The previously shown results suggest an increase in the resonance intensity of Choline-containing compounds on ADHD-children after 6-month treatment with oral supplementation of EPA-DHA and CHO/INO. Choline is the precursor of acetylcholine and phosphatidylcholine. Mainly obtained from the diet, Choline constitutes a crucial intermediate in several clinically relevant neurochemical processes. Studies performed on animals demonstrate an increase of Choline metabolites in their brains after oral administration (50-51) . Quite a few MRS reports differ from finding similar increases in human subjects (52-57). In this study, choline-containing compounds in human brain (phosphocholine, glycerol-phosphocholine and choline) were MRS-measured before and after the ingestion of 50 mg/Kg Choline Bitartrate-Inositol in forty ADHD-children.

Cho/Cr ratios obtained were compared and referred to HR?s basal ganglia Cho/Cr ratios. Substantial and remarkably similar increases in the brain choline resonance occurred, with a nearly 22% rise in the choline resonance observed in ADHD-children (Case No 5 reported in sequence on Figures 2, 3 and 4) after oral supplementation (p < 0.05 versus baseline). Our data agrees on other authors? reports on the increase of brain Choline levels after Choline ingestion (52-55). Choline metabolites decrease has been observed in basal ganglia, as an age related process (58), and in psychiatric conditions, in which basal ganglia are involved (59). Cho/Cr increased-ratio corresponded with the improvement of the clinical signs of ADHD.

Spearman correlation coefficient shows significant statistical association (p<0.05) between the improvement in cognitive abilities of ADHD-children (Verbal/Performance Scales as measured by Wechsler Intelligence Scale for Children-Revised and Visual-motor functioning / Visual-perceptual skills measured by Bender-Gestalt test) and a raise in Cho/Cr ratio. However, our results could be explained on the basis of positive interactions between CHO/INO and EPA/DHA simultaneous administration.

The beneficial effects of LCPUFA on ADHD have been brought into focus in the last years. The consistent findings of both clinical signs of fatty acid deficiency and blood biochemical indices of fatty acid abnormalities in a subset of ADHD-children indicate that supplementation with LCPUFA might be helpful in the management of this condition in, at least, some cases. Now, the challenge is to determine what proportion of diagnosed ADHD-children might benefit from such supplementation, and how they may be well identified. Only a few pilot studies about gamma linoleic acid?s deficiency effects on ADHD have been published.

Two double-blind placebo-controlled trials of gamma linoleic acid (GLA) supplementation gave equivocal results in ADHD-subjects who weren?t selected as having low levels of n-6 fatty acids (60-61). The second study reported modest benefits for GLA supplementation over placebo, although it was less effective than D-amphetamine (61). In addition, the level of serum triglyceride GLA found correlated inversely with Conners? scale scores (62). The GLA?s modest benefit is unsurprising. Evidence gathered since then suggests that n-3 rather than n-6 fatty acid deficiency may be more relevant in ADHD. The design of this study and its treatment duration cannot be considered appropriate for the evaluation of fatty acid treatment because second study-subjects were randomly allocated to GLA, D-amphetamine or placebo for 1 month each.

Unlike D-amphetamine, fatty acids cannot be expected to act rapidly for changing symptoms or behavior. Rather, recent evidence has shown that LCPUFA levels in the brain may take up to 3 months to recover from a chronic deficiency state (63-64) and this must, therefore, be regarded as an essential consideration in the design of future treatment studies. A published report on the results from a random, double-blind treatment trial on ADHD-children with clinical signs of fatty acid?s deficiency (65) showed its authors? findings that combined-supplementation of DHA, EPA, AA and DGLA (weighted in favor of the n-3 fatty acids) was successful in changing the blood fatty acid profile of ADHD-children. These changes were associated with reductions in ADHD symptoms. In fact, DHA alone may be, indeed, ineffective as other fatty acids (EPA) may account for the benefits detected (65).

The differences could be on the basis of subject selection. Further studies are required to determine if the Choline signals raise that we observed is related to the pharmacological combination used, which may suggest a possible increase either in the brain uptake or in the bioavailability of Choline due to EPA/DHA coadministration. Stoll?s data from unstable bipolar disorder patients treated with high-dose omega-3 fatty acid supplementation, previously treated with Choline to attenuate cell signaling through the phosphatidylcholine system (66), agrees on our findings. The biochemical basis that could possibly support this hypothesis is the evidence that omega-3 fatty acids can also inhibit hydrolysis of membrane phospholipids, such as phosphatidylinositol, and may thus inhibit receptor-linked G-protein signal transduction (66). On the other hand, phosphatidylcholine is also effective in protecting DHA/EPA from free radical oxidative stress. Inositol is a simple polyol precursor in a second messenger system important in the brain. Cerebrospinal fluid Inositol decrease has been reported on depression. Inositol clinically controlled trials are few for patients with depression, panic disorder, and obsessive-compulsive disorder (OCD) (67-70). Positive psychoactive effects on animals (71) clearly strengthen the necessity of further clinical trials and Inositol?s potential for general therapeutic use in humans. The possibility of a pharmacological synergism between EPA/DHA, Choline and Inositol on ADHD is already open for further studies.