major depressive disorder ( mdd ) constitutes the second leading cause of disability worldwide and is associated with a substantial socio - economic burden ( licinio and wong , 2011 ; vos et  al . , 2012 ;
the sequelae of mdd comprise several emotional as well as cognitive symptoms , which are considered to merely reflect a bias towards negatively - valenced information processing leading to adverse emotional responsiveness , attention , and dysfunctional executive function ( nolen - hoeksema , 1991 ; beck , 2008 ; disner et  al . , 2011 ; elliott et  al . ,
imaging studies have provided compelling evidence of altered emotion networks in mdd encompassing the amygdala and the anterior cingulate cortex ( drevets et  al .
, 1997 ; pezawas et  al . , 2005 ; price and drevets , 2012 ) , highlighting the superior role of the cortical midline structures in the pathogenesis of mdd and antidepressant treatment response ( liotti et  al . , 2002 ; lozano et  al . , 2008 ; kupfer et  al . , 2012 ) .
recently , more attention has been paid to cognitive control mechanisms in patients with concurrent major depressive episodes ( mdes ) ( harvey et  al . , 2005 ; rose et  al .
, 2006 ; matsuo et  al . , 2007 ; walsh et  al . , 2007 ; fitzgerald et  al . , 2008 ; schlosser et  al . ,
2014 ) demonstrating increasingly converging evidence of less default mode network ( dmn ) suppression during performance of attention - demanding tasks ( sheline et  al . , 2009 ; disner et  al . , 2011 ;
, 2012 ; rodriguez - cano et  al . , 2014 ) . while the dmn ( gusnard et  al .
, 2001 ; raichle et  al . , 2001 ) is physiologically activated at rest and deactivated during goal - directed cognition , insufficient dmn suppression has been repeatedly associated with goal - irrelevant functions such as self - referential thought , introspective processing or rumination ( mason et  al .
complementary evidence of dysfunctional dmn activation in mdd has also been detected at rest ( greicius et  al .
, 2007 ; sheline et  al . , 2010 ; zhang et  al . , 2011 ;
, 2013 ; li et  al . , 2013 ; sambataro et  al . , 2013 ;
while an abundance of imaging research on cognitive control or functioning was conducted in patients with concurrent major depressive episodes ( mdes ) , studies dedicated to remitted mdd ( rmdd ) are relatively sparse and inconclusive ( walsh et  al . , 2007 ;
okada et  al . , 2009 ; schoning et  al . , 2009 ;
, 2012a , 2012b ; nixon et  al . , 2012 ; li et  al . , 2013 ;
, 2013 ; jacobs et  al . , 2014 ; young et  al . , 2014 ) .
nonetheless , rmdd is of significant clinical interest since it often represents a euthymic state with increased relapse risk ( bhagwagar and cowen , 2008 ; kendler and gardner , 2010 ) and , together with information on the number of previous mdes , guides clinical recommendations for antidepressant maintenance treatment ( apa , 2013 ) .
apart from providing complementary evidence to disease concepts of symptomatic mdd , the study of rmdd raises the possibility to elucidate the neurobiological and psychological mechanisms underlying maintenance of remission as well as determinants of relapse ( marchetti et  al . ,
2012 ) . while the majority of above - mentioned rmdd studies focused on possible alterations in task - positive networks , the involvement of task - negative dmn regions gains increasing attention ( jacobs et  al . , 2014 ;
specifically , the extent of dmn suppression , which has been shown to be crucial for goal - directed cognition and to be dysfunctional in symptomatic mdd ( disner et  al .
