since the introduction of the kraepelinian dichotomy which divides major endogenous psychoses into two distinct groups of diseases that are known today as schizophrenia ( sz ) and bipolar disorder ( bd ) , this concept has strongly influenced modern psychiatric diagnostic classification systems .
however , recent findings have cast doubt on this classification into two separate entities ( craddock and owen , 2005 ) . therefore , finding evidence of shared clinical features and/or pathophysiological pathways between these disorders represents a field of great interest in psychiatric neuroscientific research . direct comparisons of cognitive and clinical variables revealed that sz and bd share important clinical and cognitive features ( mann - wrobel et al . , 2011 ; schaefer et al . , 2013 ) , for example some symptoms of psychosis , memory deficits or affective disturbances .
episodic memory deficits are persistent in both disorders , even in symptom - free intervals ( mann - wrobel et al . , 2011 ; schaefer et al . , 2013 ) . in bd however , the deficits are usually less severe than in sz patients ( seidman et al . , 2002 ; reichenberg et al . ,
in addition to that , some anatomical alterations may be shared across psychosis disorders using multimodal imaging parameters ( fibre integrity , volumes , cortical thickness ) although the severity of the alterations or the location may be different .
for instance , regarding volumetric findings , reduced hippocampal volume has been found frequently in sz ( wright et al . , 2000 ) , but not as consistently in bd ( adler et al .
, 2007 ; koo et al . , 2008 ; scherk et al . , 2008 ;
this is in line with reports of temporal , occipital and parietal volume and cortical thickness reductions in sz but not in bd patients in comparison with controls ( rimol et al . , 2012 ) .
regarding diffusion tensor imaging ( dti)-studies , current knowledge indicates partly analogical location of fibre integrity ( fa ) changes in sz and bd : the recent meta - analysis of ( williamson and allman , 2012 ) yielded two regions with significant fibre integrity ( fa ) changes in sz : the left frontal deep white matter and the left temporal deep white matter , and a meta - analysis in bd by vederine et al .
( 2011 ) showed two significant right - hemispheric clusters of fa alterations that were located in the parahippocampal gyrus and close to the subgenual anterior cingulate cortex ( acc ) .
functional imaging findings in both disorders suggest altered functional connectivity within frontal and between frontal and limbic regions in sz ( meyer - lindenberg et al .
 limbic network disturbance in bd ( yurgelun - todd et al . , 2000 ; blumberg et al .
current findings in the field of resting - state fmri support the idea that sz and bd share core pathophysiological pathways .
resting - state fmri is an attractive tool because it allows to measure functional activation independently of a specific task .
a recent meta - analysis of resting - state studies in sz showed decreased resting - state activity compared with control subjects in the left hippocampus , the ventromedial prefrontal cortex , the posterior cingulate cortex and the precuneus ( kuhn and gallinat , 2013 ) . in bd patients ,
, 2010 ; chai et al . , 2011 ) and between the frontal cortex and the striatum ( anand et al . , 2009 ; chepenik et al . ,
, the previous literature thus suggests that both disorders may share deficits in episodic memory and structural abnormalities in the hippocampus , although the results are less consistent in bd compared with sz .
therefore , in the present study , we combined behavioral testing and structural imaging with resting - state fmri which allowed us to probe the functional connectivity of the hippocampus with other parts of the brain . in the current study we investigated the hypothesis that potential shared cognitive symptoms in sz and bd
we included 21 patients with the diagnosis of a paranoid sz ( m [ mean ]  =  38.38  years [ sd [ standard deviation ]  =  10.30 ] ) and 21 patients with the diagnosis of a bd i ( mean age : m  =  35.67 [ sd  =  10.68 ] years ) without any comorbid axis - i or ii disorders ( including drug abuse ) according to the dsm - iv criteria ( apa , 1994 ) .
we ensured the diagnosis using the structured clinical interview for dsm - iv ( scid - i and scid - ii ; german version ( wittchen et al . , 1996 ) ) followed by an interview to examine sociodemographic factors .
we ensured their remitted status by using the diagnostic criteria according to the dsm - iv ( wittchen et al . , 1996 ) . also , we only included bp patients that scored less than 18 points in the german version of the beck depression inventory ii ( bdi ii ( hautzinger et al . , 2006 ) ) and less than 7 points in the german version of the bech rafaelsen mania scale ( brmas ; bech , 1981 ) .
all patients were treated in the department of psychiatry , goethe - university , frankfurt , germany during the time of the experiment .
all patients were asked to participate in the current study during their treatment period , and we examined those patients who were willing to participate and who did not fulfil any exclusion criteria . to guarantee a good comparability between the two groups we ensured that the duration of illness ( at a minimum of 5  years ) , the number of episodes of illness and the years of treatment with medication were comparable across disease groups ( see table 1 for further details ) .
all patients had to be in a stable medication status ( no significant change ) during the last month preceding testing .
we also computed chlorpromazine equivalents for each sz patient using the formula by woods ( 2003 ) and almeida scores as described by almeida et al .
