attention - deficit / hyperactivity disorder ( adhd ) is a neurodevelopmental disorder with three distinct clinical subtypes ; the inattentive , the hyperactive / impulsive , and the combined type .
the pooled prevalence of children and adolescents with adhd worldwide is estimated to 5.3% ( polanczyk et al . , 2007 ) .
approximately 65% of affected children show persistent symptoms with functional impairment into adulthood ( faraone et al . , 2006 ) , whereas some children experience an improvement or even complete elimination of symptoms during adolescence , which may be explained by a delay and later catch - up in cortical maturation ( shaw et al . , 2007 ) .
adults with persisting adhd thus may represent a subgroup with symptoms caused by other neurobiological underpinnings than a mere delay of cortical development . although adhd is regarded as a neuropsychologically heterogeneous disorder ( willcutt , 2005 ; doyle , 2006 ; sonuga - barke et al . ,
a cognitive control process presumably taps the executive control network ( hugdahl et al . , 2009 ) , which is one of the three networks described in the attentional networks model ( fan et al . , 2005 , 2009 )
the anterior cingulate cortex ( acc ) is part of the executive control network ( posner and rothbart , 2007 ) and its function is essential for the exertion of cognitive control ( bush et al . , 2000 ;
studies using functional neuroimaging ( bush et al . , 2005 ) suggest that a dysfunction in the dorsal acc plays a role in the pathophysiology of adhd .
the acc has a high density of glutamate receptors ( vogt , 2009 ) , and glutamate may be an important metabolite for cognitive functions ( oneill and dix , 2007 ) .
glutamatergic neurotransmission may prove a key target in the treatment of several psychiatric disorders ( javitt , 2004 ) , and growing research on the psychopharmacology of glutamate receptor agonists and antagonists documents an increasing interest for its therapeutic use in psychiatry ( parsons et al .
, 2005 ; krystal et al . , 2010 ; lesage and steckler , 2010 ) . a recent study ( ludolph et al . , 2010 )
highlights the role of glutamate in adhd by demonstrating that the norepinephrine reuptake inhibitor atomoxetine , which is effective against adhd symptoms , is also an nmda receptor antagonist .
magnetic resonance spectroscopy ( mrs ) is a non - invasive method to measure metabolites in the brain ( graaf , 2007 ) .
earlier mrs studies of persons with adhd have focused on metabolites like choline compounds , n - acetyl aspartate ( naa ) , glutamate ( glu ) , and glutamine ( gln ; perlov et al . ,
a synthesis of glu and gln ( glx ) has often been used , because the separation of glu and gln proves difficult at lower field strengths .
the separation of glu from gln is , however , possible at field strengths as low as 2  t if using a short echo time ( te ) and the linear combination of model ( lcmodel ; provencher , 1993 , 2001 ) .
the concentration of total creatine ( cre ) is relatively constant , which is why this metabolite has often been used as an internal concentration reference ( graaf , 2007 ; dager et al . , 2008 ) . a recent meta - analysis including 16 mrs studies of participants with adhd concluded with altered glx / cre , naa / cre , and choline / cre ratios ( perlov et al . , 2009 ) in patients relative to controls
a total of seven mrs studies of adults with adhd have been published ( hesslinger et al .
, 2007 , 2010 ; colla et al . , 2008 ; kronenberg et al . , 2008 ; ferreira et al . , 2009
; rusch et al . , 2010 ) , of which the acc has been examined specifically in four studies .
although a significantly reduced glx / cre ratio in acc was reported in one study ( perlov et al . , 2007 ) , other findings have been inconsistent across studies , possibly explained by heterogeneity of the sample and different spectroscopic methodologies . in this mrs
study we aimed at focusing on the midfrontal region due to the assumed importance of the acc for cognitive control functions , which in turn are central in the pathophysiology of adhd .
glutamate is essential in neurotransmission in the acc and may prove a key metabolite in cognitive functions , and we thus hypothesized that adults with adhd would show a reduction of the glutamate level in the midfrontal region compared with the controls .
the sample of 29 participants with adhd and 38 healthy controls was recruited from the norwegian adhd - project in bergen .
the adhd group consisted of 15 men and 14 women with mean age 32.9  years ( sd  =  7.1 , age range 2148  years ) and mean wechsler abbreviated scale of intelligence ( wasi ) iq 110.6 ( sd  =  14.3 , iq range 78128 ) .
