Juan Carlos Soliva Cognitive Neuroscience Research Unit (URNC)

Decreased cerebebelar myo-inositol and N-acetylaspartate concentrations in pediatric attention/deficit hyperactivity

disorder

Juan Carlos SolivaCognitive Neuroscience Research Unit (URNC) Dept. of Psychiatry. Autonomous University of Barcelona (UAB)

Introduction

• Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in childhood

• Between 8-12 % of the pediatric population• Half of children with ADHD will display the

disorder in adulthood• The diagnosis is made according to the DSM-

IV-TR

IntroductionDSM-IV Criteria for ADHD

• Six or more symptoms of inattention have been present for at least 6 months to a point that is disruptive and inappropriate for developmental level

• Six or more symptoms of hyperactivity-impulsivity have been present for at least 6 months to an extent that is disruptive and inappropriate for developmental level

• Some symptoms that cause impairment were present before age 7 years

• Some impairment from the symptoms is present in two or more settings (e.g. at school/work and at home)

• There must be clear evidence of significant impairment in social, school, or work functioning

Introduction• Cerebello–thalamo-striatal-prefrontal circuit

dysfunction could partially explain ADHD motor control/inhibition and executive function deficits

• In a voxel-based morphometry (VBM) study (Carmona et al, 2005), we found decreased gray matter volume in several regions, especially in the right prefrontal cortex and left cerebellar posterior lobe

• Employing a diffusion tensor imaging (DTI) technique, Ashtari et al (2005) has reported white matter abnormalities in these regions

Objective

• To examine the absolute concentration of NAA (N-acetylaspartate), Cre (creatine), Cho (choline), MI (myo-inositol) and Glx (glutamate-glutamine) in the right prefrontal region and left cerebellar posterior lobe

Hypotesis

• We hypothesize that the prefrontal region and the left cerebellar hemisphere in ADHD subjects should show neurometabolite abnormalities

Material and Methods: study design and sample

• Case–control proton magnetic resonance spectroscopic study comparing the cerebellar and prefrontal regions

• Sample: a group of 17 ADHD medicated children and a group of 17 control children matched for laterality, gender and age.

Material and Methods: MR adquisition

• FSPGR-T1 3D axial sequence (TR = 13.2 ms; TE = 4.2 ms; FA= 15; NEX= 1; 256×256 matrix) with 2mm partitions

• FSE-PD-T2 axial sequence (TR = 3980 ms; TE = 20/100 ms; NEX= 2; 512×512 matrix), with 5mm sections and 2mm gap

• Spectral acquisition: single-voxel PRESS sequence (TR = 2000 ms; TE = 30ms; NEX= 256; bandwidth = 2500 Hz)

Material and Methods: MR adquisition

• Two volumes of interest of 2cm×2cm×2 cm were selected using the FSPGR-T1 3D axial sequence in the right dorsolateral prefrontal region and the left cerebellar hemisphere (posterior lobe) by a experienced neuroradiologist encompassing gray and white matter

Material and Methods: MR adquisition

Material and Methods: post-processing

• Water signal was first modeled by a non-linear time-domain analysis procedure (AMARES)

• Water resonance intensity and metabolite resonance intensity were quantified as damping-sinusoids amplitude

• Water resonance intensity was suppressed using the HSVD method

• Normalized values were obtained by dividing the intensity of each peak by the water signal

Material and Methods: statistical analyses

• Due to the violation of the normality assumption (Shapiro-Wilk tested), non-parametric statistical analyses were used (Mann–Whitney U for two independent samples)

• Multiple comparisons Bonferroni correction was applied (p-value = 0.005)

Results

ResultsControlM (SD)

ADHDM (SD) U (Z) P CI(95%)Md ES

NAA (F) 5.991×10-4 (5.226×10-4)

3.839×10-4 (2.098×10-4) 97 (1.405) 0.168 -7.78×10-5 to

3.47×10-4 0.166

Cre (F) 3.295×10-4 (1.587×10-4)

2.186×10-4 (1.592×10-4) 81 (1.981) 0.049 -2.58×10-5 to

2.49×10-4 0.667

Cho (F) 3.256×10-4 (1.641×10-4)

2.429×10-4 (1.584×10-4) 94 (1.513) 0.136 -6.16×10-5 to

2.15×10-4 1.109

MI (F) 4.761×10-4 (3.159×10-4)

6.362×10-4 (5.598×10-4) 118 (-0.648) 0.533 -4.30×10-4 to

2.56×10-4 -0.843

Glu (F) 1.414×10-3 (1.066×10-3)

1.251×10-3 (1.031×10-3) 116 (0.720) 0.488 -7.54×10-4 to

9.23×10-4 0.048

NAA (C) 6.054×10-4 (2.946×10-4)

3.223×10-4 (1.424×10-4) 38 (3.241) 0.001 7.75×10-5 to

3.84×10-4 1.083

Cre (C) 4.439×10-4 (2.122×10-4)

2.435×10-4 (1.197×10-4) 52 (2.688) 0.006 1.92×10-5 to

3.39×10-4 0.814

Cho (C) 3.793×10-4 (1.845×10-4)

2.583×10-4 (1.408×10-4) 78 (1.660) 0.101 -6.75×10-5 to

3.11×10-4 0.139

MI (C) 1.185×10-3 (7.622×10-4)

6.113×10-4 (4.055×10-4) 49 (2.807) 0.004 1.53×10-4 to

8.23×10-4 1.184

Glx (C) 1.502×10-3 (9.346×10-4)

1.269×10-3 (9.006×10-4) 103 (0.672) 0.520 -4.70×10-4 to

8.95×10-4 0.163

Results

Cr (F)* NAA (C) Cr (C)** Mi (C)

Dosage -0.377(0.150)

0.1030.715

-0.047(0.868)

-0.121(0.668)

Time

-0.016(0.954)

0.013(0.964)

0.115(0.696)

0.082(0.781)

*F: frontal; ** cerebelar

Discussion

• This is the first proton MR spectroscopic study examining the cerebellum in pediatric ADHD

• NAA and MI roles in the CNS are not fully understood

• NAA is found almost exclusively in neurons; hystopathologically, changes in NAA peaks are associated with neuronal density

• MI is primarily found in glia and MI increases indicate gliosis

Discussion

• The decrease in NAA absolute concentration in our ADHD sample could be related to a gray matter decrease in the same cerebellar region found in our previous voxel-based morphometry MRI study with a different sample (Carmona et al, 2005)

Discussion

• The decrease in MI absolute concentration could express a decreased glial density

• Ashtari et al (2005) found a decreased fractional anisotropy (FA) in the left cerebellar hemisphere in a pediatric ADHD sample

• FA and glial density decreases have been correlated

Conclusion

• The main results of our study, consistent with previously reported findings from morphometric andfunctional MRI studies, reinforce the emerging role of the cerebellum in ADHD neurobiology.