Abbreviations

Introduction

Heinrich Hoffman (1), a physician who wrote books on medicine and psychiatry, first described Attention Deficit Hyperactivity Disorder (ADHD) in 1845. Hoffman realized he could not find suitable readings for his 3-year-old son, so he became a poet. The result was an illustrated book of poems about children and their characteristics. "The Story of Fidgety Philip" was an accurate description of a little boy with ADHD. Yet it was not until 1902 that Still (2) described a group of impulsive children with significant behavioral problems caused by a genetic dysfunction and not by poor child rearing children who still would be easily recognized as having ADHD. Since then, thousand scientific papers on ADHD have been published providing information on its nature, course, causes, impairments, and treatments. Almost 3-5% of the school-age population suffers from ADHD. According to the most recent version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (3) there are three ADHD?s patterns of behavior: predominantly hyperactive-impulsive type (that does not show significant inattention); predominantly inattentive type (that does not show significant hyperactive-impulsive behavior) sometimes called ADHDían outdated term for this entire disorder; and combined type (that displays both inattentive and hyperactive-impulsive symptoms). The symptoms appear early in the child's life. As many ordinary children may show these symptoms, at a lower level or caused by another disorder, it is important that the child receive a thorough examination and appropriate diagnosis by a well-qualified professional team. Prominent symptoms of this disorder are: poor attention span, inability to complete tasks, hyperactivity, and a tendency to interrupt others. Almost one quarter of children with ADHD also suffer from one or more specific learning disabilities in mathematics, spelling or reading. ADHD?s symptoms usually spend many months to appear. Impulsiveness and hyperactivity may precede inattention symptoms, which may not emerge for a year or more. Different symptoms may appear in different settings, depending on the demands the situation may pose for the child's self-control. A child who can not sit still or is otherwise disruptive will be noticeable in school, but the inattentive daydreamer may be overlooked. The impulsive child who acts before thinking may be considered just as a discipline problem, while the passive or sluggish one may be seen as merely unmotivated. Yet both may have different types of ADHD. Sometimes, children are restless; sometimes, they act without thinking and, sometimes, they daydream the time away. When the child's hyperactivity, distractibility, poor concentration, or impulsivity begins to affect its performance in school, social relationships with other children or behavior at home, ADHD may be suspected. However, as the symptoms vary so much across settings, ADHD is not easy to diagnose, especially when inattentiveness is the primary symptom.

Neuroimaging in ADHD
Brain structure?s knowledge is helpful to understand the researches scientists are doing looking for ADHD?s biochemical basis. Scientists have focused their attention in the brainís frontal lobes, which allow us to solve problems, plan ahead, understand people?s behavior and restrain our impulses. Both frontal lobes, right and left, communicate with each other through the corpus callosum (connection nerve fibers). The basal ganglia are the interconnected gray masses located deep in the cerebral hemisphere that link the cerebrum and the cerebellum. Together, basal ganglia, cerebrum and cerebellum, are responsible for motor coordination. The cerebellum is divided into three parts. The middle part is called the vermis. There are several methods available that allow us to look into the brain and imaging it: Magnetic Resonance Imaging (MRI), Magnetic Resonance Spectroscopy (MRS), functional Magnetic Resonance Imaging (fMRI), Positron Emission Tomography (PET), and Single Photon Emission Computed Tomography (SPECT).

MRI findings on ADHD
Abnormalities in patients with ADHD have been observed in different brain regions (4). Structural neuroimaging studies have shown volumetric abnormalities of the frontal lobes (5-7), basal ganglia (8-9), corpus callosum (8), and parietal lobes (7). Low frontal and striatal volumes found correlate with impaired performance on tasks of response inhibition (9). Recent findings direct the research to cerebellar vermis? lobules suggesting an influence of the cerebellar vermis on prefrontal and striatal circuitry on ADHD (10-11). Durston et.al. (12) reported that volumetric reductions in cortical gray and white matter in subjects with ADHD are also present in their unaffected siblings suggesting that they are related to an increased familial risk for the disorder. In contrast, the cerebellum is unaffected in siblings suggesting that the volume?s reduction observed in subjects with ADHD may be more directly related to the pathophysiology of this disorder.

