rix 256 × 256 pixel, FOV =
256 × 256 cm2. The previously published LC-algorithm
[21] in combination with the CSILcmodel-Tool [22] was
used for postprocessing of the data, the Cramer-Row
lower bound values smaller then 20% were used as a
quality criterion. The regions of interest (ROI) covering
the right and left ventral ACC were placed manually by a
neuroanatomically trained rater (EP) in a blinded way.
Only selected parts of the ROI without contamination
with CSF were included. Ratios of metabolites (NAA,
Cho, Glx and Ins) to Cre were calculated following es-
tablished procedures in LC-Mo del (Figure 1).
The software program SPSS 13.0 was used for statis-
tical analysis. Subgroups with respect to subliminal de-
pressive symptoms (n = 7 for each) were defined by me-
dian split of the overall group (13) based on BDI-scores.
Multiple analysis of covariance (MANCOVA) with me-
tabolites to Cre ratios (Glx, NAA, Cho, Ins) as dependant
variables and age, scores of ADHD-CL and WURS as
covariates were chosen independently for the right and
left ACC. Additionally a Pearson correlation coefficient
for BDI scores and metabolite signals was calculated. A
p-value of 0.05 was chosen here as the criterion of sig-
[MRS = Magnet Resonance Spectroscopy, Cre = Creatine, NAA = N-acetylaspartate, Cho = Choline, mI = Myoinositol, Glx = Glutamate + Glutamine]
Figure 1. CSI-voxels localization on a superposition of the MRS slice onto the anatomical data set (in red – selected voxels)
and MR spectrum of the anterior cingulum.
Copyright © 2011 SciRes. JBBS
Copyright © 2011 SciRes. JBBS
3. Results
The groups did not differ with respect to age, education
and values of WURS and ADHD-CL scores (Table 1).
We found a significant influence of the factor group
(ADHD patients with higher versus lower BDI scores) in
multivariate Wilks-Lambda-test for the left (F = 7.515;
df = 5.00; p = 0.024) but no t for the right (F = 0.37; df =
5.00; p = 0.822) ACC. MANCOVA revealed that the
more depressive patients with ADHD displayed signifi-
cant reductions in NAA and Glx signals in the left ACC.
There were no significant differences with respect to
other MRS signals (Table 2)
The correlation analysis revealed a significant nega-
tive correlation between the BDI-scores and Glx/Cr ra-
tios (r = 0.610; p = 0.02) and NAA/Cr ratios (r = 0.654; p
= 0.0 1) in t he left ACC. Th ere were no significant corre-
lations of BDI-scores and any other metabolite concen-
tration in the right or left ACC. The scatter plots of the
correlation analyses are presented in Figures 2 and 3.
Table 1. Patient assessment.
n = 14 Depressive
n = 7 Non-depressive
n = 7 Statistics
Age 31.0 11.0 27.2 5.8 32.4 10.1 t = 1.196; df = 9.5 5; p = 0.255
Years of school education 12.4 1.3 12.1 1.5 12.6 1.1 t = 0.612; df = 11.29; p = 0.552
WURS 62.4 10.8 61.4 12.7 63.4 9.3 t = 0.335; df = 11 .01; p = 0.744
ADHD-CL 25.5 4.4 25.1 5.7 26.4 2.8 t = 0.535; df = 8.6 4; p = 0.606
BDI 13.3 5.7 17.7 2.4 8.9 4.4 t = –4.682; df = 9.38; p = 0.001
Spectroscopic findings
Table 2. Spectroscopic findings.
Figure 2. Correlation between BDI-value and Glx/Cr ratio in left ACC.
ROI Metabolite/Cr Side
More depressive
n = 7 Less depressive
n = 7 Statistics
left 1.33 0.11 1.53 0.22 F= 5.004; df = 1; p = 0 .045
NAAx right 1.41 0.21 1.38 0.25 not significant
left 0.31 0.04 0.34 0.02 not significant
Cho right 0.32 0.02 0.32 0.03 not significant
left 0.85 0.17 0.79 0.11 not significant
Ins right 0.89 0.13 0.84 0.05 not significant
left 1.62 0.23 2.22 0.64 F = 5.283; df = 1; p = 0.040
Glx right 1.61 0.29 1.79 0.51 not significant
Figure 3. Correlation between BDI-value and NAAx/Cr ratio in left ACC.