, 2011 ; hamilton et  al . , 2011 ; anticevic et  al . , 2012 ; nejad et  al . , 2013
; leech and sharp , 2014 ) , has yet to be thoroughly studied in this specific patient group ( marchetti et  al . , 2012 ) . additionally , several limitations present in previously published rmdd studies such as concomitant antidepressant treatment ( walsh et  al . , 2007 ; schoning et  al . , 2009 ; nixon et  al . , 2012 ; li et  al . ,
2013 ) , moderate sample size ( okada et  al . , 2009 ; norbury et  al . ,
2013 ) , or incomplete remission ( walsh et  al . , 2007 ; schoning et  al . ,
hence , we conducted a cross - sectional functional magnetic resonance imaging ( fmri ) study in a large sample of adult fully remitted and drug - free mdd patients as well as adult healthy controls ( hc ) without any previous psychiatric life - time diagnosis . additionally , we investigated possible behavioral and neural differences with respect to age of mdd onset , because adolescent - onset mdd contrasts clinically with its adult - onset counterpart with regard to chronicity , severity , vulnerability , and stress - sensitivity ( harrington et  al . , 1990 ;
, 1999 ; aalto - setala et  al . , 2002 ; gilman et  al .
, 2009 ; pajer et  al . , 2012 ; schosser et  al . , 2012 ; ramirez et  al . ,
the main goal of this study was to assess both task - positive ( cole et  al . , 2014 ) and task - negative ( anticevic et  al
. , 2012 ) differences of neural networks that are engaged or suppressed during working - memory ( wm ) performance . based on recent findings demonstrating a relationship between reduced dmn suppression and increased rumination in symptomatic mdd ( hamilton et  al . ,
2011 ) , we hypothesized to observe similar deficits in full remission , a condition , where maladaptive self - referential processing has been associated with onset of depressive symptoms ( nolen - hoeksema , 1991 ; michl et  al . , 2013 ) .
moreover , we expected that adolescent - onset rmdd patients would be more severely affected than those with adult - onset given the more deleterious course of adolescent - onset mdd .
study volunteers recruited by online advertisements , announcements on bulletin boards or word of mouth were invited to the outpatient clinic of the department of psychiatry and psychotherapy , medical university of vienna ( muv ) , vienna , austria , to participate in this cross - sectional fmri study .
study procedures were approved by the ethics committee ( ec ) of the muv ( ec number : 11/2008 ) according to the declaration of helsinki ( wma , 2013 ) .
all participants , who were adult and fully capable to give written informed consent , were considered and financially compensated for their expenditure of time . after a comprehensive clinical assessment comprising previous history , neurological and medical examinations involving electrocardiography , blood pressure measurement and routine laboratory testing
diagnoses were evaluated according to the german version of the structured clinical interview for dsm - iv axis i disorders ( scid - i ) ( wittchen et  al . , 1997 ) .
depressive symptoms were assessed by the 21-item version of the hamilton rating scale for depression ( ham - d ) ( hamilton , 1960 ) . only healthy participants without any previous or concurrent axis i disorder
were enrolled in this study , whereas previous single or multiple mdes without any other present or previous axis i disorders were mandatory for inclusion of rmdd patients . in order to exclude cases with questionable clinical significance , only patients reporting previous antidepressant treatment ( antidepressant medication , psychotherapy , or both ) were included .
only rmdd patients who remitted and discontinued any antidepressant treatment at least three months prior to study enrollment were considered .
based on recent recommendations for considering remission and normal levels of functionality ( romera et  al . , 2011 )
a total ham - d score 5 was required for all subjects . a complete list of further inclusion- and exclusion criteria is available in the supplemental information .
consecutively , 78 adult rmdd patients were enrolled in this study . with respect to age of onset
, adolescent - onset was defined as 19 years and adult - onset as > 19 years ( pajer et  al . , 2012 ) .