MRS findings on ADHD
Previous results from our research institute demonstrate a decrease in Cho/Cre ratio in frontal lobes on patients with ADHD (13-15). Lactate detection was also reported in 5% ADHD?s cases (14). Jin et. al (16) concluded that the striatum was bilaterally involved as revealed by the NAA/Cr ratio, approximately 20?25% neurons in the globus pallidus may have died or may be severely dysfunctional on ADHD-children. The role of Glutamate-Glutamine (Glu-Gln) metabolism in ADHD-patients has also been studied by MRS. Carrey et. al. (17) reported that a striking decrease in the Glu/Cr (mean change 56.1%) of the striatum was observed between 14 and 18 week-therapy on four ADHD-children. In the prefrontal cortex, however, changes in the Glu/Cr ratio were noticed only in subjects who received atomoxetine, not in those who received methylphenidate, suggesting that in vivo MRS measurement has the potential to assess ADHD-childrenís response to psychopharmacological treatment. Recently, Carrey et. al (18) reported a significant decreased Gln/Glu/GABA to Cr/PCr ratio in the striatum. Other metabolites did not react to the medication used. These findings suggest that Glu may be involved in treatment response on ADHD, especially in the striatum. MacMaster et. al. (19) reported high frontal-striatal Glutamatergic (Glx) resonances on ADHD-children in comparison to Healthy Control subjects without differences in NAA, Cho, or Cr metabolite ratios, suggesting that frontal-striatal Glx resonances may be increased in children with ADHD. Courvoisie et.al. (20) pointed that MRS revealed increased Glu/Gln ratio in both frontal areas, and increased NAA and Cho in the right frontal area on ADHD-subjects. Changes on NAA/Creatine ratio in the right frontal region and mI/Cr ratio in the right and left frontal regions appear to be highly associated with the regulation of sensorimotor, language, and memory and learning functioning in children with ADHD. On the other hand, Yeo et.al. (21) found evidence that suggests sex-specific neurobiological differences in ADHD using MRS.

fMRI findings on ADHD
A fMRI study performed by Chandan et.al. (22) revealed differences between ADHD-children and healthy controls in their frontal-striatal function and its modulation by Methylphenidate during response inhibition. Children performed two go/no-go tasks with and without drug. ADHD-children had impaired inhibitory control on both tasks. Off-drug frontal-striatal activation during response inhibition differed between ADHD and healthy children: ADHD-children had greater frontal activation on one task and reduced striatal activation on the other task. Drug effects differed between ADHD and healthy children: the drug improved response inhibition in both groups on one task and only in ADHD-children on the other task. The drug modulated brain activation during response inhibition on one task only: it increased frontal activation to an equal extent in both groups. In contrast, it increased striatal activation in ADHD-children, but reduced it in healthy children. The results suggest that ADHD is characterized by atypical frontal-striatal function and Methylphenidate affects ADHD-childrenís striatal activation differently than healthy childrenís. Rubia et. al (23) reported mesial hypofrontality on ADHD-adolescents during the performance of two different executive tasks suggesting a task-unspecific deficit in higher-order attentional regulation of the motor output. Lower than normal activation of the right inferior prefrontal cortex and caudate nucleus during the stop task may be responsible for poor inhibitory control on ADHD-patients. Anderson et. al. (24) suggested that further research is needed to clarify the relationship between vermal size, vermal blood flow, stimulant response, and the developmental pathophysiology of ADHD using fMRI.

PET findings on ADHD
During preliminary researches, PET scans of ADHD revealed that ADHD-patients? frontal lobes absorbed less radioactive tracer, which was similar to glucose, than the frontal lobes of patients without ADHD. Zametkin et.al. (25) reported that glucose metabolism, both global and regional, was reduced in adults who had been hyperactive since childhood. The largest reductions were found in the premotor cortex and the superior prefrontal cortex--areas earlier shown to be involved in the control of attention and motor activity.

SPECT findings on ADHD
Amen et.al (26-27) divided ADD into 6 subtypes using SPECT. Type 1 or classic ADHD involves a normal resting brain, but during concentration there are decreases in metabolic activity on the topside (dorsolateral) and underside (orbito-frontal) prefrontal cortex. Thus, reduced brain metabolic activity necessarily equals reduced brain electrical activity and drives neurotransmitter release reducing brain metabolic activity; it also equals reduced brain neurotransmitter activity. Type 2 or inattentive ADHD involves a normal resting brain with reduced metabolic activity in the dorsolateral prefrontal cortex during concentration. Type 3 is called over-focused ADHD. SPECT findings show increased metabolic activity at rest and during concentration in the anterior cingulate gyrus (brain region that connects the prefrontal cortex and limbic system). During concentration, there is also reduced metabolic activity in the orbitofrontal and dorsolateral prefrontal cortex. Type 4 is temporal lobe ADHD. Both, at rest and during concentration, there is decreased (occasionally increased) temporal lobe activity. During concentration, there is typically reduced activity in the orbitofrontal and dorsolateral prefrontal cortex. Type 5 is limbic ADD. SPECT findings include increased deep limbic activity (thalamus and hypothalamus) both, at rest and during concentration, and decreased activity in orbitofrontal and dorsolateral prefrontal cortex. Type 6 corresponds with hyperactive ADHD. SPECT findings include both, at rest and during concentration, patchy increased activity across the cerebral cortex with focal areas of increased activity, especially in the parietal lobes, temporal lobes and prefrontal cortex.