the control group consisted of 15 men and 23 women with mean age 29.8  years ( sd  =  6.5 , age range 2141  years ) and mean wasi - iq 116.3 ( sd  =  9.4 , iq range 96136 ) .
the groups did not differ significantly neither in their composition of sex (   =  1.00 ; df  =  1 ; p  =  0.32 ) , nor with respect of means of age [ t(65 )  =  1.84 ; p  =  0.07 ] or means of iq [ t(65 )  =  1.97 ; p  =  0.053 ] .
all patients had been diagnosed according to icd-10 or dsm - iv criteria for hyperkinetic disorder / adhd by a psychiatrist or psychologist before the inclusion in the norwegian adhd - project in bergen .
controls were randomly selected from the comparison group in the norwegian adhd - project in bergen ( halmoy et al . , 2009 ) , recruited from the database of the medical birth registry of norway .
details concerning the recruitment procedure are described in recent publications by the bergen group ( johansson et al . , 2008 ;
all participants in both groups were interviewed with the adhd module of k - sads ( kaufman et al . , 1997 ) adjusted to adults , administered by an experienced psychiatrist ( margaretha dramsdahl ) . based on symptoms reported in childhood , the participants were categorized into the following subgroups : seven with inattentive type , three with hyperactive / impulsive type and 19 participants with combined type . according to the present symptoms , however , nine participants had an inattentive type , one had symptoms of the hyperactive / impulsive type and 19 participants had a combined type . the adult adhd self - report scale ( asrs-18 ; kessler et al . , 2005 )
it consists of two subscales , one scale measuring inattentive symptoms , the other scale measuring hyperactive / impulsive symptoms .
the 16 patients medicated with stimulants ( n  =  15 ) or atomoxetine ( n  =  1 ) were instructed to withhold medication 48  h prior to testing to reduce the possible influence of medication .
nine participants followed this instruction , whereas five reduced the dosage during the last 48  h ( including the sole participant on atomoxetine ) , and two participants continued their ordinary medication .
thirteen of the participants in the adhd group had not used stimulants or atomoxetine during the past 6  months .
participants with adhd consisted of 23 right - handed and 6 left - handed participants , whereas 33 right - handed and 5 left - handed controls were included .
handedness was determined by the hand that the subject preferred to draw and write with .
exclusion criteria for both groups were current severe psychiatric axis i disorder or substance abuse , epilepsy , or other neurological or physical disease with cognitive impairment .
participants with a lifetime history of developmental delay , premature birth before 34  weeks of gestational age , or iq below 70 were neither included . to ensure as representative adhd sample as possible , we included participants with current mild psychiatric comorbidity ( anxiety disorders and mild depressive symptoms ) .
eleven of the adhd participants had diagnosis of an anxiety disorder ( panic disorder , agoraphobia , social phobia , and/or specific phobia ) , two had a depressive disorder or dysthymia , and three adhd participants had diagnosis of both anxiety and depressive disorder .
no participant , however , reported ongoing , severe symptoms at the time for the mr scanning .
further exclusion criteria for the controls were lifetime history of adhd , current adhd symptoms ( score > 36 on asrs-18 , or > 20 on one of the two subscales ) , or first - degree relatives ( parents , children , siblings ) with adhd .
three of the controls had diagnosed specific phobia , but none had ongoing symptoms at the time of scanning . written informed consent was obtained from all participants after receiving detailed information about the procedure .
the study was approved by the norwegian regional medical research ethics committee west irb # 3 ( fwa00009490 , irb00001872 ) .
h - mr scanning was performed with a 3.0-t ge signa hdx scanner , using an eight - channel head coil .
single voxel point - resolved spectroscopy ( probe - press ) was used with the following parameters : te  =  35  ms , tr  =  1500  ms .
line - width was less than 8  hz and water suppression level at least 94% . a t1-weighted image using a 3d fast spoiled gradient recall sequence ( te  =  14  ms , tr  =  400  ms , ti  =  500  ms ; scan matrix : 256    256 ; field of view of 256  mm    256  mm , 188 sagittal slices of 1  mm thickness )
was acquired to position the slices parallel to the line connecting the lowest edge of the splenium and the rostrum of the cc .
in addition to the t1-weighted image an axial t2-weighted image was acquired prior to the proton mrs imaging sequences .
the t2-weighted image was used as reference for cerebrospinal fluid ( csf ) within the area of interest to avoid csf contamination of the mrs voxel .