21 healthy participants ( mean age : m  =  36.90 [ sd  =  11.06 ] years ) who were matched with the patient groups in age , gender and education were included in the study . exclusion criteria for control subjects were current drug - abuse , any kind of neurological disease , a history of psychiatric disorders including axis i and axis ii disorders according to dsm - iv ( using the scid i and ii ( wittchen et al .
we ensured that none of the controls had any positive family history of affective or psychotic disorder .
statistical tests ( anova , scheff post - hoc contrast analyses , chi - square - tests ) for differences between the groups regarding age , handedness and parental education revealed no significant group differences ( all p - values  >  0.05 ) .
the anatomical mri scans of all participants were reviewed by a neuroradiologist who did not find any clinically relevant pathology .
participants were provided with a description of the study and gave written informed consent before participating .
experimental procedures were approved by the ethical board of the medical department of the goethe - university , frankfurt / main , germany .
we assessed crystallized intelligence using the mwt - b ( mehrfachwahl - wortschatz - test ( lehrl , 2005 ) , the german equivalent of the  spot - the - word test  ) , verbal learning with the hopkins verbal learning test - revised [ hvlt - r ] and non - verbal ( visual ) learning using the brief visuospatial memory - test revised [ bvmt - r ] ( view table 2 for further details ) ( all tests taken from the matrics test battery ( nuechterlein and green , 2006 ) ) . we explored the clinical state of the illness across patient groups using disease - specific questionnaires . for sz patients , the positive and negative syndrom scale ( panss ( kay et al .
, we used the bdi ii ( hautzinger et al . , 2006 ) and the brmas ( bech , 1981 ) .
this was done also for the healthy control group in order to rule out potential affective symptoms . within 1  week of the diagnostic , cognitive and clinical testing functional and anatomical images
were acquired using a siemens magnetom allegra 3  tesla mri system ( siemens medical systems , erlangen , germany ) at the goethe university brain imaging center , frankfurt am main , germany .
each scanning session began with a resting - state functional measurement ( echo - planar - imaging [ epi]-sequence , 400 volumes , voxel size : 3    3    3  mm , tr  =  2000  ms , te  =  30  ms , 33 slices covering the whole brain , slice thickness  =  3  mm , distance factor  =  20% , flip angle  =  90 ) , followed by a high - resolution t1-weighted anatomical measurement ( mdeft sequence ( deichmann et al . , 2004 ) , 176 slices , 1    1    1  mm ) .
three diffusion tensor imaging datasets were also acquired for each subject using generalized auto - calibrating parallel acquisitions ( grappa ; griswold et al . , 2002 ) with an epi sequence ( tr  =  8760  ms ; te  =  100  ms ; bandwith  =  1302  hz / pixel , acquisition voxel size  =  2    2    2  mm ; 60 axial adjacent slices ; slice thickness  =  2  mm ( no gap ) ; fov  =  192    92    120  mm ; acquisition matrix  =  96    96 ; 10 images without diffusion weighting ( b0 ) with 60 diffusion - encoded images ( b - values  =  1000  s / mm 60 noncolinear directions , acquisition time  =  10  min . ) ) .
participants were scanned with dimmed lights and were instructed to lie still and look at a white fixation cross presented in the centre of the visual field .
participants did not engage in any overt speech during the scanning sequences . the brainvoyager qx software version 2.3 ( goebel et al .
