in patients with intractable partial epilepsies , optimal adjustment of antiepileptic drugs ( aed ) fails to improve seizure frequency in at least 65  % of patients . presurgical evaluation of these patients leaves a substantial proportion of an estimated 40  % unresected , either due to ineligibility for surgery or because patients decide against this non - reversible but potentially curative procedure . this difficult - to - treat patient group needs alternative treatment options . in the last decade , deep brain stimulation ( dbs ) has received increasing interest as a therapeutic option for these patients [ 4 , 5 ] . even though dbs is reversible and verifiably safe , this may be partly due to the fact that in contrast to most resective treatment strategiesdbs is not a causative treatment approach and rarely results in seizure freedom . also , in patients treated with dbs for indications other than epilepsy , cognitive [ 8 , 9 ] , psychiatric [ 8 , 10 , 11 ] , or behavioural side effects [ 12 , 13 ] have been known for decades and might overshadow a differential view on this new treatment strategy for particular epilepsy patients . recently , a randomised controlled clinical trial demonstrated efficacy of electrical stimulation of the anterior nucleus of the thalamus ( ant ) in terms of seizure frequency reduction . in particular , patients with temporal lobe epilepsy appear to benefit from ant stimulation [ 14 , 15 ] . another single - blind trial evaluated the antiictal efficacy of centromedian thalamic ( cmt ) nucleus dbs . the authors found no relevant effect in terms of seizure frequency reduction in patients with frontal lobe epilepsy , whereas in patients with generalised epilepsy , mean reduction in seizure frequency was 77  % . recently , this target has been chosen for distinct epilepsy syndromes , such as progressive myoclonus epilepsy   and epilepsy due to ring chromosome 20 . to identify and characterise new dbs targets for patients with difficult - to - treat epilepsy , we assessed safety and indications of chronic bilateral stimulation of the nucleus accumbens ( nac ) . this structure plays a decisive role in both functional and anatomical connectivity between frontal and temporal lobes [ 21 , 22 ] . in rodent models of generalised [ 23 , 24 ] and both temporal [ 2528 ] and frontal lobe seizures , furthermore , nac stimulation has been demonstrated to elicit euphoria in psychiatrically unaffected patients   and to ameliorate symptoms in patients with major depression . patients with epilepsy are at high risk for comorbid depression   and common network characteristics for both disorders have been proposed [ 32 , 33 ] . in the following , we report clinical outcome of nac stimulation in five patients with intractable partial epilepsy following an in - house protocol . we assessed the effect of electrical stimulation on quality of life , psychiatric and neuropsychological parameters , and additionally on severity and frequency of disabling seizures . five patients with medically intractable partial epilepsy ( defined as failure of at least two aeds in adequate doses to produce seizure freedom for at least 12  months ) became part of our in - house protocol for bilateral dbs of the nac between january 2010 and december 2012 . resection or advised invasive eeg monitoring was refused by the patients , or resection was not advisable at all or had been ineffective . subsequently , patients were only offered dbs surgery if they had an average frequency of at least one disabling seizure per month ( complex partial seizure [ cps ] , and/or generalised tonic patients were not offered dbs if they suffered from progressive neurodegenerative disorders or had additional non - epileptic seizures , if iq was lower than 70 , if they were pregnant , or if they were currently treated with vagus nerve stimulation . as chronic stimulation of the vagus nerve and of the ant has been shown to be efficacious in large - scale controlled trials [ 14 , 35 ] , all patients with intractable and non - resectable partial epilepsy were subsequently offered these widely accepted minimally invasive surgery options and our in - house protocol for nac stimulation ( details see below ) . the five patients reported here took part in pre - operation interviews , in which all eligible patients were informed about different levels of evidence concerning safety and efficacy , current legal status of approval , and the extent of invasiveness of each surgical procedure . the possible risk of any surgical intervention led ten eligible patients to decide against any optional minimally invasive procedure . two patients opted for vns because the surgical intervention does not involve the brain , and another two patients decided for dbs of the ant