Long Chain Polyunsaturated Fatty Acids (LCPUFA) and ADHD
Stevens? et. al. study (28) first reported in 1995 linked ADHD to a deficiency of certain long-chain fatty acids. Arachidonic Acid (AA), EPA, and DHA are all metabolites of the two essential Fatty Acids, Linoleic Acid (Ω-6) and Alpha-Linoleic acid (Ω-3). Some authors (29) are now leaning towards the conclusion that a subclinical deficiency in DHA is responsible for the abnormal behavior of ADHD-children. They point out that supplementation with a long-chain Ω-6 fatty acid (evening primrose oil) has been unsuccessful in ameliorating ADHD because ADHD-children need more Ω-3 acids rather than more Ω-6 acids (30-42). Researchers also found that children with ADHD were less often breast fed as infants than children without ADHD. Breast milk is an excellent source of DHA. Now, studies are carried out underway to investigate the effect of oral supplementation with DHA on the behavior of ADHD-children. DHA is the building block of human brain tissue and is particularly abundant in the gray matter of the brain and the retina. Low levels of DHA have recently been associated with depression, memory loss, dementia, and visual problems. DHA is particularly important for fetuses and infants.The DHA content of the infant's brain triples during the first three months of life. Optimal levels of DHA are, therefore, crucial for pregnant and lactating mothers. United States? breast milk?s DHA average content is the lowest in the world, due to low fish?s comsumption. Therefore, World Health Organization recommended in 1995 that baby formulas should provide 40 mg of DHA per Kilogram of infant?s body weight. Postpartum depression, ADHD and low IQs may be all linked to the dismally low DHA intake common in the United States. Other researchers also point out that low DHA levels have been linked to low brain serotonin levels, which again are connected to an increased tendency to depression, suicide and violence (42-44). DHA is abundant in marine phytoplankton and cold-water fish. Nutritionists now recommend people to consume two to three servings of fish every week to maintain DHA levels. Recent results (43-44) report that hyperactive children have lower levels of key fatty acids in their blood than ordinary children do. Analyses showed that boys with ADHD had significantly lower levels of AA, EPA, and DHA acids in their blood. Hyperactive children suffered more from symptoms associated with essential fatty acid deficiency (thirst, frequent urination, dry hair and dry skin) and were also much more likely to have asthma and many ear infections. Researchers conclude that ADHD may be linked to a low intake of Ω-3 Fatty Acids (Linoleic, EPA and DHA Acids) or to a poorer ability to convert 18-carbon fatty acids to longer more highly unsaturated acids. As a result, they believe that supplementation with the missing fatty acids may be a useful treatment for hyperactivity (43-44).

CHOLINE and ADHD
Phosphatidilcholine (PCho) and Phosphatidylserine (PS) are natural extracts of lecithin and vital phospholipids for brain cell structure and function. Phospholipids are molecules with an amino acid component and a Fatty Acid component, which are found in every cell membrane in our bodies. ADHD, dyslexia, dyspraxia and autism are now studied as phospholipids disorders because of phospholipids? importance in the natural history, symptoms and prevalence of these conditions within families (45-47). PS plays an important role in neurotransmitter systems, brain metabolism levels and maintaining nerve connections in the brain. PS helps lowering cortisol levels, which are increased in chronically stressed individuals, and improves brain cell membrane fluidity, which helps with dementia and depression (45-47). Despite the experimental data available on using PS for ADHD, its cognitive benefits suggest it should prove extremely helpful (48). A recent study found that the genetic and structural indicators of poor memory in the brain (called developmental instability) correlate with lower concentrations of Cr-PCr and Cho containing compounds, whereas Cre and N-acetyl-aspartate correlate with good memory. These findings may be due to differences in frontal lobe energy metabolism (49) .

Purpose

To assess Choline signal intensity at Basal Ganglia level changes that result from treating children with Attention Deficit Hyperactivity Disorder (ADHD) with Eicosapentaenoic-Docosahexaenoic Acids (EPA/DHA) and Choline-Inositol (CHO/INO) oral supplementation and correlate them with the improvement of the ADHD symptoms.