, 2006 ) was used to preprocess and co - register the functional and anatomical mr images .
the preprocessing steps of the functional data included slice - time correction , rigid - body motion correction ( levenberg  marquardt algorithm ; cut - off for head motion : 2  mm ) , linear trend removal and high - pass temporal filtering ( 3  cycles  per  time course , cutoff  =  0.0075  hz ) . three - dimensional ( 3d ) anatomical scans were transformed into talairach space ( talairach and tournoux , 1988 ) using a 12-point affine transformation .
we used automated routines of the brainvoyager software to co - register the functional data to the anatomical scans of the same participant , and resampled the functional data to an iso - voxel size of 3    3    3  mm . for a seed - based analysis ( sba )
, we used an anatomically defined hippocampus mask ( hippocampus total ) provided by the brain voyager qx program .
the seeds were then used to do a seed correlation analysis ( sca ) . during sca ,
the functional time - series of one or more pre - defined brain areas (= seed regions ) are sampled and correlated with all other functional time - series .
following previous recommendations , we corrected the seed time - series for potential nuisance variables ( z - normalized ) , which included fmri signal from ventricles , white matter , the global ( whole - brain ) signal and the six head movement parameters ( birn et al .
the analysing steps of the resting - state fmri data were done with custom - written routines and freely available toolboxes in matlab ( mathworks , natick , ma ) .
the vbm preprocessing and statistical analysis were performed with spm8 ( statistical parametric mapping [ wellcome department of imaging neuroscience , london , uk ] ) running on matlab version 7.7.0 .
second , customized t1 templates and prior images of grey matter ( gm ) , white matter ( wm ) and cerebro - spinal fluid ( csf ) were created from all participants in order to use it for the group analysis .
we used modulated data and prior probability maps ( voxel intensity ) to guide segmentation in spm .
the segmentation included six different tissue types , light bias regularization ( 0.001 ) , 60  mm bias fwhm cut - off , warping regularization of 4  mm , affine regularization to the icbm european brain template ( linear registration ) and a sampling distance of 3  mm .
finally , the images were smoothed with a gaussian kernel of 8    8    8  mm ( fwhm ) . using this procedure the intensity of each voxel
was replaced by the weighted average of the surrounding voxels , in essence blurring the segmented image . the wfu pickatlas toolbox in spm8 ( maldjian et al . , 2003 )
in the following step we compared grey matter volume differences in the rois between individual images , using the voxel - based morphometry ( vbm ) tool of the spm8 software . afterwards , group comparisons in the rois of gm using vbm were tested with linear statistical contrasts resulting in a t - statistic for each voxel .
the respective global volumes of grey and white matter and csf as obtained during segmentation were included as nuisance variables .
diffusion mri data were pre - processed and analysed using the standard tbss routine of fsl 4.1 ( oxford centre for functional mri of the brain  fmrib software library ; fsl , http://www.fmrib.ox.ac.uk/fsl ) ( smith et al . , 2006 ) .
tbss is a specific voxel - wise approach to analyse dti data , which projects individual dti parameters of each participant onto a mean skeleton of a white matter mask ( smith et al . , 2006 ) .
the different steps applied for the preprocessing of the diffusion mri data included motion correction , correction for eddy - current distortion and averaging the three dti datasets into one single-4d dataset per subject .
after that , the preprocessed images were fitted using a tensor model that generated the diffusion maps ( fractional anisotropy [ fa ] , mean diffusivity [ md ] ) used in the following tbss analysis .
this was followed by a non - linear registration of all images into standard mni space and the creation of an averaged fa skeleton on which individual fa and md values were projected ( for further details of the procedure see oertel - knchel et al . , 2014 ) .
the resulting dti parameters on the skeleton were used for roi analyses of all tracts which are connected to the grey matter regions of the hippocampus region .
the tracts were selected using the jhu white - matter tractography atlas provided by fsl ( hua et al . , 2008 ) .
this atlas tool is recommended by fsl and was used to mark the topographical boundaries of all rois in mni space and to create white matter masks .
the tracts were selected as follows : bilateral uncinate fasciculus , bilateral cingulum , fornix . to generate a two - level general linear model ( glm ) ( biswal et al . , 1995 ; rotarska - jagiela et al . , 2010
) , we sampled the averaged and normalized ( z - normalization ) functional time - series of the predefined seed regions .
then , the functional connectivity coefficients of the seed regions were entered into a second - level , mass - univariate one - way analysis of a covariance ( ancova ) model . in this model
the different groups were defined as a between - subject factor while the variables age , sex and education were considered as nuisance covariates . to correct for multiple comparisons , we used the fdr correction for main effect of functional connectivity ( thresholded at p  <  0.05 ( genovese et al . , 2002 ) ) .