because of the greater evidence for efficacy . according to our pre - interventional discussions with patients , those who elected to undergo dbs felt that the risk of invasive surgery was outweighed by the possible benefit of direct effects on deep brain structures , as opposed to an indirect influence via a cranial nerve . outcome parameters of interest were mean change in patient - reported outcome questionnaires including liverpool seizure severity scale ( lsss ) , beck depression inventory ( bdi - ia ) , quality of life in epilepsy questionnaire ( qolie-31-p ) , and a standardised psychiatric interview employing mini international neuropsychiatric interview ( mini ) , as well as a neuropsychological test battery . the latter covered in detail the areas of attentional performance [ test of attentional performance ( tap 2.2 ) ] , cognitive speed [ trail making test ( tmt ) , performance evaluation system subtest 7 ( lps , i.e. leistungspruefungssystem , subtest 7 ) , d2attention stress test ] , executive function [  regensburger  word fluency test ( rwt ) , hamasch 5-point test [ h5pt ) ] , memory and learning functions [ verbal learn and memory test ( vlmt ) , wechsler memory scale - revised ( wms - r ) ] , and word retrieval ( boston naming test ) . all parameters were preoperatively assessed and compared to the results at the end of 6-month nac stimulation . we also assessed the proportion of responders ( 50  % seizure frequency reduction ) comparing the mean frequency of disabling seizures surveyed in the 3  months prior to electrode implantation to the data after 6  months of nac stimulation . aeds remained unchanged 3  months before electrode implantation and during 6  months of follow - up . using standardised stereotactic technique , four medtronic model 3387 dbs leads ( medtronic , minneapolis , mn , usa ) were implanted bilaterally into the nac and ant and subsequently connected to a single impulse generator ( ipg ; activa - pc , medtronic , ma , usa ) . we defined the nac target referred to the most distal contact of the quadripolar electrode to a point 2  mm rostral to the anterior commissure at the level of the mid - sagittal plane , 34  mm ventral and 68  mm lateral of the midline . in addition , we modified the atlas coordinates according to the individual treatment planning - mri displaying on coronal reconstructions of a 3d - mprage series ( 3  t scanner , 0.8  mm resolution ) the medial border ( vertical limb of broca s diagonal band ) and the ventral border ( olfactory tubercle / horizontal limb of broca s diagonal band ) of the nac region ( fig . the angulation of the trajectory relative to the intercommissural line was chosen to cover with two electrode contacts the central / lateral part ( nac core ) and the medial part ( nac shell ) [ 40 , 41 ] . ant targeting was also guided by atlas - based coordinates ( schaltenbrand and wahren , 6  mm lateral to , 8  mm anterior to and 12  mm above the midcommisural point ) and direct visualisation of this nucleus on 3d - mprage images . the electrode localisation was documented intraoperatively by stereotactic x - ray imaging using x - ray tubes installed in the or and by postoperative ct examinations . ct as well as x - ray images were fused with the planning - mri ( fig .  1).fig .  1distal electrode position in the nac , depicted postoperatively with ct - fused presurgical t1mri in coronal and axial view ( red circles ) . both distal contacts of the quadripolar electrodes were placed in the nac as intended , the third contact within the transition area to the medial border of the abutting internal capsule and the highest , i.e. the fourth contact at a point in the most medial part of the capsule or in the transition area to the caudate . the red square depicts an electrode lead to the left anterior nucleus of thalamus distal electrode position in the nac , depicted postoperatively with ct - fused presurgical t1mri in coronal and axial view ( red circles ) . both distal contacts of the quadripolar electrodes were placed in the nac as intended , the third contact within the transition area to the medial border of the abutting internal capsule and the highest , i.e. the fourth contact at a point in the most medial part of the capsule or in the transition area to the caudate . the red square depicts an electrode lead to the left anterior nucleus of thalamus following surgery , nac stimulation was initiated after mean 20.4  days ( 10.5 ) and continued for 6  months ( 125  hz , 5  v , 90  s , 1  min on , 5  min off ) . voltage reduction in 2  v steps was allowed in case of unexpected events such as pending series of disabling seizures , status epilepticus , or severe cognitive or psychiatric impairments . additional ant electrode implantation was chosen to