voxel size was 20  mm    20  mm    20  mm localized in the left and the right midfrontal region including the dorsal acc .
the position of the mrs voxel was parallel to the cc , midway between the upper part of the mid - body of the cc , and the most anterior part of the genu , close against the edge of the white matter in the cc ( figure 1 ) .
scanning was performed with the mrs voxel localized first in the left and then in the right midfrontal region .
the position of the 20-mm    20-mm    20-mm voxel in the midfrontal region
. the ratio of glu to cre were estimated by lcmodel software version 6.2 - 1a using a simulated basis - set for a te of 35  ms , delivered by provencher ( 2011 ) .
lcmodel automatically quantifies in vivo spectra , avoiding analyses of individual peaks or use of any subjective influenced model .
estimated sd ( cramr  rao lower bounds ) below 20% were accepted , which is a rough criterion for estimates of acceptable reliability ( provencher , 2011 ) .
all statistical analyses were made by general linear model ( glm ) using the statistica 8 software ( http://www.statsoft.com/ ) .
group comparisons were made between the adhd and control group and between the left and right side in a multivariate analysis of variance ( manova ) including glu / cre left and glu / cre right as dependent variables and group as categorical variable . in order to control for any effect of covariates
, the data were reanalyzed with multivariate analysis of covariance ( mancova ) including glu / cre left and glu / cre right as dependent factors , group , sex , and handedness as categorical predictors , and age and iq as continuous predictors .
since none of the interactions were significant , we removed the interaction terms before re - running the analysis twice with glu / cre left and glu / cre right , respectively , as dependent variables , group as categorical predictor , and sex , handedness , age , and iq as covariates .
medication and comorbidity were not included as covariates in the glm analyses , since these variables had implications mainly for the adhd group , and some of the subgroups would be very small or even give empty cells in the statistical design .
thus , to investigate the effect of comorbidity and medication we did independent t - tests of the adhd group with glu / cre ratio left side as dependent variable and comorbidity and medication , respectively , as grouping variables . as a last analysis we correlated the value of glu / cre in the left midfrontal region and scores of the two asrs subscales to explore a possible association .
the sample of 29 participants with adhd and 38 healthy controls was recruited from the norwegian adhd - project in bergen .
the adhd group consisted of 15 men and 14 women with mean age 32.9  years ( sd  =  7.1 , age range 2148  years ) and mean wechsler abbreviated scale of intelligence ( wasi ) iq 110.6 ( sd  =  14.3 , iq range 78128 ) .
the control group consisted of 15 men and 23 women with mean age 29.8  years ( sd  =  6.5 , age range 2141  years ) and mean wasi - iq 116.3 ( sd  =  9.4 , iq range 96136 ) .
the groups did not differ significantly neither in their composition of sex (   =  1.00 ; df  =  1 ; p  =  0.32 ) , nor with respect of means of age [ t(65 )  =  1.84 ; p  =  0.07 ] or means of iq [ t(65 )  =  1.97 ; p  =  0.053 ] .
all patients had been diagnosed according to icd-10 or dsm - iv criteria for hyperkinetic disorder / adhd by a psychiatrist or psychologist before the inclusion in the norwegian adhd - project in bergen .
controls were randomly selected from the comparison group in the norwegian adhd - project in bergen ( halmoy et al . , 2009 ) , recruited from the database of the medical birth registry of norway .
details concerning the recruitment procedure are described in recent publications by the bergen group ( johansson et al . , 2008 ;
all participants in both groups were interviewed with the adhd module of k - sads ( kaufman et al . , 1997 ) adjusted to adults , administered by an experienced psychiatrist ( margaretha dramsdahl ) . based on symptoms reported in childhood , the participants were categorized into the following subgroups : seven with inattentive type , three with hyperactive / impulsive type and 19 participants with combined type . according to the present symptoms , however , nine participants had an inattentive type , one had symptoms of the hyperactive / impulsive type and 19 participants had a combined type . the adult adhd self - report scale ( asrs-18 ; kessler et al . , 2005 )
it consists of two subscales , one scale measuring inattentive symptoms , the other scale measuring hyperactive / impulsive symptoms .
the 16 patients medicated with stimulants ( n  =  15 ) or atomoxetine ( n  =  1 ) were instructed to withhold medication 48  h prior to testing to reduce the possible influence of medication .
nine participants followed this instruction , whereas five reduced the dosage during the last 48  h ( including the sole participant on atomoxetine ) , and two participants continued their ordinary medication .