42 adult hc chosen from a larger sample were automatically age- and gender - matched for both adult rmdd subgroups comprising 42 adolescent- and 36 adult - onset patients using an optimal full matching procedure ( hansen and olsen klopfer , 2006 ) . prior to scanning , subjects received a standardized instruction and computerized training for the classical digit variant of the n - back task ( callicott et  al . , 1999 ) with two complexity conditions .
the n - back task was designed to engage subjects to constantly update their mental set while minimizing interference from incoming stimuli ( digits 14 ) .
briefly , subjects had to follow a simple visual instruction ahead of each task block that indicated if they had to recall any number seen two presentations before ( two - back ; 2b ) or if they had to identify the digit currently seen ( zero - back ; 0b ) . this wm paradigm consisted of four 2b blocks and four 0b blocks in total , each lasting for 30  s. fourteen digits were pseudo - randomly presented for 1000  ms and followed by a 1000  ms inter - stimulus - interval at the corners of a trapeze - shaped array within each block .
visual stimuli were displayed using standard software ( presentation 10.3 , http://www.neurobs.com/ ) and presented via a back - projection screen by a beamer placed outside the scanner room .
performance data represented as percentage ( accuracy ) as well as latencies ( given in milliseconds ) of correct responses were recorded via response buttons of an mri - compatible response box fixed on the right thigh .
subjects replied with their right hand , using the middle finger for digit 1 , the ring finger for digit 2 , the index finger for digit 3 and the little finger for digit 4 . demographic and psychometric differences between subgroups ( adolescent- and adult - onset rmdd patients , hc ) were investigated utilizing a one - way analysis of variance ( anova ) or a chi - squared contingency table test .
( wst ) ( schmidt and metzler , 1992 ) , an operationalization of verbal intelligence , was assessed to confirm comparable education levels between the investigated subgroups .
additionally , response style questionnaire ( rsq ) ( nolen - hoeksema , 1991 ) data were available for a subsample of 39 participants ( adolescent - onset rmdd patients : n  =  14 , adult - onset rmdd patients : n  =  9 , hc : n  =  16 ) , and were utilized to study the relationship between the personality trait rumination and imaging results within a post - hoc regression analysis .
clinical differences between the rmdd subgroups were tested by a two - sample t - test or a two - sample wilcoxon test , where appropriate . in accordance with previous studies employing the n - back task ( rose et  al . , 2006 ; schoning et  al . , 2009 ) , wm performance represented by accuracy and reaction time ( rt ) was recorded after stimulus onset for each complexity condition and examined by a repeated - measures anova using one within - subject factor ( wm load : two levels ) and one between - subject factor ( group : three levels ) .
behavioral analyses including scanner motion parameters were also examined by an anova . including age and gender in an additional analysis of co - variance ( ancova ) did not alternate these results .
all analyses were performed in r ( version 3.1.1 , http://cran-r-project.org/ ) . the significance threshold was set at p  <  0.05 , two tailed .
briefly , fmri data processing was carried out using afni ( http://afni.nimh.nih.gov/afni/ ) implemented into an r framework ( http://cran.r-project.org/ ) ( boubela et  al . , 2012 ) .
second - level activation analysis was conducted utilizing a mixed - effects meta - analysis approach ( 3dmema ) , which takes advantage of both beta - coefficients and t - values thereby accounting for between - subject variability and also the precision estimates of individual subject analyses ( chen et  al . , 2012 ) .
functional connectivity ( fc ) analysis was performed for two 4  mm spherical seeds representing maximal task - negative and -positive group differences ( anterior - medial prefrontal cortex , ampfc : 5 , 46 , 12 ; dorsolateral pfc , dlpfc :  25 , 26 , 38 ) .
fisher z - transformed correlation maps were used as dependent variable within a general linear model for between group comparisons using age and gender as covariates of no interest .
second - level results have been corrected for multiple comparisons in a whole - brain analysis of regions activated by the task for activation , and within a whole - brain mask for fc analysis using family - wise error ( fwe ) rates .
proportional variance estimation ( s ) for regression analysis of behavioral imaging correlates was based on the package 
demographic , clinical as well as behavioral data of all subjects are displayed in table  1 .
