hypothesis (Castellanos, Giedd, Ellia al. Et al. 1997b; Faraone al. Et al. 1998; Swanson al. et al., 1998).
Of the various known neurotransmitters believed to be involved in ADHD dopamine and norepinephrine. Speaks in favor of this hypothesis the fact that the drugs can lessen the symptoms of ADHD (especially psychic stimulants such as methylphenidate and d-amphetamine) are substances that increase the amount of available dopamine and norepinephrine in the brain (Castellanos, Giedd, Ellia, Marsh, Ritchie, Hamburger, Rapport 1997b; Comings, Wu, Chiu, Ring, Gad, Ahn, Macmurray, Dietz, Muhleman 1996).
Some molecular studies focusing on the neurotransmitter dopamine found that impulsive and compulsive behaviors especially in people with Tourette Syndrome and ADHD are associated with the gene for dopamine type "a" and "two" (D1 and D2) (Knell and Comings 1993; Correia and Rohde, 1998; Swanson, Sunohara, Kennedy, Regino, Fineberg, Wigal, 1998). These genes (D1 and D2) were candidates for initial investigations, as the carrier protein is inhibited by stimulants used to treat ADHD. Another gene in the dopaminergic system investigated in this disorder is the gene for dopamine D4 receptor (DRD4), was observed at 7-repeat allele of the DRD4 gene may be associated with the change of personality (humor) and "novelty seeking" . In addition, the product of this gene is concentrated in areas of the brain whose functions are implicated in disease symptoms. Children with repetition of this allele can easily feel bored in the absence of highly stimulating conditions, with an aversion to protracted situations and do not like to wait (Faraone, Biederman, Weiffenbach, Keith Chu, Weaver 1999; Jesena, 2000, Swanson et al. al., 2000, Swanson et al. al., 1998). Comings et al. (1996) and Comings, Gade-Andavolu, Gonzalez, Blake, Wu, Macmurray (1999), found that the gene for dopamine b-hydroxylase (DBH) (noradrenergic system genes) has been associated with social problems and learning disabilities, oppositional defiant and aggressive behavior often observed in subjects with ADHD.
The gene DBH converts dopamine to norepinephrine and low levels of this enzyme in the blood have been associated with ADHD and conduct disorder. These studies have to confirm that no evidence of an involvement of serotonin in ADHD. So is that the serotonergic agents, such as fluoxetine and other, although they may be useful in treating co-morbid conditions such as anxiety and depressive disorders, have no effect on the core symptoms of ADHD (Anderson, Dover, Yang 2000).
To better understand this study will be necessary to review the paradoxical aspects of the disorder ADHD, and there are several among them two prominent it should be noted: the fact is not necessarily the sign marked inattention (may be maladaptive, anti-sociability and aggressiveness); as well as being a psychostimulant (methylphenidate and pemoline that's not available in Brazil) that has the best drug treatment outcomes. The psychostimulant that acts preferentially in the increased activity of dopamine, could be responsible for activating circuits linked to attention and synchronization of the thalamus to the frontal cortex, the general mechanism of attention / concentration voluntary.
However, both the lack of attention may not be the predominant element, as well as the use of psychostimulants can trigger a calming effect and not exciting, as one would expect. Methylphenidate and other stimulant drugs of its kind, act by blocking the reuptake of dopamine, which in principle has the effect of enhancement of motor activity and / or intellectual and hardly calming or antidepressant (typically tied to action in two other classes of neurotransmitters: norepinephrine and serotonin) (Bennett, Brown, Graver, 1999 Anderson, Berman, Douglas, Barr, 1999; Biederman, Faraone, Mick Moore, Lelon, 1996; Buitelaar, Van Der Gaag, Swaab-Barneveld, Kuiper 1995, 1998 Carom, Zrull 1967, Zrull, Posnansky 1970).
Given these many apparent paradoxes lies a consideration of the brain and complexity. Higher nervous functions, among which stands out behavior, learning, sociability, mood, thinking and values and tend to interconnect so that punctual and linear reasoning can commit adultery and impoverish the clinic and research. Because it is strongly non-linear dynamics of interaction of neuronal populations responsible for higher functions, paradoxes are not always scary, but only evidence of complexity and interaction between different systems and different brain neurotransmitters (Carom 1998, Popper 1997).
Confirming this feature multiconectado a brain and complex, which sometimes scares us in the face of so-called "paradoxical reactions", a recent article on ADHD has shed light on the role of methylphenidate and other psychostimulants in the treatment of similar problems.
Gainetdinov (1999) published the article "Role of Serotonin in the Paradoxical Calming Effect of Psychostimulants on Hyperactivity" (The role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity). The researchers, in a brilliant series of experiments, rats are able to select a substance that does not have the DAT (dopamine transporter), which carries the dopamine neuron to the synapse and thence back to the neuron that produced it. DAT-deficient mice, which can be obtained through genetic manipulation laboratory, exhibit features markedly similar to those of ADHD, including hyperactivity and different reactions in the face of new environments that require conditioning, operation and faster response time after learning.
Although mice with DAT exhibit high concentrations of dopamine in the striatum cortex (primarily responsible for motor skills), it is shown through a series of experiments, that the action of methylphenidate and other psychostimulants has no role in dopamine and serotonin but in the would explain its role soothing. Is not the place to report the complexity of the methods employed, although it should be noted its elegance and consistency.
Given this fact, one could point to another role of methylphenidate in the treatment of ADHD, which would be better replaced by direct action of drugs on serotonin (fluoxetine, paroxetine, clomipramine, sertraline, etc..) Which is not totally true in clinical terms. These substances tend to have poor results compared to the results of psychostimulants. A possible compromise comes from the fact that there are many subtypes of serotonin receptors in the brain, which could explain the fact that a drug acting on some of them and one other, and therefore, the first effective for the control of hyperactivity and another for the treatment of anxiety or binge eating (sibutramine case).
Although the data of these investigations are not yet definitive, they are consistent with the idea that dopaminergic and noradrenergic changes have an important role in the pathophysiology of ADHD. Barkley (1997) proposes a unifying theory for such systems, the central deficit in ADHD would be a failure of behavioral inhibition and, consequently, the other executive functions.
This failure would cause the symptoms seen in patients, such as hyperactivity, inattention and impulsivity. That is, the above experiments suggest new directions for research and pharmacotherapy in the treatment of ADHD, and shows that rather than being a disorder of attention or hyperactivity, which is at stake, says Barkley, one of the world's authorities on the problem, is a disorder of resource allocation and cognitive self-monitoring. In this sense, it is difficult to complete that therapy is limited to pharmacological intervention, should be added the psychotherapeutic process.
The brain is so complex shows, in this case ADHD in two directions: either that in which the neurotransmitters and their subtypes interact in a way that may seem paradoxical, but in need of assistance being focussed on the individual and on their environment in order to remedy the problem or at least understand it in its entirety and undertake all actions that reduce the consequences of poor performance functional.