allow for alternative chronic stimulation of the ant in case of ineffective nac stimulation ( but in all five patients , ant stimulation has not been used ) . chronic stimulation of the ant has been shown to be effective regarding frequency of cps and severely impairing seizures . the institutional review board of the university of magdeburg approved the surgical procedure ( registration number 03/08 ) . all patients granted written informed consent for implantation of the neurostimulation system . due to interindividual heterogeneity , scores of neurocognitive testing at the end of the nac stimulation period were related to values collected prior to electrode implantation and expressed as fractions of one . after testing for gaussian distribution ( kolmogorov  smirnov test ) , which was negative for all parameters , the wilcoxon rank sum test was used for comparison of ordinal data . five patients with medically intractable partial epilepsy ( defined as failure of at least two aeds in adequate doses to produce seizure freedom for at least 12  months ) became part of our in - house protocol for bilateral dbs of the nac between january 2010 and december 2012 . resection or advised invasive eeg monitoring was refused by the patients , or resection was not advisable at all or had been ineffective . subsequently , patients were only offered dbs surgery if they had an average frequency of at least one disabling seizure per month ( complex partial seizure [ cps ] , and/or generalised tonic patients were not offered dbs if they suffered from progressive neurodegenerative disorders or had additional non - epileptic seizures , if iq was lower than 70 , if they were pregnant , or if they were currently treated with vagus nerve stimulation . as chronic stimulation of the vagus nerve and of the ant has been shown to be efficacious in large - scale controlled trials [ 14 , 35 ] , all patients with intractable and non - resectable partial epilepsy were subsequently offered these widely accepted minimally invasive surgery options and our in - house protocol for nac stimulation ( details see below ) . the five patients reported here took part in pre - operation interviews , in which all eligible patients were informed about different levels of evidence concerning safety and efficacy , current legal status of approval , and the extent of invasiveness of each surgical procedure . the possible risk of any surgical intervention led ten eligible patients to decide against any optional minimally invasive procedure . two patients opted for vns because the surgical intervention does not involve the brain , and another two patients decided for dbs of the ant because of the greater evidence for efficacy . according to our pre - interventional discussions with patients , those who elected to undergo dbs felt that the risk of invasive surgery was outweighed by the possible benefit of direct effects on deep brain structures , as opposed to an indirect influence via a cranial nerve . outcome parameters of interest were mean change in patient - reported outcome questionnaires including liverpool seizure severity scale ( lsss ) , beck depression inventory ( bdi - ia ) , quality of life in epilepsy questionnaire ( qolie-31-p ) , and a standardised psychiatric interview employing mini international neuropsychiatric interview ( mini ) , as well as a neuropsychological test battery . the latter covered in detail the areas of attentional performance [ test of attentional performance ( tap 2.2 ) ] , cognitive speed [ trail making test ( tmt ) , performance evaluation system subtest 7 ( lps , i.e. leistungspruefungssystem , subtest 7 ) , d2attention stress test ] , executive function [  regensburger  word fluency test ( rwt ) , hamasch 5-point test [ h5pt ) ] , memory and learning functions [ verbal learn and memory test ( vlmt ) , wechsler memory scale - revised ( wms - r ) ] , and word retrieval ( boston naming test ) . all parameters were preoperatively assessed and compared to the results at the end of 6-month nac stimulation . we also assessed the proportion of responders ( 50  % seizure frequency reduction ) comparing the mean frequency of disabling seizures surveyed in the 3  months prior to electrode implantation to the data after 6  months of nac stimulation . aeds remained unchanged 3  months before electrode implantation and during 6  months of follow - up . implantation of dbs systems was performed under general anaesthesia . using standardised stereotactic technique , four medtronic model 3387 dbs leads ( medtronic , minneapolis , mn , usa ) were implanted bilaterally into the nac and ant and subsequently connected to a single impulse generator ( ipg ; activa - pc , medtronic , ma , usa ) . we defined the nac target referred to the most distal contact of the quadripolar electrode to a point 2  mm rostral to the anterior commissure at the level of the mid - sagittal plane , 34  mm ventral and 68  mm lateral of the midline . in addition , we modified the atlas coordinates according to the individual treatment planning - mri displaying on coronal reconstructions of a 3d - mprage series ( 3  t scanner , 0.8  mm resolution ) the medial border ( vertical limb of broca s diagonal band ) and the ventral border ( olfactory tubercle / horizontal limb of broca s diagonal band ) of the nac region ( fig .  