no significant group differences were detected with respect to age ( f(2 , 117 )  =  1.35 , p  =  0.11 ) , gender ( (5 )  =  3.9 , p  =  0.56 ) , years of education ( f(2 , 117 )  =  0.88 , p  =  0.42 ) , and the wst ( f(2 , 116 )  =  0.85 , p  =  0.43 ) .
ham - d scores differed significantly between the subgroups ( f(2 , 117 )  =  6.45 , p  =  0.002 ) given the large sample size .
it is noteworthy , that all subjects were below a conservative ham - d cut - off 5 , considered to indicate clinical relevance ( romera et  al . , 2011 ) .
as expected , there was a significant effect of wm load ( 2b minus 0b ) for both accuracy ( f(1 , 117 )  =  216.87 , p  <  0.001 ) and rt ( f(1 , 117 )  =  34.14 , p  <  0.001 ) .
no significant main effects were observed for both accuracy ( f(2 , 117 )  =  2.00 , p  =  0.14 ) and rt ( f(2 , 117 )  =  0.52 , p  =  0.59 ) between all three investigated groups .
no significant interaction effects for group and wm load were detected for either accuracy ( f(2 , 117 )  =  2.41 , p  =  0.094 ) or rt ( f(2 , 117 )  =  1.22 , p  =  0.298 ) . also here , although all subjects showed adequate cognitive performance ( 0b accuracy  >  80% ) , a separate condition analysis revealed subtle but significant subgroup differences for 0b rt ( f(2 , 117 )  =  3.37 , p  =  0.038 ) given the large sample size . with respect to scanner motion , we observed rather low maximum translation parameters ( mean 0.46  mm , sd  =  0.28  mm ) with strongest movement of 1.32  mm .
furthermore , we did not observe any significant difference of maximal displacement between all three groups ( f(2 , 117 )  =  1.86 , p  =  0.16 ) .
adolescent - onset rmdd patients exhibited more previous mdes ( p  =  0.001 ) , a higher cumulative number of months of mdes ( p  =  0.009 ) , a longer duration of illness ( t(76 )  =  4.83 , p  <  0.0001 ) , a longer duration of remission ( p  =  0.036 ) , and a longer time - span since termination of psychotherapy ( p  =  0.006 ) than adult - onset rmdd patients .
no significant differences were found for ham - d scores ( t(76 )  =  0.96 , p  =  0.34 ) , cumulative number of months of antidepressant medication ( p  =  0.37 ) , cumulative number of psychotherapy units ( p  =  0.62 ) , and duration of the last mde in months ( p  =  0.99 ) between the rmdd subgroups . to test if the employed paradigm recruited both , the task - positive wm network ( wmn ) as well as the task - negative dmn , in our study , we performed a within - group comparison for wm load ( 2b minus 0b ) . in all three groups , significantly increased activation was detected in the dlpfc , the ventrolateral pfc ( vlpfc ) as well as the inferior parietal lobe ( table  2 , fig . 
concurrently , significant load - dependent deactivation was found in the ampfc , posterior cingulate cortex ( pcc ) , as well as in the adjacent frontal- , temporal- , and parahippocampal gyrus ( table  2 , fig . 
s1 ) . while the overall peak of activation was clearly found in the dlpfc , maximal deactivation was located in the ampfc in all three groups ( table  2 , fig . 
, rmdd patients showed a significantly diminished deactivation of dmn regions with punctum maximum in the ampfc , while no significant group differences were found in typical wm areas ( fig . 
significant effects were even more pronounced , when comparing hc to adolescent - onset rmdd patients , where the latter exhibited significantly reduced dmn deactivation , which was most prominent in the ampfc , the pcc , and the temporal lobe ( fig . 
interestingly , adolescent - onset rmdd patients differed similarly from adult - onset rmdd patients , though not reaching significance ( fig .  1c , fig . 
in contrast , activation patterns of adult - onset rmdd patients did not significantly differ from hc ( fig .  1c , fig . 