We found no significant correlation between WURS-
or ADHD-CL-scor es and any neurometabolite.
4. Discussion
In this pilot study we specifically tested th e hypo th esis of
an influence of subliminal depressive symptoms as
measured with BDI on the glutamatergic neurochemistry
in adult male patients with ADHD. We did find prelimi-
nary evidence for alterations in glutamatergic metabo-
lism and, additionally, in NAA signals, both in the left
ACC in the group of patients with depressive symptoms.
Supporting the noting of a pathogenetic link between
depressive symptoms and left ACC NAA and Glx me-
tabolism, we found a significant and rather strong corre-
lation between Glx/Cr and NAAX/Cr ratios in the left
ACC and BDI-scores.
To our knowledge this is th e first report of such a link
between ACC Glx signals and depressive symptoms in
adult ADHD. The prefrontal glutamatergic neurons
modulate the release of other neurotransmitters including
dopamine and serotonin in the midbrain [23]. The dopa-
minergic system is well known to be important in the
pathogenesis of ADHD. The dopaminergic neurotrans-
mission of course is of critical importance for depression.
Furthermore, in our recent study we reported lower
Glx-signals in the ACC of adult patients with ADHD
compared to healthy controls [11]. On the other hand
there is an increasing body of evidence for disturbed
glutamatergic neurotransmission in MDD and depressive
comorbidity in medical disorders like for example dia-
betes mellitus [12-15]. NAA, a marker of functional or
structural integrity of the neurons, has also been reported
to be altered in ADHD but not in MDD [5,24].
There are many limitations to this pilot study. First of
all the number of included subjects is very small. Second,
the results have been obtained only in male subjects and
therefore cannot be generalized to females. Most impor-
tantly, there is no control group of healthy subjects or
patients with depressive symptoms without ADHD and
for that reason we cannot conclude if or not this associa-
tion might be restricted to ADHD patients or not. The
precise meaning of altered Glx or NAA signals with re-
spect to specific pathophysiological mechanisms are also
not yet resolved.
Therefore, these findings have to been taken with cau-
tion and should be regarded as preliminary evidence or
hypothesis-generating evidence which does need replica-
Nevertheless, we feel that when looking at the raw
data with respect to group differences and correlation
analyses the signal seems to be rather strong and valid.
Therefore, further research should aim at establishing if
or not there is an association between left ACC gluta-
mate metabolism and if this is restricted to subliminal
symptoms or ADHD patients only. If this relationship
could be established for depressive symptoms in general
irrespective of severity and neuropsychiatric comorbidity
such a signal could be of relevance as possible neuro-
biological marker of depressive symptoms in general.
Further studies in ADHD patients should analyze possi-
ble relationships between depressive symptoms and
neurochemical findings. Vice versa, further MRS studies
in ADHD should be controlled for possible influence of
subclinical depressive symptoms on glutamatergic signal
in order to avoid the misinterpretation of the findings.
5. Acknowledgments
Copyright © 2011 SciRes. JBBS
6. References
[1] J. Biederman, S. V. Faraone, T. Spencer, T. Wilens, E.
Mick and K. A. Lapey, “Gender Differences in a Sample
of Adults with Attention Deficit Hyperactivity Disorder,”
Psychiatry Research, Vol. 53, No. 1, 1994, pp. 13-29.
[2] J. E. Alpert, A. Maddocks, A. A. Nierenberg, R. O’Sulli-
van, J. A. Pava, J. J. Worthington, J. Biederman, J. F.
