Depressive Cognitions May Affect Cingulate Neurochemistry in ADHD Patients

doi:10.4236/jbbs.2011.11002

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Journal of Behavioral and Brain Science, 2011, 1, 6-11

doi:10.4236/jbbs.2011.11002 Published Online February 2011 (http://www.SciRP.org/journal/jbbs)

Depressive Cognitions May Affect Cingulate

Neurochemistry in ADHD Patients

Evgeniy Perlov1, Alexandra Philipsen1, Simon Maier1, Martin Buechert2, Bernd Hesslinger1,

Dieter Ebert1, Ludger Tebartz van Elst1

1University Hospital Freiburg, Department of Psychia try and Psychotherapy, Hauptstr , Freiburg, Germany

2University Hospital Freiburg, Department of Diag nostic Radiology, Hugstetterstr, Freiburg, Germany

E-mail: [email protected]

Received December 29, 2010; revised January 28, 2011; accepted Febr uary 14, 2011

Abstract

Objectives: The anterior cingulate is thought to be essentially involved in impulsivity and affect regulation

and in the pathogenesis of depression as well as of attention deficit/hyperactivity disorder. At the same time

alterations in glutamatergic neurotransmission in the frontal forebrain have been found in imaging studies in

Attention Deficit Hyperactivity Disorder (ADHD) and in depressive patients. Therefore we hypothesized that

glutamate/glutamine (Glx) signals in the anterior cingulate cortex (ACC) of depressed ADHD patients might

differ from that in non-depressed patients. Methods: Fourteen male adult patients with ADHD were included

into the study. Chemical Shift Imaging of ACC was performed. Subgroups were defined based on scores on

the Beck Depression Inventory (BDI) and ratios of metabolites were compared between groups. Additionally

correlation analyses of BDI scores with metabolite ratios were calculated. Results: Significantly lower Glx

signals and N-acetyl-aspartate (NAA) signals were found in the left anterior cingulate cortex of depressed

ADHD patients. The Glx/Cr and NAAX/Cr ratios in the left ACC correlated significantly with BDI-scores.

Conclusions: To our knowledge this is the first report about a relationship between depressive symptoms

and metabolite disturbances in ACC of adult patients with ADHD. Our preliminary data produce first evi-

dence for a putative link between neurochemical alterations in the ACC and depressive symptoms. They

should be controlled for in further studies.

Keywords: ADHD, MR-Spectroscopy, Depression, Anterior Cingulum, Glutamate

1. Introduction

Most psychiatric disorders are known to be overrepre-

sented in ADHD patients throughout the life from child-

hood into adulthood. Psychiatric comorbidities include

alcohol and other substance abuse as well as mood and

anxiety disorders and borderline and antisocial personal-

ity disorders [1-4] . Co morbidities with differential types

of depression – major depressive disorder (MDD), dyst-

hymia and brief recurrent depression – are particularly

common [5]. This might be due to underachievement in

school, further education and professional life as well as

to frequent interperso nal proble ms in the family and rela-

tionships. Depression in ADHD patients is often atypical.

Anhedonia and physiological concomitants of depression

are often absent whereas restlessness and inattention

seem to be dominant [1,6].

Dopaminergic disturbance is thought to be a crucial

pathogenetic mechanism in ADHD [7,8]. Additionally,

glutamatergic alterations in the prefrontal cortex have

been thought to be involved in the pathogenesis of this

disorder in children [9,10] as well as in adults [11]. At

the same time glutamatergic disturbances in prefrontal

cortex and in particular in the anterior cingulated cortex

(ACC) have been reported in MDD [12,13] and in some

disorders in association with depressive symptoms

[14,15].

Proton-Magnet-Resonanz-Spectroscopy (1H-MRS) is a

non-invasive method which allows to detecting signals

from neurometabolites in vivo. Amongst others N-ace-

tylaspartate (NAA), N-acetylaspartate-glutamine (NAAG)

– taken together – NAAx, creatine and phosphocreatine

(Cre), choline compounds (Cho), glutamate and gluta-

mine (Glx) and myo-inositol (Ins) can be measured with

E. PERLOV ET AL.

1H-MRS [16].

Based on the observations summarized above we

wanted to analyse in this study if glutamate sign als in the

prefrontal cortex are altered in relation to symptoms of

depression in adult patients with ADHD.

2. Methods

Approval from the local ethics committee was obtained

before onset of the study.

The data presented here are part of larger and ongoing

project at the University Hospital of Freiburg in which

we attempt to define the cross-sectional and longitudinal

neuroanatomy and neurochemistry in adult ADHD pa-

tients [Freiburg ADHD Imaging Study in Adults (FAISA)]

and had be en partly reported elsewhere [11,17].

Fourteen male ADHD patients (age 31.0  11.0) from

our out-patient department were included in this study.

The previous and current medication experiences and

comorbidity of other psychiatric (including major de-

pression) and neurological diseases which may affect

brain metabolism served as exclusion criteria for this

study. That means that none of the subjects included did

suffer from clincally relevant depressive disorder ac-

cording to DSM-IV or ICD-10 criteria. Psychometric

assessment included the Wender Utah Rating Scale

(WURS [18]; German version [19]) and the ADHD

check list, corresponding to the DSM-IV criteria. All the

patients suffered from combined subtype of ADHD. Sub-

liminal symptoms of depression at time of scanning were

assessed using the Beck Depression Inventory (BDI)

[20].

Spectroscopic data and anatomical 3D datasets were

obtained on a 1.5 Tesla MR-scanner (Magnetom Sonata,

Siemens Erlangen, Germany). The method of Chemical

Shift Imaging (CSI) was employed with the following

parameters: TR = 1670 ms, TE = 3.9 ms, TI = 1100 ms,

flip angle = 15 degrees, matrix 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-

nificance.

[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.

E. PERLOV ET AL.

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.

Complete

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

ACC

Glx right 1.61  0.29 1.79  0.51 not significant

E. PERLOV ET AL.

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-

tion.

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

None.

10 E. PERLOV ET AL.

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.

doi:10.1016/0165-1781(94)90092-2

[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.

doi:10.1037/0021-843X.111.2.279

[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.

doi:10.1034/j.1600-0447.2003.00112.x

[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.

doi:10.1016/S0006-3223(00)00889-1

[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.

doi:10.1016/S0006-3223(02)01401-4

[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.

doi:10.1176/appi.ajp.163.2.316

[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.

doi:10.1016/j.jpsychires.2006.12.007

[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.

doi:10.1001/archgenpsychiatry.2009.39

[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.

doi:10.1016/S0006-3223(99)00159-6

[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.

doi:10.1001/archgenpsychiatry.2009.86

[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.

doi:10.1097/00001756-200403010-00033

[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.

doi:10.1016/0272-7358(88)90050-5

[21] S. W. Provencher, “Estimation of Metabolite Concentra-

E. PERLOV ET AL.

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.

doi:10.1016/S0006-3223(96)00215-6

[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.

doi:10.1016/j.pscychresns.2005.12.004