s2c ; table  3 ) . to investigate the degree of coupling between the dmn and the wmn , we calculated fc for regions with maximal task - negative ( ampfc ) and -positive ( dlpfc ) group differences .
analogous to activation results , fc analyses revealed significant differences between adolescent - onset rmdd patients and hc .
compared to hc , adolescent - onset rmdd patients exhibited significantly reduced coupling of the ampfc with most brain regions ( fig . 
inversely , the dlpfc as seed region mirrored this result demonstrating increased fc with the ampfc and decreased fc between the dlpfc and the remaining brain regions ( fig . 
in contrast , adult - onset rmdd patients exhibited a qualitatively similar , but less - pronounced coupling pattern for both seed regions , which did not significantly differ from hc or adolescent - onset rmdd patients ( fig . 
, we performed a post hoc linear regression analysis of accuracy and neural activation on a regional as well as brain systems level while controlling for age and gender .
we correlated the strongest group difference for deactivation ( ampfc ) and fc ( ampfc was used as seed region ) , and observed a significant negative relationship between 2b accuracy and ampfc - dlpfc coupling ( s  =  8.1% ; t(116 )  =  3.22 , p  =  0.0016 , fig . 
in addition , we found a trend - wise significant positive correlation of 0b accuracy with ampfc - medial frontal gyrus ( mfg ) coupling ( s  =  2.9% ; t(116 )  =  1.93 , p  =  0.0557 ) as well as a negative correlation with the ampfc activation ( s  =  2.3% ; t(116 )  =  1.7 , p  =  0.0896 ) .
a post - hoc regression analysis of rsq data and imaging results indicated that reduced dmn deactivation is significantly associated with an increased ruminative response style ( s  =  14.3% , t(35 )  =  2.39 , p  =  0.023 ; fig . 
. moreover , rumination differed significantly between subgroups ( f(2 , 35 )  =  6.26 , p  =  0.0047 ) with maximal rumination values in adolescent - onset rmdd patients and lowest in hc , while adult - onset rmdd patients showed intermediate scores ( fig . 
similar to previous analyses , age and gender were modeled as covariates of no interest .
the main goal of the present study was to investigate putative functional alterations of neural networks that are engaged or suppressed during wm performance in a large sample of adult drug - free rmdd patients and hc .
briefly , in comparison to hc , rmdd patients showed a significantly diminished deactivation of dmn nodes , which are known to be suppressed during externally directed wm performance ( anticevic et  al . , 2012 ) .
moreover , the present study revealed that such reduced suppression of the dmn was significant only in adolescent - onset rmdd patients , putatively reflecting the more chronic course of early - onset mdd from a neurobiological perspective . on a brain systems level , adolescent - onset rmdd patients showed increased ampfc - dlpfc coupling , while all other connections within the wmn and dmn regions showed an inverse directionality .
this tight coupling might underlie decreased reciprocal inhibition between the anterior parts of these antagonistic networks .
moreover , the fact that the strongest dmn disinhibition was detected in the ampfc underlines the superior role of this cortical midline structure in the dynamic interplay between several large - scale neural circuitries , encompassing the fronto - parietal central executive network , cingulo - opercular salience network ( sn ) , and the medial prefrontal - medial parietal dmn , which has been shown to be dysfunctional in depression ( lemogne et  al .
, 2012 ; li et  al . , 2013 ; liston et  al . ,
2014 ) and other major neuropsychiatric disorders ( meyer - lindenberg and tost , 2012 ; chen et  al . , 2013 ;
2014 ) . in detail , the present findings are in line with the idea that a dysfunctional ampfc interferes with bottom - up processes during wm - related computations in mdd patients . as a consequence , top - down control mechanisms are likely initiated to down - regulate the dmn system , but fail to completely suppress its activity ( disner et  al . , 2011 ;
the key finding of this study is the reduced dmn suppression in mdd patients existing even after full recovery , which mirrors findings in symptomatic- ( rose et  al . , 2006 ;
, 2009 ; sheline et  al . , 2010 ; disner et  al . , 2011 ; zhang et  al . , 2011 ;
, 2012 ; davey et  al . , 2012a ; zhu et  al . , 2012 ; connolly et  al .