1 ) . the angulation of the trajectory relative to the intercommissural line was chosen to cover with two electrode contacts the central / lateral part ( nac core ) and the medial part ( nac shell ) [ 40 , 41 ] . ant targeting was also guided by atlas - based coordinates ( schaltenbrand and wahren , 6  mm lateral to , 8  mm anterior to and 12  mm above the midcommisural point ) and direct visualisation of this nucleus on 3d - mprage images . the electrode localisation was documented intraoperatively by stereotactic x - ray imaging using x - ray tubes installed in the or and by postoperative ct examinations . ct as well as x - ray images were fused with the planning - mri ( fig . 1distal electrode position in the nac , depicted postoperatively with ct - fused presurgical t1mri in coronal and axial view ( red circles ) . both distal contacts of the quadripolar electrodes were placed in the nac as intended , the third contact within the transition area to the medial border of the abutting internal capsule and the highest , i.e. the fourth contact at a point in the most medial part of the capsule or in the transition area to the caudate . the red square depicts an electrode lead to the left anterior nucleus of thalamus distal electrode position in the nac , depicted postoperatively with ct - fused presurgical t1mri in coronal and axial view ( red circles ) . both distal contacts of the quadripolar electrodes were placed in the nac as intended , the third contact within the transition area to the medial border of the abutting internal capsule and the highest , i.e. the fourth contact at a point in the most medial part of the capsule or in the transition area to the caudate . the red square depicts an electrode lead to the left anterior nucleus of thalamus following surgery , nac stimulation was initiated after mean 20.4  days ( 10.5 ) and continued for 6  months ( 125  hz , 5  v , 90  s , 1  min on , 5  min off ) . voltage reduction in 2  v steps was allowed in case of unexpected events such as pending series of disabling seizures , status epilepticus , or severe cognitive or psychiatric impairments . additional ant electrode implantation was chosen to allow for alternative chronic stimulation of the ant in case of ineffective nac stimulation ( but in all five patients , ant stimulation has not been used ) . chronic stimulation of the ant has been shown to be effective regarding frequency of cps and severely impairing seizures . the institutional review board of the university of magdeburg approved the surgical procedure ( registration number 03/08 ) . due to interindividual heterogeneity , scores of neurocognitive testing at the end of the nac stimulation period were related to values collected prior to electrode implantation and expressed as fractions of one . after testing for gaussian distribution ( kolmogorov  smirnov test ) , which was negative for all parameters , the wilcoxon rank sum test was used for comparison of ordinal data . five patients ( 2 females ) , 3053  years old ( mean , 41.6    10.6  years ) , were diagnosed with epilepsy 1732  years ( mean 23.6    7.3  years ) prior to dbs surgery . presurgical video - eeg evaluation revealed seizure onset zones in left mesio - temporal ( 2 patients ) , bilateral mesio - temporal , left fronto - temporal or bilateral frontal ( each 1 patient ) structures . only one patient with left mesio - temporal epilepsy had undergone prior resective surgery ( anterior temporal lobectomy due to hippocampal sclerosis , no seizure freedom ) , all other patients had non - lesional 1.5 or 3.0  t mri . at time of electrode implantation , patients were administered 24 ( mean 2.6 ) aeds.table  1clinical dataparticipantsexage ( years)epilepsy duration ( years)region of seizure onsetmriseizures during studyaeds during study1male3018bilateral frontalnormalcps , gtcspht , ltg , zns , lcm2female5320bilateral mesio - temporalnormalcps , gtcslcm , ltg3 
 male4031left mesio - temporalhippocampal sclerosissps , gtcslcm , ltg4male3332bilateral frontal and left mesio - temporalnormalsps , gtcsstp , oxc , clb5female5217left mesio - temporalnormalsps , cps , gtcsltg , lcm 