thirteen of the participants in the adhd group had not used stimulants or atomoxetine during the past 6  months .
participants with adhd consisted of 23 right - handed and 6 left - handed participants , whereas 33 right - handed and 5 left - handed controls were included .
handedness was determined by the hand that the subject preferred to draw and write with .
exclusion criteria for both groups were current severe psychiatric axis i disorder or substance abuse , epilepsy , or other neurological or physical disease with cognitive impairment .
participants with a lifetime history of developmental delay , premature birth before 34  weeks of gestational age , or iq below 70 were neither included . to ensure as representative adhd sample as possible , we included participants with current mild psychiatric comorbidity ( anxiety disorders and mild depressive symptoms ) .
eleven of the adhd participants had diagnosis of an anxiety disorder ( panic disorder , agoraphobia , social phobia , and/or specific phobia ) , two had a depressive disorder or dysthymia , and three adhd participants had diagnosis of both anxiety and depressive disorder .
no participant , however , reported ongoing , severe symptoms at the time for the mr scanning .
further exclusion criteria for the controls were lifetime history of adhd , current adhd symptoms ( score > 36 on asrs-18 , or > 20 on one of the two subscales ) , or first - degree relatives ( parents , children , siblings ) with adhd .
three of the controls had diagnosed specific phobia , but none had ongoing symptoms at the time of scanning . written informed consent was obtained from all participants after receiving detailed information about the procedure .
the study was approved by the norwegian regional medical research ethics committee west irb # 3 ( fwa00009490 , irb00001872 ) .
h - mr scanning was performed with a 3.0-t ge signa hdx scanner , using an eight - channel head coil .
single voxel point - resolved spectroscopy ( probe - press ) was used with the following parameters : te  =  35  ms , tr  =  1500  ms .
line - width was less than 8  hz and water suppression level at least 94% .
a t1-weighted image using a 3d fast spoiled gradient recall sequence ( te  =  14  ms , tr  =  400  ms , ti  =  500  ms ; scan matrix : 256    256 ; field of view of 256  mm    256  mm , 188 sagittal slices of 1  mm thickness ) was acquired to position the slices parallel to the line connecting the lowest edge of the splenium and the rostrum of the cc .
in addition to the t1-weighted image an axial t2-weighted image was acquired prior to the proton mrs imaging sequences .
the t2-weighted image was used as reference for cerebrospinal fluid ( csf ) within the area of interest to avoid csf contamination of the mrs voxel .
voxel size was 20  mm    20  mm    20  mm localized in the left and the right midfrontal region including the dorsal acc .
the position of the mrs voxel was parallel to the cc , midway between the upper part of the mid - body of the cc , and the most anterior part of the genu , close against the edge of the white matter in the cc ( figure 1 ) .
scanning was performed with the mrs voxel localized first in the left and then in the right midfrontal region .
the position of the 20-mm    20-mm    20-mm voxel in the midfrontal region .
the ratio of glu to cre were estimated by lcmodel software version 6.2 - 1a using a simulated basis - set for a te of 35  ms , delivered by provencher ( 2011 ) .
lcmodel automatically quantifies in vivo spectra , avoiding analyses of individual peaks or use of any subjective influenced model .
estimated sd ( cramr  rao lower bounds ) below 20% were accepted , which is a rough criterion for estimates of acceptable reliability ( provencher , 2011 ) .
all statistical analyses were made by general linear model ( glm ) using the statistica 8 software ( http://www.statsoft.com/ ) .
group comparisons were made between the adhd and control group and between the left and right side in a multivariate analysis of variance ( manova ) including glu / cre left and glu / cre right as dependent variables and group as categorical variable . in order to control for any effect of covariates
, the data were reanalyzed with multivariate analysis of covariance ( mancova ) including glu / cre left and glu / cre right as dependent factors , group , sex , and handedness as categorical predictors , and age and iq as continuous predictors . since none of the interactions were significant , we removed the interaction terms before re - running the analysis twice with glu / cre left and glu / cre right , respectively , as dependent variables , group as categorical predictor , and sex , handedness , age , and iq as covariates .
medication and comorbidity were not included as covariates in the glm analyses , since these variables had implications mainly for the adhd group , and some of the subgroups would be very small or even give empty cells in the statistical design .
thus , to investigate the effect of comorbidity and medication we did independent t - tests of the adhd group with glu / cre ratio left side as dependent variable and comorbidity and medication , respectively , as grouping variables .