Rosenbaum and M. Fava, “Attention Deficit Hyperacti-
vity Disorder in Childhood among Adults with Major
Depression,” Psychiatry Research, Vol. 62, No. 3, 1996,
pp. 213-219. doi:10.1016/0165-1781(96)02912-5
[3] R. A. Barkley, M. Fischer, L. Smallish and K. Fletcher,
“The Persistence of Attention-Deficit/Hyperactivity Dis-
order into Young Adulthood as a Function of Reporting
Source and Definition of Disorder,” Journal of Abnormal
Psychology, Vol. 111, No. 2, 2002, pp. 279-289.
[4] T. E. Wilens, “Impact of ADHD and Its Treatment on
Substance Abuse in Adults,” Journal of Clinical Psy-
chiatry, Vol. 65, No. 3, 2004, pp. 38-45.
[5] B. Hesslinger, T. Thiel, L. T. van Elst, J. Hennig and D.
Ebert, “Attention-Deficit Disorder in Adults with and
without Hyperactivity - Where is the Difference? A Study
Using Short Echo 1H-magnetic-resonance Spectro-
scopy,” Neuroscience Letters, Vol. 304, No. 1, 2001, pp.
117-119. doi:10.1016/S0304-3940(01)01730-X
[6] B. Hesslinger, v. E. Tebartz, F. Mochan and D. Ebert, “A
Psychopathological Study into the Relationship between
Attention Deficit Hyperactivity Disorder in Adult Pa-
tients and Recurrent Brief Depression,” Acta Psychiatrica
Scandinavica, Vol. 107, No. 5, 2003, pp. 385-389.
[7] D. D. Dougherty, A. A. Bonab, T. J. Spencer, S. L. Rauch,
B. K. Madras and A. J. Fischman, “Dopamine Trans-
porter Density in Patients with Attention Deficit Hyper-
activity Disorder,” Lancet, Vol. 354, No. 9196, 1999, pp.
2132-2133. doi:10.1016/S0140-6736(99)04030-1
[8] S. V. Faraone, J. Biederman, T. Spencer, T. Wilens, L. J.
Seidman, E. Mick and A. E. Doyle, “Attention-Deficit/
Hyperactivity Disorder in Adults: An Overview,” Bio-
logical Psychiatry, Vol. 48, No. 1, 2000, pp. 9-20.
[9] F. P. MacMaster, N. Carrey, S. Sparkes and V. Kusu-
makar, “Proton Spectroscopy in Medication-free Pedia-
tric Attention-Deficit/Hyperactivity Disorder,” Biological
Psychiatry, Vol. 53, No. 2, 2003, pp. 184-187.
[10] C. M. Moore, J. Biederman, J. Wozniak, E. Mick, M.
Aleardi, M. Wardrop, M. Dougherty, T. Harpold, P.
Hammerness, E. Randall and P. F. Renshaw, “Differ-
ences in Brain Chemistry in Children and Adolescents
with Attention Deficit Hyperactivity Disorder with and
without Comorbid Bipolar Disorder: A Proton Magnetic
Resonance Spectroscopy Study,” American Journal of
Psychiatry, Vol. 163, No. 2, 2006, pp. 316-318.
[11] E. Perlov, A. Philipsen, B. Hesslinger, M. Buechert, J.
Ahrendts, B. Feige, E. Bubl, J. Hennig, D. Ebert and v. E.
Tebartz, “Reduced Cingulate Glutamate/Glutamine-to-
Creatine Ratios in Adult Patients with Attention Defi-
cit/hyperactivity Disorder - A Magnet Resonance Spec-
troscopy Study,” Journal of Psychiatric Research, Vol.
41, No. 11, 2007, pp. 934-941.
[12] M. Walter, A. Henning, S. Grimm, R. F. Schulte, J. Be ck,
U. Dydak, B. Schnepf, H. Boeker, P. Boesiger and G.
Northoff, “The Relationship between Aberrant Neuronal
Activation in the Pregenual Anterior Cingulate, Altered
Glutamatergic Metabolism, and Anhedonia in Major De-
pression,” Archives of General Psychiatry, Vol. 66, No. 5,
2009, pp. 478-486.
