Bipolar Disorder (BD) is prevalent in 1 to 3% of the adults and 1% of adolescents. The early onset has been proposed as the clinical feature that distinguishes a BD subtype that has an important genetic load. Children with at least one parent diagnosed with bipolar disorder (bipolar offspring) are 4 times more likely to suffer from mood disorders than children of healthy parents. With the advent of neuroimaging it has been possible to investigate in vivo in the Central Nervous System the pathophysiological mechanisms involved in BD. In Magnetic Resonance (MR) studies, it has been shown smaller amygdala volumes in children with BD whereas in adults with BD bigger amygdala volumes; and smaller prefrontal cortex (PFC) and anterior cingulate volumes in children and adults with BD. Using Proton Magnetic Resonance Spectroscopy (1H MRS) that measures N-acetyl aspartate (NAA), myo-inositol (Ino), glutamate (Glu), glutamine (Gln), it has been demonstrated lower levels of NAA in the dorsolateral PFC (DLPFC) and higher levels of myo-inositol in the anterior cingulate in adults and adolescents with BD. The few studies evaluating BD offspring including only children who were also diagnosed with BD, showing lower NAA/Cr ratios in the DLPFC. However, there is no study that has been conducted on non-affected high risk population where could be evident BD prodromical abnormalities. Our hypotheses are that BD offspring compared to healthy children of healthy parents will have smaller bilateral DLPFC, anterior cingulate, basal ganglia and amygdala volumes; and lower levels of NAA in the left DLPFC and higher levels of Glu+Gln in the bilateral anterior cingulate and left basal ganglia. We also hypothesized that these abnormalities will be more pronounced in BD affected offspring of BD patients than non-affected BD offspring. Methods: We will recruit 30 subjects who will fulfill inclusion criteria: a) between 6 and 18 years old; b) one parent diagnosed with BD; and 15 of them will not have any psychiatric disorder and 15 will have BD. We will also recruit 30 healthy controls matched for gender, age and puberty degree; that will not have any first-degree relatives with psychiatric disorder. Psychiatric diagnosis will be established according to the DSM-IV criteria, using the Kiddie-SADS-PL interview and Structured Clinical Interview for DSM-IV (SCID). The MR will be conducted at a 1.5 Tesla GE scanner at the Institute of Radiology Medical School University of São Paulo. Aquisition: SPGR will be performed in the coronal plane with repetition time (TR) of 25 ms, echo time (TE) of 5 ms, flip angle of 40o, field of view (FOV) 24cm, slice thickness of 1.0 mm, number of averages (NEX) of 1 and matrix size of 256x192 to obtain 128 images. The volume of the regions of interest will be estimated using a semi-automated software BRAINS2. 1H-MRS Aquisition: a first 8 cm3 single voxel will be located at the left DLPFC, a second one at the bilateral anterior cingulated and a third one at the left basal ganglia. A PRESS sequence with TE of 30ms, TR of 6s and 96NEX will be used. The spectra will be processed using the LC Model software (Provencher, 1993). The statistical analyses: the Shapiro-Wilks test will be performed to examine the distribution of the data. Assuming that the data will follow normal distribution, we will utilize ANCOVA with the subjects groups (BD offspring affected and non-affected and healthy controls) and gender as independent variables, age as co-variant, and the 1H-MRS metabolites levels and MR volumetric measures as dependent variables. Alpha will be established at p=< 0.05.
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