 mri magnet resonance imaging , sps simple partial seizures , cps complex partial seizures , gtcs generalised tonic  clonic seizures , aeds , antiepileptic drugs , pht phenytoin , ltg lamotrigine , zns zonisamide , lcm lacosamide , stp stiripentole , oxc oxcarbazepine , clb clobazam 
 ineffective epilepsy surgery 
 mri magnet resonance imaging , sps simple partial seizures , cps complex partial seizures , gtcs generalised tonic  clonic seizures , aeds , antiepileptic drugs , pht phenytoin , ltg lamotrigine , zns zonisamide , lcm lacosamide , stp stiripentole , oxc oxcarbazepine , clb clobazam 
 ineffective epilepsy surgery regarding seizure severity , the lsss was significantly reduced after 6  months of nac stimulation as compared to scores prior to implantation of electrodes ( p  =  0.043).the qolie-31-p total score as well as its subscales  seizure worry  and  overall  improved only by trend ( both p  =  0.068 ) . neuropsychological testing , the mini and the bdi - ia did not show significant differences after nac stimulation in comparison to examinations before electrode implantation ( table  2 ) . two out of five patients were responders with 50  % frequency reduction of disabling seizures ( patient # 3 , 50  % , and patient # 4 , 85.4  % reduction ) . both responders and non - responders distal contacts were inside the target zone , as postoperative ct as well as x - ray images fused with the planning - mri have revealed.table  2clinical outcome after six months of nac stimulationprior to electrode implantationafter nac stimulationwilcoxon testfisher s exact testpatients reported outcome questionnaires ( mean    sd )  lsss59.00    3.6749.60    8.41 
 0.043 
 bdi-1a10.80    7.466.60    6.070.104  qolie-31-p - total score45.87    09.8250.72    08.320.068  subscale mini ( number of participants )  major depression2/51/51.000  suicidal tendency1/51/51.000  mania0/50/5n.c . psychosis0/50/5n.c .  generalised anxiety disorder0/52/50.444neurocognition 
 11.06    0.180.225  attentional performance1 1.08    0.18 

 0.465 
 cognitive speed10.97    0.050.225  executive functions11.29    0.470.255  memory and learning function10.95 0.300.500  word retrieval11.03    0.040.258frequency of seizure types in 28-day periods ( mean    sd )  sps 
 0.27    0.370.50    0.870.593  cps 
 1.27    1.642.20    4.011.000  gtcs 
 2.27    3.231.40    1.040.893  disabling seizures3.53    2.793.60    4.930.893 
 sd standard deviation , n.c not calculated , nac nucleus accumbens , sps simple partial seizure , cps complex partial seizure , gtcs generalised tonic clonic seizure , lsss liverpool seizure severity score , bdi-1a beck depression inventory , version ia , qolie-31-p quality of life in epilepsy , m.i.n.i mini international neuropsychiatric interview 
 3 out of 5 patients with sps 
 3/7 cps 
 all experienced gtcs 
 due to interindividual heterogeneity , results of neurocognitive testing after nac stimulation were related to the individual values prior to electrode implantation and expressed as fractions of 1 ( sd ) clinical outcome after six months of nac stimulation 
 sd standard deviation , n.c not calculated , nac nucleus accumbens , sps simple partial seizure , cps complex partial seizure , gtcs generalised tonic  clonic seizure , lsss liverpool seizure severity score , bdi-1a beck depression inventory , version ia , qolie-31-p quality of life in epilepsy , m.i.n.i mini international neuropsychiatric interview 
 3 out of 5 patients with sps 
 all experienced gtcs 
 due to interindividual heterogeneity , results of neurocognitive testing after nac stimulation were related to the individual values prior to electrode implantation and expressed as fractions of 1 ( sd ) overall , we found a median reduction of disabling seizure frequency of 37.5  % , but no significant changes in the mean frequencies of simple partial seizures ( sps ) , cps and gtcs ( table  2 ) . the time course of mean frequency of sps , cps and gtcs is depicted in fig . 2time course of mean frequency of simple partial ( sps ) , complex partial ( cps ) and generalised tonic clonic seizures ( gtcs ) . following 3  months of seizure survey before electrode implantation ( black arrow , surgery ) , stimulation of the nucleus accumbens ( nac ) was started 22.4  days ( 10.5 ) days post - surgery ( red arrow , dbs on ) . frequency of all seizure types was assessed 3 and 6  months after onset of nac stimulation ( black arrow , 6-month follow - up ) . after 6  months of nac stimulation , frequency of cps has increased , whereas that of gtcs has decreased . dbs : deep brain stimulation time course of mean frequency of simple partial ( sps ) , complex partial ( cps ) and generalised tonic clonic seizures ( gtcs ) . following 3  months of seizure survey before electrode implantation ( black arrow , surgery ) , stimulation of the nucleus accumbens ( nac ) was started 22.4  days ( 10.5 ) days post - surgery ( red arrow , dbs on ) . frequency of all seizure types was assessed 3 and 6  months after onset of nac stimulation ( black arrow , 6-month follow - up ) . after 6  months of nac stimulation , frequency of cps has increased , whereas that of gtcs has decreased . dbs : deep brain stimulation bdi - ia and/or mini revealed depressive symptoms in three patients ( # 3 , # 4 , # 5 ) prior to electrode implantation . following nac stimulation , depressive symptoms resolved in one of them ( patient # 4 ) . patients # 1 and # 2 did not have depressive symptoms before surgery and at the end of nac stimulation . with regard to other psychiatric entities assessed by mini , patients # 3 and # 5 had new onset generalised anxiety disorder after 6-month nac stimulation . however , only patient # 5 had an increase in the total number of psychiatric conditions ( from 0 to 2 [ generalised anxiety and major depression ] ) . in this patient , stimulation voltage had to be reduced as a precaution from 5 to 3  v in accordance with our in - house protocol due to abrupt increase in seizure frequency . in five patients with intractable partial epilepsy , clinical consequences of 6-month nac stimulation were comprehensively assessed including quality of life , and psychiatric and neuropsychological signs or symptoms , and seizure severity . the main finding was a lack of deterioration of neuropsychological parameters or psychiatric conditions , and overall reduction in subjectively perceived seizure severity . concerning seizure frequency , our small cohort revealed a median frequency reduction of disabling seizures of 37.5  % , two out of five patients experienced a seizure reduction of at least 50  % . looking at the time course of seizure frequency postsurgically , there was a decrease before stimulation was initiated ( fig .  2 ) . this is similar to the observation by fisher et al .   and hodaie et al . after insertion of electrodes for ant stimulation , and has also been reported by valentin et al . whether this pre - stimulation decrease in seizure frequency suggests a short - term placebo effect or a microlesional effect by electrode implantation is still a matter of discussion . the sante ( stimulation of the anterior nuclei of thalamus for epilepsy ) trial , so far the only large - scale randomised controlled dbs study in epilepsy , showed that ant stimulation results in significant seizure frequency reduction after 3  months . complementary to the 110 patients reported in sante , our five patients showed significantly reduced seizure severity after 6  months of nac stimulation in spite of an overall unchanged mean seizure frequency . the non - significant decrease in frequency of gtcs and increase of cps might be an explanation for this significant reduction in seizure severity . the trend to less gtcs may also be reflected by the decrease in  seizure worry  score in the quality - of - life assessment . also , the item  seizure worry  correlated with seizure severity , as found in other studies . thus , we tend to interpret the non - significant trend to reduction in  seizure severity  as plausible . the lack of statistical significance with regard to improvement of this item and the summarised quality - of - life score is likely due to the small number of patients . comprehensively assessed the effect of dbs of the cmt nucleus in a small number of patients ( n  =  11 ; frontal lobe and generalised epilepsies ) . in seven of their patients , seizure severity score and quality of life assessments were available . compared to the results before implantation , a significant improvement both in seizure severity and qolie-32-p total score thus , they found that quality - of - life score improves parallel to reduction of seizure severity score . this correlation has already been validated in large cohorts and seems to be independent from seizure frequency [ 4345 ] . nac stimulation has been shown to ameliorate symptoms in patients with major depression [ 31 , 46 ] . . it can not be determined whether this observation is seizure- or target - dependent , because this patient ( # 4 ) was a responder with an 85.4  % reduction in seizure frequency . worsening of cognition and depressive symptoms as reported due to ant stimulation in the sante trial , however , are probably target - dependent . even though seizure frequency declined after ant stimulation , patients complained significantly more often of depressive symptoms and memory deficits than unstimulated control subjects . in one of our patients ( # 4 ) , depressive symptoms resolved with decreased seizure frequency , and patient # 5 experienced an increase both in seizure frequency and in numbers of psychiatric symptoms . we therefore can