the effect of the group factor was then visualized on an anatomical template ( courtesy of montreal neurologic institute ( mni ) ) . in a following step ,
all significant regions on this level were defined as regions - of - interest ( rois ) , which were used for a roi - averaged connectivity analysis ( post - hoc , pairwise , two - sample t - test [ two - tailed ] ) using voxel functional connectivity coefficients of each participant to assess group contrasts ( corrected for multiple comparisons using the cluster - level correction tool ( p  <  0.05 ; cluster - level correction , minimum cluster size of 200  mm ) ) .
the resulting statistical maps of the roi grey matter analysis using vbm showed all voxels of the rois with a significant group difference being set at a ( minimum cluster size  =  100  mm ) p - value threshold of p  <  0.001 ( small volume correction ) .
we also computed t - tests assessing group differences of roi fa and md values ( bilateral uncinate fasciculus , fornix , bilateral cingulum ) from the dti analysis ( at an alpha set at p  <  0.05 ; tfce [ threshold free cluster enhancement ] corrected ) , using the spss 21.0 software package ( statistical package for social sciences , http://www.spss.com ) .
moreover , we performed group comparisons of cognitive measures ( bvmt - r , hvlt - r ) using two independent anovas with group being a fixed factor and the test scores defined as independent variables .
group comparisons of bdi ii and brmas were conducted using t - tests to compare the two groups ( bd , con ) . all comparisons of cognitive and neurobehavioral measures were conducted with the spss 21.0 software package .
we controlled for a potential influence of medication on the results performing a bivariate correlation analysis ( pearson product - moment correlation , two - tailed ) between the functional connectivity values and the medication doses computed according to the method by almeida et al .
in addition , a correlation between the years of medication and the beta values of the functional activation during the resting - state measurement was calculated .
mean ( sd ) panss scores in the group of sz patients were : global scale : m  =  63.20 ( sd  =  5.20 ) , positive symptoms : m  =  15.40 ( sd  =  3.00 ) , negative symptoms : m  =  15.11 ( sd  =  1.90 ) and general symptomatology : m  =  32.60 ( sd  =  4.89 ) ( see table 1 ) .
assessing current psychopathology in the groups of healthy control subjects ( con ) and of the bd patients , we found that the bdi ii scores of the bd patients were significantly higher compared to the control group ( bd patients : m  =  9.85 [ sd  =  8.97 ] , con : m  =  2.10 [ sd  =  3.45 ] ; t  =  3.65 , p  =  0.001 ) indicating subclinical depressive symptoms in bd patients . brmas scores showed no significant group differences ( bd patients : m  =  0.38 [ sd  =  0.25 ] , con : m  =  0.25 [ sd  =  0.44 ] ; t  =  0.83 , ns ) .
however , none of the patients or controls fulfilled a score of > 18 in the bdi ii and a score of > 7 in the brmas , indicating acute symptoms .
verbal ( hvlt - r ) and non - verbal ( bvmt - r ) learning parameters showed significant group differences across groups ( hvlt - r : f  =  17.76 , p  <  0.001 ; bvlt - r : f  =  14.89 , p  <  0.001 ) .
the group differences in both memory parameters reached a significant level in the post - hoc contrasts between controls and sz patients and between bd patients and sz patients ( all p values  <  0.001 ) .
however , the group contrast between controls and bd patients showed significant differences only in the verbal learning values ( hvlt ; p  <  0.01 ) .
controls , sz and bd patients did not differ significantly in crystallized intelligence ( z  =  1.75 , ns ) ( see table 1 ) . the multi - subject result map ( voxel - by - voxel one - sample t - test of connectivity values ) with voxel clusters of significant bilateral hippocampus total functional connectivity included left frontal lobe , right lentiform nucleus , right putamen , left thalamus , bilateral parahippocampal gyrus and bilateral cingulate gyrus ( ancova , f - map corrected for fdr ) .
post - hoc pairwise comparisons ( two - sample t - tests , corrected for nuisance variables ) showed a significant reduction of functional connectivity scores in the left frontal lobe , the right lentiform nucleus , the right putamen and the left thalamus in sz patients compared with control subjects .
higher functional connectivity scores in sz patients when compared with controls were found in the bilateral parahippocampal gyrus and in the bilateral cingulate gyrus ( all ps  <  0.001 ; cluster - level correction ; view fig . 1 , table 2 ) . left frontal lobe functional connectivity was also decreased in bd patients in comparison with controls ( p  <  0.001 ; cluster - level correction ; view fig . 1 , table 2 ) .