as a last analysis we correlated the value of glu / cre in the left midfrontal region and scores of the two asrs subscales to explore a possible association .
all spectra of the 67 included participants were of good quality ( see figure 2 for a representative spectrum ) . a representative spectrum indicating position of peaks and calculation of signal - to - noise ratios .
the manova including glu / cre left and glu / cre right as dependent variables and group as categorical variable revealed significant main effects of group and of side ( table 1 ; figure 3 ) .
the mean glu / cre ratio was reduced in the adhd group compared to the control group and the difference was only significant in the left midfrontal area .
the mean glu / cre ratio was significantly lower in left midfrontal region compared to right midfrontal region in both groups .
the mancova including glu / cre left and glu / cre right as dependent factors , group , sex , and handedness as categorical predictors , and age and iq as continuous predictors , revealed a significant main effect of group , but no longer any significant side effect ( table 2 ) .
age and iq had each a significant main effect , but , more importantly , no interactions between the factors became significant .
main and interaction effects of general linear model including glutamate / creatine ratios at left and right side as dependent variables and group ( adhd , control ) as categorical predictors .
main effects of general linear model including glutamate / creatine ratios at left and right side as dependent variables , group ( adhd , control ) , sex ( man , woman ) , and handedness ( left , right ) as categorical predictors , and age and iq as continuous predictors .
mean glutamate to creatine ( glu / cre ) ratio in the left and right midfrontal region in the attention - deficit / hyperactivity disorder ( adhd ) and control groups .
the ancovas with glu / cre left and glu / cre right , respectively , as dependent variables , group as categorical predictor , and sex , handedness , age , and iq as covariates confirmed a main effect of group at the left side , but not at the right ( see table a2 in appendix ) . in order to further elaborate the significant group effect in the left midfrontal area , detected by the manova ,
the t - test of the adhd group with glu / cre ratio left side as dependent variable and comorbidity as grouping variable revealed significant lower glu / cre value in the adhd group without comorbidity compared to the adhd group with comorbidity ( see table a1 in appendix ) .
the t - test of the adhd group including medication as grouping variable showed no significant difference in glu / cre ratio at left side between the medicated and non - medicated adhd participants ( see table a1 in appendix ) .
the correlation between the symptoms of severity ( asrs scores ) and the value of glu / cre in the left midfrontal region of the adhd participants revealed no significant correlation . when including the controls and thus increasing the statistical power , a significant negative correlation between inattentive symptoms and glu / cre level was revealed ( r  =  0.274 , p  =  0.025 ) .
there was no significant correlation between the hyperactive / impulsive scores and the level of glu / cre in left midfrontal region ( r  =  0.107 , p  =  0.39 ) .
the main finding of a reduced ratio of glu / cre in the left midfrontal region in participants with adhd supports the hypothesis of adhd as a hypoglutamatergic condition ( carlsson , 2001 ) .
glutamate is an important neurotransmitter in cognitive processes ( van wageningen et al . , 2009 , 2010 ) and seems to have a central role in neurotransmission in the acc ( bozkurt et al . , 2005 ; yang et al . , 2006 )
the dorsal acc , in turn , plays a crucial role in the exertion of cognitive control ( bush et al .
, 2000 ; carter and van veen , 2007 ) , and a glutamatergic deficit in the midfrontal region including the dorsal acc , may contribute to the impaired cognitive control in persons with adhd .
the hypothesis that a dysregulation of catecholaminergic neurotransmission contributes to the development of symptoms typical for adhd has been supported from different research areas , notably from pharmacological studies of psychostimulants ( staller and faraone , 2007 ; genro et al . , 2010 ) .
the exact modes of action of human adhd - medication , however , are still unknown ( solanto , 1998 ; challman and lipsky , 2000 ; cornforth et al . , 2010 ) .
although changes in dopamine or norepinephrine levels may primarily mediate the effect of psychostimulants , the putative monoamine dysfunction in adhd may also derive from an impaired glutamatergic transmission ( carlsson , 2001 ) .
our results partially replicate and extend previous studies of brain glutamate levels in persons with adhd , but comparisons between studies may be difficult because of methodological and/or positional differences .
one study concluding with significantly reduced glx / cre in the right acc ( perlov et al .
