Saturday, March 03, 2007

Juan Rodriguez :: ADHD: A Dopamine dysfunction

Juan Rodriguez

When carefully observed it becomes apparent he restlessly paces when thinking and fidgets while sitting. In his mind, a thousand random thoughts whiz by each other with no mechanism for screening out irrelevant information. He blurts out thoughts and interrupts conversations. His lack of restraint is even more so evident by his excessive impulsiveness, a tendency towards distractibility that leads him to perpetually procrastinate. Despite his neurotic behavior, he is capable of deep, creative thoughts that always manifest themselves in an unpredictable fashion and unexpected times. At his core, he is driven to tackle as many challenges as possible, but is then inevitably sidetracked by an intrinsic allure of intense and novel experiences. Although severely prone to distraction, he does not rest until his objective is complete.

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Relation to other psychological disorders
ADHD is a member of a larger family of neuropsychiatric disorders that are localized in the same region of the brain. There is genetic evidence linking ADHD to other disorders such as Tourette’s syndrome, autism, and hereditary alcoholism. Furthermore, bipolar disorder and chronic depression are so closely related to ADHD that it is difficult to distinguish the disorders in adults because of their overlapping symptoms. To further complicate the matter, comorbidity of these disorders is common, especially when substance abuse is also involved. ADHD has been linked with a tendency toward substance abuse, but it is not usually diagnosed when addiction is involved because the effects of the drug abuse tend to mask the underlying problem of ADHD. Afflicted individuals often use alcohol, marijuana, and cocaine to “self-medicate.” Although these drugs provide temporary relief from the anxiety, irritability, and inattentiveness of ADHD, their continued use worsens the symptoms. ADHD can manifest itself in misleading ways; to find the root of the problem, one must examine the inner workings of the human brain.

Neurobiological Underpinnings
Neurotransmitters: The chemical messengers of the brain
The overriding theory behind ADHD relies on the malfunction of neurotransmitters. Neurotransmission is the chemical process by which the brain’s vast network of neurons communicate with each other. Neurotransmitters are stored in small “bubbles” (synaptic vesicles) inside the nerve ending. When an electrical signal travels to a nerve ending it triggers the release of neurotransmitters that diffuse across the synapse (the gap between the nerve ending and the neighboring neuron). Once they are released into the synapse, neurotransmitters either bind to specific receptors in the post-synaptic neuron (the neuron receiving the signal) or get cleaned up and recycled by a reuptake mechanism. This process happens very quickly with the neurotransmitter molecules binding to precise receptors, much like a puzzle piece that only fits well with the pieces around it. In general, neurotransmitters either excite or inhibit the post-synaptic neuron where they bind. In other words, they either speed up or slow down the receiving cell’s rate of firing.

Dopaminergic Dysfunction in ADHD
Dopamine is the neurotransmitter that serves to regulate the activity of neurons in the brain involved in emotion, motor activity, and disinhibition. Dopamine, epinephrine, and norepinephrine (also known as adrenaline and noradrenaline, respectively) form the neurotransmitter group of catecholamines, which mediate human cognition and motivation in addition to controlling emotion and motor activity. Norepinepherine plays a large role in sleep and arousal, attention and vigilance, and learning and memory, whereas dopamine neurons in the midbrain regulate motor control & emotion, as well as several cognitive processes and various forms of memory (Nestler, et al., 2001). In the corpus striatum, dopamine functions to ensure the smooth coordination of arms and legs (Fig. 2). The degeneration of dopamine pathways and the resulting depletion of dopamine cause the decreased movement, tremors, and rigidity that characterize Parkinson’s disease (Snyder, 1996).

Dopamine targets the dopamine D1 through D5 receptors. Each receptor has a special purpose in its pharmacologic properties, localization in the brain, and role in normal brain function. The dopamine receptors are either categorized as D1-like or D2-like; receptors D1 and D5 are classified as D1-like and receptors D2-D4 are considered D2-like. The main difference between the two categories of dopamine receptors is the effects they produce in their respective neuron. D1-like receptors can produce both excitatory and inhibitory responses when activated, whereas D2-like receptors tend to produce inhibitory responses. Although the D3 and D4 receptors appear to respond similar to D2 when they are activated, their behavior has not yet been thoroughly verified. However, the effect of the D2 receptor has been well documented. It serves as a “negative feedback” mechanism by which it slows the release or synthesis of dopamine, decreases cell firing rates, and slows the flow of norepinephrine (Nestler, et al., 2001). The function of dopamine and norepinephrine are also terminated inside the synapse by norepinephrine transporters (NET) and dopamine transporters (DAT). Despite the fact that there are many receptors for dopamine and the rest of the catecholamine family, only one transporter has been identified for each neurotransmitter.

Although not yet proven conclusively, there is a wealth of evidence for dopaminergic dysfunction as the primary cause of ADHD. The research in this field has continually produced results that implicate dopamine and its corresponding genes as an unmistakable factor in ADHD.

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Neuroimaging Studies
The development of neuroimaging techniques was able to provide concrete evidence for ADHD’s biological basis. In 1990, a research team led by A.J. Zametkin revealed the biochemical differences of an adult with the disorder (Zametkin, et al., 1990). These experiments at the National Institute for Mental Health (NIMH) compared the cerebral glucose metabolism of hyperactive adults with childhood histories of hyperactivity to the metabolism of a “normal” control group. Brain images were taken for thirty minutes as the subjects participated in an auditory-attention task. The results showed an 8.1% decrease in overall brain glucose metabolism as well as a more significant metabolism decrease in the premotor cortex and the superior prefrontal cortex in the hyperactive adults relative to the control group (Zametkin, et al., 1990). Decreased glucose metabolism signals reduced brain cell activity, as glucose is an energy source for the brain. The relevance of this finding relies on the regulation of activity and attention by the premotor cortex and the prefrontal cortex, respectively (Fig. 2). Specifically, the prefrontal cortex controls higher cognitive functions like formulating and executing plans of action as well as providing a person with a sense of time.

More recent MRI (magnetic resonance imaging) studies have repeatedly verified a reduced basal ganglia volume in both adults and children with ADHD (Mostofsky, et al., 2002). The basal ganglia (caudate nucleus, putamen, globus pallidus in Fig. 2) are a cluster of nerve cells deep within the brain that act as a feedback mechanism for the cortex. By controlling inhibitory processes and automatic responses, the basal ganglia provide the cortex with more processing time when it is engaged in an attentional task. The abnormal size and function of the basal ganglia in ADHD has provided new insight into this disorder. The malfunction of the basal ganglia’s control over the brain’s inhibitory processes suggests that ADHD is better characterized as an impairment of inhibition and self-control rather than an attentional disorder.

Another brain structure critical to focusing attention and selecting responses accordingly is the anterior cingulate (Fig. 2). Through MRI studies on volunteers, the cingulate cortex has been shown to be activated during cognitive and attentional tasks such as divided attention tasks where a subject has to focus on relevant stimuli amongst a stream of competing information. Since individuals with ADHD tend to score poorly on divided attention tests, researchers from the Bush team at Harvard Medical School decided to examine the function of the anterior cingulate in patients with ADHD while they performed a divided attention task. The results were amazing. While the control group demonstrated a much higher activity level in the anterior cingulate during the divided attention task, the ADHD group did not activate it at all (Bush, et al., 2002). However, they did demonstrate activation in other regions of the prefrontal cortex and in the caudate and putamen as well. This clearly points to an anterior cingulate dysfunction in ADHD, which might force these individuals to develop other response pathways to compensate for the sub par function of the anterior cingulate.

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