if graded differences are defined as significant differences between all groups ( sz  >  bd  >  con ) , none of the functional connectivity parameters fulfilled this criterion .
however , in the left thalamus , bd patients showed mean values that lay between controls and sz patients without showing statistically significant differences in comparison with the control group ( view fig . 1 , table 2 ) . the vbm roi analysis of the left and right hippocampus revealed significant differences across groups ( left : f  =  11.77 , right : f  =  10.89 , all ps  <  0.001 ) .
in the right hippocampal volumes sz had significantly lower beta scores in comparison with controls .
differences in beta scores in bd as compared to controls did not reach a significant level ( con :   =  0.017 [ sd  =  0.04 ] , bd :   =  0.007 [ sd  =  0.05 ] , sz :   =  0.031 [ sd  =  0.05 ] ) . in left hippocampal volumes , controls had the significantly highest beta scores , followed by bd patients and sz patients ( left : con :   =  0.017 [ sd  =  0.009 ] , bd :   =  0.007 [ sd  =  0.009 ] , sz :   =  0.030 [ sd  =  0.010 ] ; see fig .
dti roi analyses revealed significant group differences in the cingulum bilaterally ( md ) , in the fornix ( fa , md ) and the uncinate fasciculus bilaterally ( fa , md ) ( all p ; tfce  <  0.05 ) .
scheff post - hoc single contrasts for the left and right cingulum showed the lowest values for md in controls ( all p ( tfce )  <  0.05 ) .
post - hoc group comparisons between the two patient groups showed significantly higher md scores in sz than in bd patients in the left cingulum , and  the other way around  for the right cingulum ( highest md scores in bd ) ( all p ( tfce )  <  0.05 ) .
after computing post - hoc single contrasts of the fornix we found significantly lower fa / higher md values for both patient groups in comparison with controls ( p ( tfce )  <  0.05 ) , but no significant group contrast between the patient groups ( p ( tfce )  >  0.05 ) . in the left and right uncinate fasciculus , sz patients showed lower fa values in comparison with controls ( p  <  0.001 ) .
a comparison of md values in the bilateral uncinate fasciculus resulted in higher values in controls as compared to sz patients ( all ps ( tfce )  <  0.05 ) .
bd patients showed trend level significance in the md scores of the right uncinate fasciculus compared with controls ( p  =  0.10 ) .
furthermore , in computing a direct comparison between the two patient groups , md scores of the right uncinate fasciculus proved to be significantly increased in sz patients in comparisons with bd patients .
there was also trend level significance in the md scores of the left uncinate fasciculus and the fa scores of the right uncinate fasciculus between sz and bd patients ( p  <  0.10 ) ( see fig .
none of the clinical parameters separately assessed for each disease group ( positive and negative symptoms in sz [ panss ] , acute affective symptoms [ bdi ii for depressive , brmas for manic symptoms ] ) showed a significant correlation with any of the functional or structural imaging parameters ( all p values  >  0.05 ) .
the bvmt - r ( non - verbal learning ) values were not significantly associated with any of the imaging parameters across groups ( p  >  0.05 ) .
verbal learning , however ( measured using the hvlt - r ) was significantly correlated with right hippocampus volumes in the bd ( r  =  0.490 , p  =  0.03 ) and in the sz ( r  =  0.395 , p 
=  0.04 ) patient groups ( but not in controls ; p  >  0.05 ) . yet
these correlations did not reach significance after correcting for multiple comparisons ( bonferroni correction ) .
none of the imaging parameters showed any significant correlation with the medication scores or with years of medication in bd or sz patients ( p  >  0.05 ) .
our seed - based functional connectivity analysis ( resting - state fmri ) with the bilateral hippocampus as the seed region revealed markers of hypo- and hyperconnectivity between hippocampal and fronto - limbic regions in both , sz and bd patients , when compared with controls .
in particular , sz patients showed hypoconnectivity between the bilateral hippocampus , the left frontal lobe , the left thalamus , the bilateral lentiform nucleus and the right putamen .
the results confirm current neurophysiological models that suggest altered functional connectivity within frontal and between frontal and limbic regions in sz ( meyer - lindenberg et al .