, 2013 ; guo et  al . , 2013 ; li et  al . , 2013 ; sambataro et  al . , 2013 ; dutta et  al . , 2014 ;
rodriguez - cano et  al . , 2014 ) and euthymic- ( walsh et  al .
, 2007 ; schoning et  al . , 2009 ; smoski et  al . , 2013 )
this reduction of dmn suppression , which is accompanied by increased ruminative response style in our study , might therefore be interpreted as increased self - referential processing as well as insufficient inhibition of conflicting computations in line with previous literature ( mason et  al .
it is noteworthy that rumination has been found to be mediated by midline cortical structures of the dmn ( northoff et  al . , 2006 ;
, 2011 ; northoff et  al . , 2011 ; nejad et  al .
, 2013 ) and to predict mdd onset , severity ( liotti et  al . , 2002
; northoff et  al . , 2011 ) , and duration ( nolen - hoeksema , 1991 ; michl et  al . , 2013 )
hence , we are tempted to speculate that the dysfunctional dmn suppression present in non - symptomatic mdd patients could also render the biological signature of increased relapse likelihood .
this assumption is further supported by significantly pronounced dmn suppression deficits in adolescent - onset rmdd patients , who are prone to a more severe and chronic course compared to mdd patients with later onset , as repeatedly suggested in previous studies ( harrington et  al . , 1990 ; klein et  al . , 1999 ; weissman et  al . , 1999 ; aalto - setala et  al . , 2002 ; zisook et  al . , 2007 ; kendler et  al . , 2009 ; pajer et  al . , 2012 ; schosser et  al . , 2012 ; ramirez et  al . ,
our data are further underlined by a recently published imaging study of remitted depressed young adults demonstrating that hyperconnectivities of the dmn and the sn with cognitive control networks are related to rumination and sustained attention ( jacobs et  al . , 2014 ) .
similar neural alterations of the medial prefrontal cortex ( mpfc ) have been observed in another recent study in rmdd patients reporting an association between dysfunctional deactivation of the dorsomedial pfc and impaired autobiographical memory ( young et  al . , 2014 ) .
our results resembling the critical role of the mpfc in neural alterations being found in symptomatic - as well as euthymic mdd patients ( young et  al . , 2014 ; jacobs et  al . , 2014 )
hint at the possibility that neural dysfunction may persist even after full recovery of mdd .
the mpfc is known to represent a critical neural hub that is involved in self - referential processing such as autobiographical memory , rumination , and cognitive control .
it is noteworthy that one important function of the mpfc is to integrate contextual information of autobiographical memory in order to imagine the future ( schacter and addis , 2007 ; euston et  al . , 2012 ) .
the context - dependent autobiographical memory has been shown to be negatively - biased and less specific in symptomatic- and to some degree also in remitted mdd patients ( euston et  al . , 2012 ; laxton et  al . , 2013 ; young et al . ,
2014 ) , and is therefore thought to reflect a specific cognitive style , which might predict antidepressant treatment response and depression relapse ( nolen - hoeksema , 1991 ; liotti et  al . , 2002 ; northoff et  al . , 2011 ; michl et  al . , 2013 ; andrews - hanna et  al . ,
2014 ) . together with the known stress - sensitivity of the mpfc , conditions of uncontrollable stress paralleled by an exacerbation of helplessness and rumination
could therefore be responsible for depression relapse ( nolen - hoeksema , 1991 ; amat et  al .