[13] D. P. Auer, “Reduced Glutamate in the Anterior Cingu-
late Cortex in Depression: An in vivo Proton Magnetic
Resonance Spectroscopy Study,” Biological Psychiatry,
Vol. 47, No. 4, 2000, pp. 305-313.
[14] I. K. Lyoo, S. J. Yoon, G. Musen, D. C. Simonson, K.
Weinger, N. Bolo, C. M. Ryan, J. E. Kim, P. F. Renshaw
and A. M. Jacobson, “Altered Prefrontal Glutamate-
Glutamine-Gamma-Aminobutyric Acid Levels and Rela-
tion to Low Cognitive Performance and Depressive
Symptoms in Type 1 Diabetes Mellitus,” Archives of
General Psychiatry, Vol. 66, No. 8, 2009, pp. 878-887.
[15] P. Ohrmann, A. Kersting, T. Suslow, J. Lalee -Mentzel, U.
S. Donges, M. Fiebich, V. Arolt, W. Heindel and B.
Pfleiderer, “Proton Magnetic Resonance Spectroscopy in
Anorexia Nervosa: Correlations with Cognition,” Neuro-
Report, Vol. 15, No. 3, 2004, pp. 549-553.
[16] B. Ross and S. Bluml, “Magnetic Resonance Spectro-
scopy of the Human Brain,” Anatomical Record, Vol. 265,
No. 2, 2001, pp. 54-84. doi:10.1002/ar.1058
[17] E. Perlov, v. E. Tebarzt, M. Buechert, S. Maier, S. Mat-
thies, D. Ebert, B. Hesslinger and A. Philipsen, “H(1)-
MR-spectroscopy of Cerebellum in Adult Attention Defi-
cit/Hyperactivity Disorder,” Journal of Psychiatric Re-
search, Vol. 44, No. 1414, 2010, pp. 938-943.
[18] M. F. Ward, P. H. Wender and F. W. Reimherr, “The
Wender Utah Rating Scale: An Aid in the Retrospective
Diagnosis of Childhood Attention Deficit Hyperactivity
Disorder,” American Journal of Psychiatry, Vol. 150, No.
6, 1993, pp. 885-890.
[19] K. H. Krause, J. Krause and G. E. Trott, “Hyperkinetic
Syndrome (Attention Deficit/Hyperactivity Disorder) in
Adulthood,” Nervenarzt, Vol. 69, No. 7, 1998, pp.
543-556. doi:10.1007/s001150050311
[20] A. T. Beck, R. A. Steer and M. G. Carbin, “Psychometric
Properties of the Beck Depression Inventory:
Twenty-five Years of Evaluation,” Clinical Psychology
Review, Vol. 8, No. 1, 1988, pp. 77-100.
[21] S. W. Provencher, “Estimation of Metabolite Concentra-
Copyright © 2011 SciRes. JBBS
Copyright © 2011 SciRes. JBBS
tions from Localized in vivo Proton NMR Spectra,”
Magnetic Resonance in Medicine, Vol. 30, No. 6, 1993,
pp. 672-679. doi:10.1002/mrm.1910300604
[22] C. W. Ko, B. Kreher and M. Buchert, “GUI for Auto-
matic Post Processing and Display of 2D-SI Data Sets
with LC Model,” ISMRM, 11th Annual Meeting, 2003.
[23] T. A. Slotkin, E. C. McCook, J. C. Ritchie, B. J. Carroll
and F. J. Seidler, “Serotonin Transporter Expression in
Rat Brain Regions and Blood Platelets: Aging and Glu-
cocorticoid Effects,” Biological Psychiatry, Vol. 41, No.
2, 1997, pp. 172-183.
[24] A. Yildiz-Yesiloglu and D. P. Ankerst, “Review of 1H
Magnetic Resonanc e Spec trosc opy Findings in Major De-
pressive Disorder: A Meta-analysis,” Psychiatry Re-
search, Vol. 147, No. 1, 2006, pp. 1-25.