, 2005 ; kuhn and gallinat , 2013 ) and a frontal  limbic network disturbance in bd ( yurgelun - todd et al . , 2000 ;
2005 ; kronhaus et al . , 2006 ; lyoo and renshaw , 2010 ) .
accordingly , current resting - state findings in bd patients revealed changes in the functional connectivity between frontal and limbic brain regions in comparison with controls ( anand et al . , 2009 ; chepenik et al . , 2010 ; ongur et al . , 2010 ;
chai et al . , 2011 ) and fronto - striatal hypoconnectivity during rest in bd patients ( anand et al .
moreover , sz patients showed higher functional connectivity scores in the bilateral parahippocampal gyrus and in the bilateral cingulate gyrus when compared with control subjects .
hypo- and hyperconnectivity in sz patients  are in line with the theory of a disconnectivity syndrome in psychiatric disorders first proposed by friston ( 1998 ) that suggested a failed connectivity between relevant brain regions .
the result of either increased or decreased functional connectivities between the hippocampus and fronto - limbic brain regions shows the complex pattern of disturbance of brain networks in sz .
furthermore , our findings in bd patients are in accordance with a recent meta - analysis ( e.g. , ( chen et al . , 2011 ) ) which mainly suggests hyperactivity of limbic regions but not directly of the hippocampus in bd patients .
both sz and bd patients showed lower grey matter volumes in the left hippocampus in comparison with controls ; however volume deficits in the right hippocampus were limited to sz patients .
this is in - line with previous findings , which robustly show hippocampal volume reductions in sz ( wright et al . , 2000 ) , but only inconsistently in bd ( adler et al . , 2007 ; koo et al . , 2008 ; scherk et al . ,
( 2011 ) that hippocampal volume may be of importance for the differentiation between sz and bd .
brown and colleagues based their assumption on direct comparisons of grey matter volumes in subcortical regions , showing lower volumes in sz patients compared with bd patients in the right hippocampus , in the putamen and the amygdala .
white matter fibre integrity , as assessed by mean diffusivity , was strongly affected in sz patients in the tracts connecting the hippocampus with other brain structures ( uncinate fasciculus , cingulum , fornix ) , whereas alterations in the bd patients were more subtle .
this result is in line with findings of multiple white matter changes in sz including the interconnections of the frontal lobe , thalamus , cingulate gyrus and white matter changes of the left temporal deep white matter ( interconnections of frontal lobe , insula , hippocampus - amygdala , temporal lobe , occipital lobe ) ( williamson and allman , 2012 ) .
accordingly , in bd patients , mainly right - sided changes in dti parameters have been reported ( parahippocampal gyrus and close to the subgenual acc ) ( vederine et al . , 2011 ) .
overall , the current data partly support the concept of graded changes across the sz and bd spectrum .
sz patients show more pronounced deficits regarding neurobehavioral measures of episodic memory performance , alongside with stronger structural alterations when compared with bd patients .
bd patients showed more subtle behavioral deficits in memory performance , and also more subtle functional and structural changes in comparison with controls . in a direct comparison , visual learning ( hvlt ) , left hippocampal volume ( vbm ) , mean diffusivity of the bilateral cingulum and the right uncinate fasciculus showed evidences for the idea that both patient groups are affected , but bd patients less severe .
however , the resting state functional connectivity and other anatomical parameters did not support this concept of graded change .
the main finding of graded changes across the sz and bd spectrum can be interpreted as partly contradictory to kraepelin 's ( kraepelin , 1896 ) distinction of two entirely different and independent disease entities .
however , our findings are in line with a large body of recent imaging and genetic research showing that bd and sz share some core molecular and pathophysiological mechanisms ( craddock and owen , 2005 ; craddock and owen , 2010 ) and thereby can not be conceptualized as two entirely distinct classes of disorders .
we may assume that bd and sz may share some pathophysiological pathways but that there might be also distinct alterations across multimodal measures
. such an interpretation would conform with the findings from recent genome - wide association studies , which reveal partial but not complete overlap of the genetic risk profiles of these disorders ( hall et al . ,
2014 ) . resting - state analysis revealed reduced functional connectivity in the left frontal lobe , the right lentiform nucleus , the right putamen and the left thalamus in sz patients compared with control subjects , and higher functional connectivity scores in sz patients when compared with controls in the bilateral parahippocampal gyrus and in the bilateral cingulate gyrus , but no alterations in bd patients . in contrast , left frontal lobe functional connectivity was decreased in bd patients in comparison with controls but not in sz patients .
right hippocampal volumes might not be affected in bd patients but in sz patients in comparison with controls .