, 2007 ) used multi - voxel chemical shift imaging ( csi ) instead of single voxel spectroscopy . a recent single voxel mrs study reported increased glutamate concentration in the left acc ( rusch et al . , 2010 ) , with the voxel of measurement positioned in the rostral part of acc , anterior to the genu of the cc , and not in the dorsal ,  cognitive  part
furthermore , women were only included when adhd was comorbid with a borderline personality disorder , making it difficult to draw conclusions about the specific impact of adhd .
in addition to the diagnostic effect , we also revealed a significant main effect of side with reduced glu / cre in the left midfrontal area . a difference in glu / cre value between the left and the right side may indicate a lateralization of the frontal region including the dorsal part of the acc .
reports of morphological differences between left and right midfrontal regions support this hypothesis , with the paracingulate sulcus more commonly found pronounced in the left compared to the right hemisphere ( huster et al . , 2007 ;
the significant difference between the glu / cre in left and right midfrontal region disappeared , however , after correction for the covariates sex , handedness , age , and iq ( see table 2 ) .
this finding is in accordance with earlier report of a slight decrease of glu concentration in the acc with increasing age ( schubert et al . , 2004 ) .
the exploratory finding of a significant negative correlation between inattentive symptoms and glu / cre level may support the presumption of glutamate in the midfrontal region as an important factor of cognitive control .
first , our sample is small with seven predictive variables ( group , sex , handedness , age , iq , medication , and comorbidity ) , and replication studies are thus necessary .
we here present a representative adhd sample , which increased the numbers of variables and possible confounding factors .
the mean iq value was lower in the adhd group compared to the control group , but not significantly different .
cognitive difficulties in neurodevelopmental disorders like adhd are , however , of such pervasive nature that matching fully for iq is likely to reduce the representativeness of the adhd group ( dennis et al . , 2009 ) .
likewise , any correction for comorbidity would result in a non - representative adhd group .
the significant lower glu / cre value in the adhd group without comorbidity compared to the adhd group with comorbidity support the presumption that comorbidity can not explain the main finding of reduced glu / cre ratio at left side in the adhd group .
second , the participants were on different medication regimes , and even if medication did not seem to have any significant influence in our study ( see table a1 in appendix ) , it may have an influence on the neurochemistry and the neuronal activity .
inclusion of only medication nave participants would be a way to eliminate a possible confounding effect of medication .
third , changes in the glu / cre ratio may be a result of changes in the concentration of cre . as an internal reference the concentration of cre
is supposed to be constant , and no changes have been reported with age , at least not before the age of 60  years ( saunders et al . , 1999 ) .
the concentration of cre , however , may vary in pathological conditions , such as mood disorders ( capizzano et al . , 2007 ) , brain tumors ( yerli et al . , 2007 ) , or ischemia ( karaszewski et al . ,
2010 ) , and even small changes in the cre value may influence the ratio of glu to cre . however , we analyzed the glu / cre ratio , because the ratio is less sensitive to relaxation and partial volume effects than the absolute concentrations of metabolites ( provencher , 2011 ) .
a last limitation is the possible confounding factors of offsets of the chemical shifts , as well as different distribution of csf and gray and white matter in the voxels .
we consider , however , the voxel size large enough to minimize these effects , but can not eliminate a contribution of these factors to the differences between the sides , as well as the groups . in conclusion ,
our results reflect a hypoglutamatergic condition in the midfrontal regions of adults with adhd , which may cause impaired cognitive control and a dysfunctional top - down regulation .
more studies mapping the glutamatergic pathways and their interaction with other transmitters in persons with adhd would help to further reveal the underlying neurobiology of the disorder .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 background : impaired cognitive control in individuals with attention - deficit / hyperactivity disorder ( adhd ) may be related to a prefrontal cortical glutamatergic deficit . 
 we assessed the glutamate level in the left and the right midfrontal region including the anterior cingulate cortex in adults with adhd and healthy controls . 
 methods : twenty - nine adults with adhd and 38 healthy controls were included . 
 we used proton magnetic resonance imaging with single voxel point - resolved spectroscopy to measure the ratio of glutamate to creatine ( glu / cre ) in the left and the right midfrontal region in the two groups . 
 results : the adhd group showed a significant reduction of glu / cre in the left midfrontal region compared to the controls . conclusion : the reduction of glu / cre in the left midfrontal region in the adhd group may reflect a glutamatergic deficit in prefrontal neuronal circuitry in adults with adhd , resulting in problems with cognitive control . 
Introduction
Materials and Methods
Participants
MR spectroscopy
Data analysis
Results
Discussion
Conflict of Interest Statement