, 2005 ) . while there is little doubt today that functioning of dmn - related brain regions is affected in mdd and other psychiatric disorders , the role of the dmn and the regional specialization of anterior and posterior parts of the human medial cortex has been increasingly investigated in the context of various mental processes ( amodio and frith , 2006 ; beckmann et  al . , 2009 ;
, 2014 ; leech and sharp , 2014 ) . accordingly , neural alterations linked to symptoms like rumination as demonstrated for the mpfc and the dmn clearly show that underlying neural signatures are not limited to dsm - defined boundaries .
hence , such neural changes observed in symptomatic as well as euthymic mdd are thought to reflect disease - related changes of neural systems that might be of diagnostic value in future neurobiology - based diagnostic systems ( nestler and hyman , 2010 ; insel , 2012 ; kapur et  al . , 2012 ) .
in contrast to the marked neural activation differences between rmdd patients and hc , the main effects on wm performance were statistically indistinguishable between the groups , which is in line with the majority of previous reports ( walsh et  al .
however , the non - isomorphism between brain function and behavior present in this study could further be related to the chosen maximal wm - load of the behavioral paradigm ( 2b ) , which might change , when wm - load increases ( e.g. 3b , 4b ) or stress - related environmental distractors , requiring a more rigorous control of the dmn , are involved .
our post hoc analysis of the relation between behavioral and imaging data revealed a significant negative correlation between ampfc - dlpfc coupling and 2b accuracy .
this finding indicates that less accuracy is accompanied by dmn - wmn hyperconnectivity , which might reflect the increased relapse risk of rmdd patients ( jacobs et  al . , 2014 ) . while our results as well as limited evidence available from recent studies ( jacobs et  al . , 2014 ; young et  al . ,
2014 ) hint at the importance of dmn - wmn interplay with respect to depression relapse prediction , future longitudinal studies are clearly needed in order to validate the assumption that a dysfunctional dmn is causally related to increased relapse likelihood in mdd patients . despite the intriguing neural alterations observed in this large study of fully - recovered drug - free rmdd patients , some limitations may apply . to address the biological heterogeneity of mdd
, we decided to sub - group our patient sample according to disease onset , which was driven by encouraging reports on distinct biological signatures of adolescent mdd patients ( pajer et  al . , 2012 ) , well - known clinical differences between adolescent- and adult - onset mdd patients ( zisook et  al . , 2007 ) , and the ease and precision of assessment . while competing sub - classifications such as typical / atypical depression , single / multiple episode mdd as well as others ( harald and gordon , 2012 ; lamers et  al .
, 2012 ; sung et  al . , 2013 ; thase , 2013 ; rodgers et  al
. , 2014 ; wakefield and schmitz , 2014 ) exist , their biological significance is still under debate and has not fully been addressed yet ( insel , 2012 ; casey et  al . , 2013 ) .
thus , we are confident that our choice to subgroup patients according to disease onset is appropriate for this study type .
notably , the present cross - sectional study targets exclusively the remitted phase of mdd , and therefore does not allow a direct comparison to symptomatic mdd .
hence , all inferences being made with respect to symptomatic mdd are purely literature - based .
however , we are confident that our conclusions are not too far - fetched given the multitude of imaging literature on symptomatic mdd . summarizing , this study demonstrates that dmn alterations persist even after full recovery of mdes .
observed neural activation patterns were related to rumination , which is a well - established indicator of mdd severity ( hamilton et  al . , 2011 ) .
brain systems level analyses mirrored the aberrant dmn suppression in rmdd patients and underlined the specific role of the ampfc as mediator of these effects ( lemogne et  al . , 2012 ; chen et  al . , 2013 ; li et  al .
in contrast to adult - onset rmdd patients , adolescent - onset rmdd patients exhibited significant local as well as systems level findings , which might reflect the more detrimental clinical course of this diagnostic subgroup . in conclusion , this study demonstrating reduced dmn suppression in rmdd patients encourages the investigation of dmn suppression measures as putative relapse predictor in future clinical trials , which might eventually lead to important implications for antidepressant maintenance treatment .
this work was partly funded by the special research project sfb-35 ( project number f3514-b11 ) and the program clinical research ( project number kli148-b00 ) of the austrian science fund ( fwf ) , and the oesterreichische nationalbank , anniversary fund ( project number 13903 ) .