regarding dti parameters , mean diffusivity ( md ) of fibre tracks related to the hippocampus showed graded changes , but this was less present in fibre integrity parameters ( fa ) .
clinical parameters specifically assessed for each disease group separately revealed no significant associations with the imaging findings .
that means that our main findings are independent of acute symptomatology , including positive and negative symptoms in sz [ panss ] , and acute affective symptoms ( bdi ii for depressive , brmas for manic symptoms ) in bd patients .
however , our study was neither powered nor specifically designed to assess such correlations because our patient samples showed relatively low severity scores of acute symptoms .
verbal learning ( hvlt - r ) scores showed significant group differences across groups , with the lowest values found for sz patients and subtle deficits in bd patients in comparison with healthy controls .
crystallized intelligence did not differ across groups , and all main group differences in imaging parameters were independent of crystallized intelligence . furthermore , verbal learning ( hvlt - r ) was significantly correlated with right hippocampal volumes in the bd and in the sz patient groups although these comparisons did not last after correcting for multiple comparisons .
although all patients of our study were treated with psychiatric medication at the time of measurement , we tested potential influence of psychiatric medication on the functional and structural brain changes in our study .
we failed to show any association between functional and structural parameters and medication status or duration of medication use .
this result confirms previous findings that report no influence or even a positive effect ( reduced group differences between patients and controls ) of psychopharmacological treatment on structural and functional findings in psychiatric patients ( dazzan et al . , 2005 ;
the sample size of the current study is relatively small , but we ensured that all patients were screened applying very strict inclusion criteria .
for instance , we included only bd patients with bd i disorder ( not bd ii ) , we included only sz patients with paranoid subtype ( no schizoaffective or other subtype ) , and we ensured that none of the patients had any history of drug addiction .
a direct comparison of sz and bd , two major psychotic disorders , is of interest regarding the ongoing debate that was started with the introduction of the kraepelinian dichotomy concept in 1896 ( kraepelin , 1896 ) .
currently this debate centres on the question whether bd and sz are distinct disorders or may share some pathophysiological pathways .
our research suggests that although both examined patient - groups may share some pathophysiological pathways , functional and structural abnormalities may be more severe in sz than in bd .
further studies are needed to explore and explain these graded changes in sz and bd to define which parameters show graded changes and which do not .
the approach to examine functional as well as structural markers in the same study follows recent developments in the field ( womer et al . , 2009 ) , suggesting a mechanistic relationship between structural and functional abnormalities .
thus , the development of a multi - modal neurophysiological model of psychoses , with shared and distinct pathways across traditional disease entities , may help to clarify the pathways that contribute to individual symptom patterns ( linden , 2012 ) .
 a potential clinical and etiological overlap between schizophrenia ( sz ) and bipolar disorder ( bd ) has long been a subject of discussion . 
 imaging studies imply functional and structural alterations of the hippocampus in both diseases . 
 thus , imaging this core memory region could provide insight into the pathophysiology of these disorders and the associated cognitive deficits . to examine possible shared alterations in the hippocampus 
 , we conducted a multi - modal assessment , including functional and structural imaging as well as neurobehavioral measures of memory performance in bd and sz patients compared with healthy controls . 
 we assessed episodic memory performance , using tests of verbal and visual learning ( hvlt , bvmt ) in three groups of participants : bd patients ( n  =  21 ) , sz patients ( n  =  21 ) and matched ( age , gender , education ) healthy control subjects ( n  =  21 ) . 
 in addition , we examined hippocampal resting state functional connectivity , hippocampal volume using voxel - based morphometry ( vbm ) and fibre integrity of hippocampal connections using diffusion tensor imaging ( dti ) . 
 we found memory deficits , changes in functional connectivity within the hippocampal network as well as volumetric reductions and altered white matter fibre integrity across patient groups in comparison with controls . 
 however , sz patients when directly compared with bd patients were more severely affected in several of the assessed parameters ( verbal learning , left hippocampal volumes , mean diffusivity of bilateral cingulum and right uncinated fasciculus ) . 
 the results of our study suggest a graded expression of verbal learning deficits accompanied by structural alterations within the hippocampus in bd patients and sz patients , with sz patients being more strongly affected . 
 our findings imply that these two disorders may share some common pathophysiological mechanisms . 
 the results could thus help to further advance and integrate current pathophysiological models of sz and bd . 
Introduction
Material and methods
Results
Discussion
Conclusions