not report an independent antidepressant effect of nac stimulation in our cohort . interestingly , our overall cohort did not show changes in neuropsychological subscores ( table  2 ) , indicating that nac stimulation seems to be inert concerning cognitive function . an open observational study on ant stimulation , which allowed for aed changes , reported amelioration in verbal memory during 12  months of stimulation . in the controlled sante trial , however , significantly more patients complained of memory deficits and similarly of depressive symptoms . a plausible explanation for the observed neurocognitive side effects is the well - known involvement of the ant in memory processing [ 48 , 49 ] . the major methodological limitation of this case series is the small number of patients , which renders our findings primarily anecdotal . also , a placebo effect of high expectation due to an invasive intervention can not be excluded due to the uncontrolled and unblinded protocol . this , however , included a long time period of 6  months , which in our view makes a pure placebo effect rather unlikely . furthermore , placebo studies found that a positive response due to elevated post - interventional expectancy is negligible for a long - term placebo effect . lastly , due to the unblinded in - house protocol we can not exclude that microlesional effects of the nac or the ancillary implanted ant electrodes are in part responsible for the significantly reduced seizure severity score . however , the sante trial showed normalisation of seizure frequency within 3  months in the cohort of unstimulated patients . in our cohort , there was a marked postsurgical seizure frequency reduction before nac stimulation onset , which was not sustained for more than a month ( fig .  2 ) . these two observations suggest a subsidence of a putative microlesional effect at the latest within 3  months . to reliably assess efficacy of nac stimulation , the cohort is underpowered compared to well - established minimally invasive procedures such vns and dbs for ant . however , initial evidence for safety and feasibility of nac stimulation in patients with intractable partial epilepsy is presented , and the findings may point to some preliminary evidence for antiictal efficacy . the lack of neurocognitive and psychiatric side effects merits possible advantages for the target nac , so we conclude that further exploration of this target would be worthwhile . to assess for placebo or microlesional effects , a randomised controlled trial would be required . furthermore , a larger number of patients would be necessary to confirm antiictal effects of nac stimulation and to discriminate putative responders and non - responders according to their electroclinical features .
in five adult patients with intractable partial epilepsy , safety and feasibility of chronic bilateral electrical stimulation of the nucleus accumbens ( nac ) were assessed , also providing initial indications of therapeutic efficacy . 
 concurrent medication remained unchanged . in this phase 1 trial , clinical outcome parameters of interest were quality of life in epilepsy questionnaire ( qolie-31-p ) , beck depression inventory , mini international neuropsychiatric interview , neuropsychological testing , and liverpool seizure severity scale . those data were obtained after 6  months of nac stimulation and compared to the equivalent assessments made directly before implantation of electrodes . 
 additionally , monthly frequencies of simple partial seizures , complex partial seizures ( cps ) , and generalised tonic  clonic seizures ( gtcs ) were assessed during 3  months before electrode implantation and at the end of 6-month nac stimulation . 
 proportion of responders , i.e. 50  % reduction in frequency of disabling seizures ( sum of cps and gtcs ) , was calculated . 
 main findings were unchanged psychiatric and neuropsychological assessment and a significant decrease in seizure severity ( p  =  0.043 ) . 
 qolie-31-p total score trended towards improvement ( p  =  0.068 ) . 
 two out of five participants were responders . 
 the median reduction in frequency of disabling seizures was 37.5  % . in summary 
 , we provide initial evidence for safety and feasibility of chronic electrical stimulation of the nac in patients with intractable partial epilepsy , as indicated by largely unchanged neurocognitive function and psychiatric comorbidity . even though our data are underpowered to reliably assess efficacy , the significant decrease in seizure severity provides an initial indication of antiictal efficacy of nac stimulation . 
 this calls for larger and at best randomised trials to further elucidate efficacy of nac stimulation in patients with pharmacologically intractable epilepsy .