lucie bartova , bernhard m. meyer , kersten diers , ulrich rabl , and lukas pezawas designed research .
lucie bartova , bernhard m. meyer , kersten diers , ulrich rabl , christian scharinger , ana popovic , klaudius kalcher , roland n. boubela , gerald pail , dominik mandorfer , christian windischberger , and ewald moser performed research .
bernhard m. meyer , kersten diers , ulrich rabl , klaudius kalcher , roland n. boubela , and lukas pezawas analyzed data .
lucie bartova , bernhard m. meyer , kersten diers , ulrich rabl , ana popovic , julia huemer , siegfried kasper , nicole praschak - rieder , harald h. sitte , ewald moser , burkhard brocke , and lukas pezawas wrote the paper .
lucie bartova , bernhard m. meyer , kersten diers , ulrich rabl , christian scharinger , ana popovic , klaudius kalcher , roland n. boubela , julia huemer , dominik mandorfer , christian windischberger , nicole praschak - rieder , burkhard brocke and lukas pezawas report no conflicts of interest .
harald h. sitte has received honoraria for lectures and consulting from astra zeneca , lundbeck , nycomed , ratiopharm , roche , sanofi - aventis , serumwerk bernburg , torrex - chiesi pharma .
gerald pail has worked as a consultant for astrazeneca , bristol - myers squibb , glaxosmithkline , lundbeck , msd and servier and he has served on speakers ' bureaus for astrazeneca , bristol - myers squibb , lundbeck , nycomed and servier .
he has been employed by lundbeck from 2005 to 2007 and has received educational grants by lundbeck and servier .
siegfried kasper has received grant / research support from bristol myers - squibb , eli lilly , glaxosmithkline , lundbeck , organon , sepracor and servier ; he has served as a consultant or on advisory boards for astrazeneca , bristol - myers squibb , eli lilly , glaxosmithkline , janssen , lundbeck , merck sharp and dome ( msd ) , novartis , organon , pfizer , schwabe , sepracor , and servier ; and he has served on speakers ' bureaus for angelini , astrazeneca , bristol myers - squibb , eli lilly , janssen , lundbeck , neuraxpharm , pfizer , pierre fabre , schwabe , sepracor , and servier .
ewald moser has received an  unrestricted research grant  by siemens healthcare , which is unrelated to the present work .
 insufficient default mode network ( dmn ) suppression was linked to increased rumination in symptomatic major depressive disorder ( mdd ) . 
 since rumination is known to predict relapse and a more severe course of mdd , we hypothesized that similar dmn alterations might also exist during full remission of mdd ( rmdd ) , a condition known to be associated with increased relapse rates specifically in patients with adolescent onset . within a cross - sectional functional magnetic resonance imaging study activation and functional connectivity ( fc ) were investigated in 120 adults comprising 78 drug - free rmdd patients with adolescent- ( n  =  42 ) and adult - onset ( n  =  36 ) as well as 42 healthy controls ( hc ) , while performing the n - back task . compared to hc , 
 rmdd patients showed diminished dmn deactivation with strongest differences in the anterior - medial prefrontal cortex ( ampfc ) , which was further linked to increased rumination response style . on a brain systems level 
 , rmdd patients showed an increased fc between the ampfc and the dorsolateral prefrontal cortex , which constitutes a key region of the antagonistic working - memory network . 
 both whole - brain analyses revealed significant differences between adolescent - onset rmdd patients and hc , while adult - onset rmdd patients showed no significant effects . 
 results of this study demonstrate that reduced dmn suppression exists even after full recovery of depressive symptoms , which appears to be specifically pronounced in adolescent - onset mdd patients . 
 our results encourage the investigation of dmn suppression as a putative predictor of relapse in clinical trials , which might eventually lead to important implications for antidepressant maintenance treatment . 